**Genetic Factors Involved in Sarcoidosis**

Birendra P. Sah and Michael C. Iannuzzi

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/55116

### **1. Introduction**

Sarcoidosis is an immune mediated disease thought to be caused by complex interaction between genetic and environmental factors. Involvement of genetic factors in sarcoidosis is supported by familial clustering, increased concordance in monozygotic twins and varying incidence and disease presentation among different ethnic groups. Studies have revealed several human leukocyte antigen (HLA) and non-HLA alleles consistently associated with sarcoidosis susceptibility. Two genome scans have been reported in sarcoidosis: one in African Americans reporting linkage to chromosome 5 and the other in German families reporting linkage to chromosome 6. Follow-up studies on chromosome 6 identified the BTNL2 gene, a B7 family costimulatory molecule to be associated with sarcoidosis. Recent genome-wide association studies have found annexin A11 and RAB23 genes associated with sarcoidosis. The ongoing refinement of genetic marker maps, genotyping technology, and statistical analyses makes genomic exploration for sarcoidosis genes appealing.

### **2. Evidence for genetic predisposition to sarcoidosis**

Familial sarcoidosis was first noted in Germany in 1923 by Martenstein, who reported two affected sisters [1]. After that several familial cases were reported across Europe and USA. Worldwide surveys revealed that familial sarcoidosis occurred in 10.3% cases from the Netherlands [2], 7.5% from Germany [3], 5.9% from the United Kingdom [4], 4.7% from Finland [5], 4.3% from Japan [5], 9.6% from Ireland[6] and 6.9 % from Sweden[7]. A family history survey of Detroit clinic–based population in USA showed that 17% of African Americans and 3.8% of white American reported a family history in first- and second degree relatives[8]. In African Americans, the sibling recurrence risk ratio, which compares disease risk among

© 2013 Sah and Iannuzzi; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

siblings with the disease prevalence in the general population, is about 2.2 (95% confidence interval [CI], 1.03–3.68) [9].

Mutation in CARD (caspase activating recruitment domain) 15 gene, located on chromosome 16, is responsible for Blau syndrome [17, 18] and Crohn's disease [19]. Nucleotide oligomeri‐ zation domain protein-2 (NOD2), encoded by CARD15, recognizes peptidoglycan, a compo‐ nent of bacterial cell walls, and is expressed mainly by antigen-presenting cells and epithelial cells [20]. Activation of NOD2 leads to nuclear factor (NF)-кB activation [20]. Rybicki and colleagues tested 35 African American affected sib pairs by using exclusion mapping and showed that the Blau syndrome/IBD1 locus did not confer risk for sarcoidosis [21]. Schurmann and coworkers [22] evaluated four main coding CARD15 polymorphisms associated with increased risk of Crohn's disease in both case–control and family-based sarcoidosis samples and concluded that CARD15 mutations play no role in sarcoidosis. Kanazawa and colleagues using a small sample analyzed 10 patients with early-onset sarcoidosis who had disease onset ranging from 6 months to 4 year of age and found that 9 of the 10 cases had heterozygous missense mutations in the CARD15 gene [23]. In conclusion, while an attractive candidate, no

Genetic Factors Involved in Sarcoidosis http://dx.doi.org/10.5772/55116 55

Chronic beryllium disease (CBD), a chronic granulomatous lung disease caused by exposure to beryllium, shares similar histological and clinical findings with sarcoidsois. Glu69, carried by allele HLADPB1\* 0201, was found not to be associated with sarcoidosis [24, 25]. In a study of 33 cases and 44 exposed persons without CBD (controls), Richeldi and colleagues found Glu69 in 97% of cases and in 30% of control subjects [26]. This HLA-DPB1 Glu69 association in beryllium disease has been widely supported [27] but is not associated with sarcoidosis.

Polymorphic variants of the natural resistance–associated macrophage protein-1 gene (NRAMP1), now named SLC11A1, have been found to be associated with tuberculosis and leprosy susceptibility in endemic areas of disease [28, 29]. SLC11A1 is expressed primarily in macrophages and polymorphonuclear leukocytes and immunolocalization studies demon‐ strate the presence of NRAMP1 in lysosomes [30]. SLC11A1, an attractive candidate, was found not to increase the risk of sarcoidosis among African Americans [31], although a more recent

Genetic studies in sarcoidosis have gone through three phases – candidate gene studies, genome scanning using affected sib pair (ASP) linkage analysis and most recently, genome

The search for sarcoidosis susceptibility genes has generally relied on the candidate gene approach [33]. Investigators have selected genes for study that fit into the prevailing disease model. Sarcoidosis is thought to be a dysregulated response to an inhaled antigen that involves

article has noted an association in Polish patients (OR, 1.68; 95% CI, 1.01–2.81) [32].

**4. Genetic associatiation studies in sarcoidosis**

firm evidence exists to support a role for CARD 15 in sarcoidosis risk.

**Chronic beryllium disease**

**Tuberculosis and leprosy**

wide association studies (GWAS).

**4.1. Candidate gene approach**

The main limitation of these familial reports is the lack of a comparison group, and therefore it was unclear whether variation in familial sarcoidosis is due to variation in familial aggre‐ gation of disease risk, disease prevalence, or both. This question was addressed in the multicenter Case-Control Etiologic Study of Sarcoidosis (ACCESS) which evaluated 706 cases and matched controls [10]. It showed that the siblings of the affected patients had the highest relative risk (odds ratio =5.8 and 95% confidence interval=2.1–15.9). The odds ratio for the parents was 3.8 (95% CI=1.2–11.3) [10]. White cases had a markedly higher familial relative risk compared with African-American cases (18.0 versus 2.8; p=0.098).

A registry-based twin study in the Danish and the Finnish population showed an 80-fold increased risk of developing sarcoidosis in monozygotic co-twins and 7-fold increased risk in dizygotic twins [11].

Differences in disease incidence among different ethnic and racial groups exist worldwide. In the United States, African Americans have about a threefold higher age-adjusted annual incidence; 35.5 per 100,000 compared with Caucasians, 10.9 per 100,000. African American females aged 30 to 39 years were found at greatest risk at 107/100,000.The lifetime risk was calculated to be 2.4% for African Americans and 0.85% for Caucasian Americans [12]. In the United Kingdom, prevalence of sarcoidosis was found to be three times higher in the Irish living in London than in native Londoners [14]. It was eight time more common in natives of Martinique living in France than in the indigenous French populations [14]. In London the annual incidence of sarcoidosis has been reported as 1.5 per 100, 000 for Caucasians, 16.8 per 100, 000 for Asians and 19.8 per 100, 000 for Africans [15]. A study of a Swedish urban population reported a lifetime risk of 1.0% and 1.3% for men and women, respectively [16]. In addition to differences in the incidence, the clinical presentation of sarcoidosis also shows characteristic variability between ethnic groups. In both Blacks and Asians the disease has been reported to be more common, more severe and more extensive than in Caucasians [13, 15].

### **3. Genetics of other granulomatous disease**

#### **Blau syndrome and Crohn's disease**

Among the granulomatous diseases with a putative genetic component, perhaps the most intriguing are Blau syndrome and Crohn's disease. Blau syndrome is an autosomal dominant granulomatous disease which is characterized by an early onset (before age 20) and involve‐ ment of skin, eye, and joints, similar to sarcoidosis. The factors that distinguish Blau syndrome from sarcoidosis are a lack of pulmonary involvement and absence of Kveim reactivity [17]. Crohn's disease is a familial granulomatous inflammatory bowel disease which, like sarcoi‐ dosis, may present with uveitis, arthritis and skin rash. Crohn's disease may involve the lung however the pattern of lung involvement differs from sarcoidosis.

Mutation in CARD (caspase activating recruitment domain) 15 gene, located on chromosome 16, is responsible for Blau syndrome [17, 18] and Crohn's disease [19]. Nucleotide oligomeri‐ zation domain protein-2 (NOD2), encoded by CARD15, recognizes peptidoglycan, a compo‐ nent of bacterial cell walls, and is expressed mainly by antigen-presenting cells and epithelial cells [20]. Activation of NOD2 leads to nuclear factor (NF)-кB activation [20]. Rybicki and colleagues tested 35 African American affected sib pairs by using exclusion mapping and showed that the Blau syndrome/IBD1 locus did not confer risk for sarcoidosis [21]. Schurmann and coworkers [22] evaluated four main coding CARD15 polymorphisms associated with increased risk of Crohn's disease in both case–control and family-based sarcoidosis samples and concluded that CARD15 mutations play no role in sarcoidosis. Kanazawa and colleagues using a small sample analyzed 10 patients with early-onset sarcoidosis who had disease onset ranging from 6 months to 4 year of age and found that 9 of the 10 cases had heterozygous missense mutations in the CARD15 gene [23]. In conclusion, while an attractive candidate, no firm evidence exists to support a role for CARD 15 in sarcoidosis risk.

#### **Chronic beryllium disease**

siblings with the disease prevalence in the general population, is about 2.2 (95% confidence

The main limitation of these familial reports is the lack of a comparison group, and therefore it was unclear whether variation in familial sarcoidosis is due to variation in familial aggre‐ gation of disease risk, disease prevalence, or both. This question was addressed in the multicenter Case-Control Etiologic Study of Sarcoidosis (ACCESS) which evaluated 706 cases and matched controls [10]. It showed that the siblings of the affected patients had the highest relative risk (odds ratio =5.8 and 95% confidence interval=2.1–15.9). The odds ratio for the parents was 3.8 (95% CI=1.2–11.3) [10]. White cases had a markedly higher familial relative

A registry-based twin study in the Danish and the Finnish population showed an 80-fold increased risk of developing sarcoidosis in monozygotic co-twins and 7-fold increased risk in

Differences in disease incidence among different ethnic and racial groups exist worldwide. In the United States, African Americans have about a threefold higher age-adjusted annual incidence; 35.5 per 100,000 compared with Caucasians, 10.9 per 100,000. African American females aged 30 to 39 years were found at greatest risk at 107/100,000.The lifetime risk was calculated to be 2.4% for African Americans and 0.85% for Caucasian Americans [12]. In the United Kingdom, prevalence of sarcoidosis was found to be three times higher in the Irish living in London than in native Londoners [14]. It was eight time more common in natives of Martinique living in France than in the indigenous French populations [14]. In London the annual incidence of sarcoidosis has been reported as 1.5 per 100, 000 for Caucasians, 16.8 per 100, 000 for Asians and 19.8 per 100, 000 for Africans [15]. A study of a Swedish urban population reported a lifetime risk of 1.0% and 1.3% for men and women, respectively [16]. In addition to differences in the incidence, the clinical presentation of sarcoidosis also shows characteristic variability between ethnic groups. In both Blacks and Asians the disease has been reported to be more common, more severe and more extensive than in Caucasians [13, 15].

Among the granulomatous diseases with a putative genetic component, perhaps the most intriguing are Blau syndrome and Crohn's disease. Blau syndrome is an autosomal dominant granulomatous disease which is characterized by an early onset (before age 20) and involve‐ ment of skin, eye, and joints, similar to sarcoidosis. The factors that distinguish Blau syndrome from sarcoidosis are a lack of pulmonary involvement and absence of Kveim reactivity [17]. Crohn's disease is a familial granulomatous inflammatory bowel disease which, like sarcoi‐ dosis, may present with uveitis, arthritis and skin rash. Crohn's disease may involve the lung

risk compared with African-American cases (18.0 versus 2.8; p=0.098).

**3. Genetics of other granulomatous disease**

however the pattern of lung involvement differs from sarcoidosis.

**Blau syndrome and Crohn's disease**

interval [CI], 1.03–3.68) [9].

54 Sarcoidosis

dizygotic twins [11].

Chronic beryllium disease (CBD), a chronic granulomatous lung disease caused by exposure to beryllium, shares similar histological and clinical findings with sarcoidsois. Glu69, carried by allele HLADPB1\* 0201, was found not to be associated with sarcoidosis [24, 25]. In a study of 33 cases and 44 exposed persons without CBD (controls), Richeldi and colleagues found Glu69 in 97% of cases and in 30% of control subjects [26]. This HLA-DPB1 Glu69 association in beryllium disease has been widely supported [27] but is not associated with sarcoidosis.

#### **Tuberculosis and leprosy**

Polymorphic variants of the natural resistance–associated macrophage protein-1 gene (NRAMP1), now named SLC11A1, have been found to be associated with tuberculosis and leprosy susceptibility in endemic areas of disease [28, 29]. SLC11A1 is expressed primarily in macrophages and polymorphonuclear leukocytes and immunolocalization studies demon‐ strate the presence of NRAMP1 in lysosomes [30]. SLC11A1, an attractive candidate, was found not to increase the risk of sarcoidosis among African Americans [31], although a more recent article has noted an association in Polish patients (OR, 1.68; 95% CI, 1.01–2.81) [32].

### **4. Genetic associatiation studies in sarcoidosis**

Genetic studies in sarcoidosis have gone through three phases – candidate gene studies, genome scanning using affected sib pair (ASP) linkage analysis and most recently, genome wide association studies (GWAS).

#### **4.1. Candidate gene approach**

The search for sarcoidosis susceptibility genes has generally relied on the candidate gene approach [33]. Investigators have selected genes for study that fit into the prevailing disease model. Sarcoidosis is thought to be a dysregulated response to an inhaled antigen that involves antigen-presenting cells, T cells (primarily a helper T-cell type 1 polar response), and cytokine and chemokine release resulting in cell recruitment and the formation of granulomas in involved organs.

Among the HLA class II antigens, HLA-DRB1 have been the most studied antigen associated with sarcoidosis. The variation in the HLA-DRB1 gene affects both susceptibili‐ ty and prognosis in sarcoidosis [39, 40]. In the ACCESS study, the HLA-DRB1\* 1101 allele was associated with sarcoidosis both in blacks and whites (p<0.01) and had a population attributable risk of 16% in blacks and 9% in whites [41]. In addition susceptibility mark‐ ers, the ACCESS study also found that HLA class II alleles might be markers for differ‐ ent phenotypes of sarcoidosis such as RB1\*0401 for eye involvement in blacks and whites, DRB3 for bone marrow involvement in blacks, and DPB1\*0101 for hypercalcemia in whites [41]. Another consistent finding across populations has been the HLA-DQB1\*0201 allele association with decreased risk and lack of disease progression [42]. Other reports strongly support the notion that several different HLA class II genes acting either in concert or independently predispose to sarcoidosis [42-44]. Linkage disequilibrium (LD) within the major histocompatibility complex (MHC) region limits the ability to precisely identify the involved HLA genes. LD exists when alleles at two distinctive loci occur in gametes more frequently than expected. Grunewald and colleagues showed that the HLA-DRB1\*03 associated with resolved disease and HLA-DRB1\*15 with persistent disease were synony‐ mous with HLA-DQB1\*0201 with resolved disease and HLA DQB1\*0602 with persistent disease [38]. Consequently, determining the effects of HLA-DQB1 on sarcoidosis risk apart from DRB1 or dissecting out other gene effects from closely linked haplotypes in the MHC region may be an intractable problem in whites. In African Americans, HLA-DRB1/DQB1

Genetic Factors Involved in Sarcoidosis http://dx.doi.org/10.5772/55116 57

HLA alleles have been consistently associated with disease course which suggests that HLA may play greater role in determining phenotype. Furthermore, the discrepant findings in HLA association among susceptibility studies could be explained by the phenotype variation in

Genes that influence antigen processing, antigen presentation, macrophage and T-cell activation, and cell recruitment and injury repair may be considered sarcoidosis candidate

Angiotensin-converting enzyme (ACE) is produced by sarcoidal granulomas and its serum level can be elevated in sarcoidosis. Serum ACE levels are thought to reflect granuloma burden. The ACE gene insertion (I)/deletion (D) polymorphism partially accounts for the serum ACE level variation, and investigators have proposed that this genotype should be used to adjust serum ACE reference values [46]. Studies to support a role for ACE gene polymorphisms in susceptibility or severity have been inconsistent. While only a few case control studies have suggested that ACE gene polymorphism is associated with sarcoido‐ sis susceptibility and disease severity [47, 48], most of the studies does not support that

genes. A summary of non-HLA candidate genes reported to date is shown in Table 2.

LD may not be as strong as in Caucasians [45].

composition of the sarcoidosis patient groups studied.

*4.1.2. Association with Non-HLA candidate genes*

**Angiotensin-Converting Enzyme**

findings [50-53].

#### *4.1.1. Association with Human Leukocyte Antigens (HLA)*

HLA genes have been the best studied candidate genes in sarcoidosis. HLA genes are involved in presenting antigen to T cells and are grouped into three classes: class I, II and III. HLA association studies in sarcoidosis began over thirty years ago. A summary of the most consistent HLA associations in sarcoidosis is shown in Table 1. In 1977 Brewerton and colleague [34] first revealed an association of acute sarcoidosis with the HLA class I antigen HLA-B8 which was later confirmed by other groups [35, 36]. Hedfors and co-workers [35] also noted that HLA-B8/DR3 genes were inherited as a sarcoidosis risk haplotype in whites. In white HLA-B8/DR3 haplotype is associated with wide variety of autoimmune diseases [37]. These earlier studies of class I HLA antigens directed to the studies focused on HLA class II. A recent report by Grunewald and colleagues [38] suggests that HLA class I and II genes work together in sarcoidosis pathophysiology.


**Table 1.** Summary of the most consistent HLA association studies in Sarcoidosis.

Among the HLA class II antigens, HLA-DRB1 have been the most studied antigen associated with sarcoidosis. The variation in the HLA-DRB1 gene affects both susceptibili‐ ty and prognosis in sarcoidosis [39, 40]. In the ACCESS study, the HLA-DRB1\* 1101 allele was associated with sarcoidosis both in blacks and whites (p<0.01) and had a population attributable risk of 16% in blacks and 9% in whites [41]. In addition susceptibility mark‐ ers, the ACCESS study also found that HLA class II alleles might be markers for differ‐ ent phenotypes of sarcoidosis such as RB1\*0401 for eye involvement in blacks and whites, DRB3 for bone marrow involvement in blacks, and DPB1\*0101 for hypercalcemia in whites [41]. Another consistent finding across populations has been the HLA-DQB1\*0201 allele association with decreased risk and lack of disease progression [42]. Other reports strongly support the notion that several different HLA class II genes acting either in concert or independently predispose to sarcoidosis [42-44]. Linkage disequilibrium (LD) within the major histocompatibility complex (MHC) region limits the ability to precisely identify the involved HLA genes. LD exists when alleles at two distinctive loci occur in gametes more frequently than expected. Grunewald and colleagues showed that the HLA-DRB1\*03 associated with resolved disease and HLA-DRB1\*15 with persistent disease were synony‐ mous with HLA-DQB1\*0201 with resolved disease and HLA DQB1\*0602 with persistent disease [38]. Consequently, determining the effects of HLA-DQB1 on sarcoidosis risk apart from DRB1 or dissecting out other gene effects from closely linked haplotypes in the MHC region may be an intractable problem in whites. In African Americans, HLA-DRB1/DQB1 LD may not be as strong as in Caucasians [45].

HLA alleles have been consistently associated with disease course which suggests that HLA may play greater role in determining phenotype. Furthermore, the discrepant findings in HLA association among susceptibility studies could be explained by the phenotype variation in composition of the sarcoidosis patient groups studied.

#### *4.1.2. Association with Non-HLA candidate genes*

Genes that influence antigen processing, antigen presentation, macrophage and T-cell activation, and cell recruitment and injury repair may be considered sarcoidosis candidate genes. A summary of non-HLA candidate genes reported to date is shown in Table 2.

#### **Angiotensin-Converting Enzyme**

antigen-presenting cells, T cells (primarily a helper T-cell type 1 polar response), and cytokine and chemokine release resulting in cell recruitment and the formation of granulomas in

HLA genes have been the best studied candidate genes in sarcoidosis. HLA genes are involved in presenting antigen to T cells and are grouped into three classes: class I, II and III. HLA association studies in sarcoidosis began over thirty years ago. A summary of the most consistent HLA associations in sarcoidosis is shown in Table 1. In 1977 Brewerton and colleague [34] first revealed an association of acute sarcoidosis with the HLA class I antigen HLA-B8 which was later confirmed by other groups [35, 36]. Hedfors and co-workers [35] also noted that HLA-B8/DR3 genes were inherited as a sarcoidosis risk haplotype in whites. In white HLA-B8/DR3 haplotype is associated with wide variety of autoimmune diseases [37]. These earlier studies of class I HLA antigens directed to the studies focused on HLA class II. A recent report by Grunewald and colleagues [38] suggests that HLA class I and II genes work

**Risk Alleles Putative Functional Significance**

B\*8 Susceptibility in several populations

several populations

Stage II/III chest X-ray

rs2076530 *BTNL2* rs2076530 G → A is associated with

black patients.

groups

Protection, Lofgren's syndrome, mild disease in

Susceptibility/disease progression in several

Acute onset/good prognosis in several groups

Susceptibility in whites and African Americans.

Protection in several populations

Associated with Lofgren's syndrome Susceptibility/disease progression in whites

sarcoidosis risk in white patients but not in

A\*1 Susceptibility

involved organs.

56 Sarcoidosis

*4.1.1. Association with Human Leukocyte Antigens (HLA)*

together in sarcoidosis pathophysiology.

**HLA gene HLA class Chromosome**

HLA-A Class I 30,018, 309-

HLA-B Class I 31, 431, 922-

HLA-DQB1 Class II 32, 735, 918-

HLA-DRB1 Class II 32, 654, 526-

HLA-DRB3 Class II 32, 654, 526-

BTNL2 Class II 32, 470, 490-

**location**

30, 021, 041 bp

31, 432, 914 bp

32, 742, 420 bp

32, 665, 559 bp

32, 665, 540 bp

32, 482, 878 bp

**Table 1.** Summary of the most consistent HLA association studies in Sarcoidosis.

\*0201 \*0602

\*0301 \*01, \*04 \*1101

\*1501 \*0101 Angiotensin-converting enzyme (ACE) is produced by sarcoidal granulomas and its serum level can be elevated in sarcoidosis. Serum ACE levels are thought to reflect granuloma burden. The ACE gene insertion (I)/deletion (D) polymorphism partially accounts for the serum ACE level variation, and investigators have proposed that this genotype should be used to adjust serum ACE reference values [46]. Studies to support a role for ACE gene polymorphisms in susceptibility or severity have been inconsistent. While only a few case control studies have suggested that ACE gene polymorphism is associated with sarcoido‐ sis susceptibility and disease severity [47, 48], most of the studies does not support that findings [50-53].


**CC-Chemokine Receptor 2 (CCR2]**

not replicate the CCR2 association [61].

**C-C chemokine Receptor 5 (CCR5)**

169 control subjects [65].

**Complement receptor 1**

**Clara cell 10 kD protein gene**

CCR 2, a receptor for monocyte chemoattractant protein, plays an important role in recruiting monocytes, T-cells, natural killer cells and dendritic cells [54]. CCR2 knockout mice die rapidly when challenged with mycobacteria [55] and display decreased IFN-γ production when challenged with *Leishmania donovani* or *Cryptococcus neoformans* [56, 57]. A single nucleotide polymorphism (SNP) in CCR2 gene (G190A, Val64Ile) is associated with protection in Japanese patients [58]. Evaluation of eight SNPs in the CCR2 gene in 304 Dutch patients showed that haplotype 2 was associated with Lofgren's syndrome [59]. Underrepresentation of the Val64Ile variant was observed in 65 Czech patients and in 80 control subjects but did not achieve statistical significance [60]. Despite using case control–based and family-based study designs and a sample much larger than the previous three studies, Valentonyte and colleagues could

Genetic Factors Involved in Sarcoidosis http://dx.doi.org/10.5772/55116 59

CCR5 serves as a receptor for CCL3 (macrophage inflammatory protein 1-α), CCL4 (macro‐ phage inflammatory protein 1-β), CCL5 (RANTES [regulated upon activation, T-cell expressed and secreted]), and CCL8 (monocyte chemotactic protein 2) [62, 63]. A 32 bp deletion in the CCR5 gene results in a non-functional receptor unable to bind its ligands [64]. Petrek and colleagues reported that 32-bp deletion in CCR5 gene was significantly increased in Czech patients [60], whereas Spagnolo and colleagues, using haplotype analysis, found no association in evaluating 106 white British patients and 142 control subjects and 112 Dutch patients and

Clara cells act as stem cells in bronchial epithelial repair, provides xenobiotic metabolism, and counter regulates inflammation [66]. Clara cell 10-kD protein (CC10) has been shown to inhibit IFN-γ, tumor necrosis factor (TNF)-α, and interleukin (IL)-1β. Murine and human CC10 gene promoter regions contain sites where inflammatory mediators, such as TNF-αand INF-α, -β, and –γ, alter transcriptional activity [67]. Increased level of CC10 in serum and BAL has been found in sarcoidosis patients whose disease had resolved compared with those whose disease had progressed [68]. The CC10 gene consists of three short exons separated by a long first and short second intron. An adenine to guanine substitution at position 38 (A38G) downstream from the transcription initiation site within the noncoding region of exon 1 has been the most studied CC10 polymorphism. The A/A genotype is believed to result in decreased CC10 levels [69]. The CC10A allele was found to be associated with sarcoidosis by Ohchi and colleague [70]. However association with the CC10 A38G polymorphism was not replicated in Dutch

Complement receptor 1 (CR1; CD35) is present on polymorphonuclear leukocytes, macro‐ phages, B lymphocytes, some T lymphocytes, dendritic cells, and erythrocytes [71]. Immune complexes bound to CR1 are transferred to phagocytes as erythrocytes traverse the liver and spleen [72]. Immune complex clearance rates correlate with CR1 density. Low expression of

population or in Japanese subjects by Janssen and colleagues [71].

\* Type of association: A = susceptibility; B = disease course; C = both.

† Association replicated (+); association refuted (-)

**Table 2.** A summary of Non-HLA candidate gene associated with Sarcoidosis

### **CC-Chemokine Receptor 2 (CCR2]**

**Candidate Gene**

Angiotensin-converting

58 Sarcoidosis

C-C chemokine receptor 5

Clara cell 10 kD protein

Complement receptor 1

Cystic fibrosis transmembrane regulator

70 1 like

Inhibitor kβ-α

Interleukin -18

Interferon-γ

(TGF)

Toll-like receptor (TLR) 4

Transforming growth factor

Tumor necrosis factor

Vascular endothelial growth factor(VEGF)

TLR10-TLR1-TLR6 cluster 9q32

HSPA1L heat shock protein

**Chromosome Location**

enzyme (ACE) 17q23 C

**Association\*† Putative Functional Significance**

needing corticosteroid therapy.

disease at 3 year follow-up.

The GG genotype for the Pro1827Arg

progression.

sarcoidosis.

R75Q increases risk.

C-C chemokine receptor 2 3p21.3 C+/- Protection/Lofgren's syndrome association

3p21.3 C-

11q 12-13 C

1q32 A

7q31.2 A+/-

6p21.3 c

14q13 C

11q22 A+/-

9p22 A

19q13.2 B

6p12 C

Vitamin D receptor 12q12-14 A- B allele elevated in sarcoidosis patients

4

\* Type of association: A = susceptibility; B = disease course; C = both.

**Table 2.** A summary of Non-HLA candidate gene associated with Sarcoidosis

(TNF-α) 6p21.3 C+/-

† Association replicated (+); association refuted (-)

Interleukin -1α 2q14 A The IL-1α -889 1.1 genotype increased risk.

Interleukin -4 receptor 16p11.2 No association detected in 241 members of 62 families

B

disease

of chronic disease

Increased risk for ID and DD genotypes.

Moderate association between II genotype and radiographic

Association of CCR5Delta32 allele more common in patients

An allele associated with sarcoidosis and with progressive

(C (5,507) G) polymorphism was significantly associated with

Association with -297T allele. Association of haplotype GTT at -881, -826, and -297, respectively. Allele -827T in Stage II.

Asp299Gly and Thre399Ile mutations associated with chronic

Genetic variation in this cluster is associated with increased risk

TGF-β2 59941 allele, TGF-β3 4875 A and 17369 C alleles were

Genotype -307A allele associated with Lofgren's syndrome and erythema nodosum and -857T allele with sarcoidosis. -307A not

associated with chest X-ray detection of fibrosis.

Protective effect of +813 CT and TT genotypes. Lower FEV1/FVC ratio observed with -627 GG genotype.

associated in African Americans.

Refuted with haplotype analysis and larger sample.

HSP(+2437)CC associated with susceptibility and LS

Genotype -607CA increased risk over AA. No association with organ involvement.

IFNA17 polymorphism (551T→G) and IFNA10 (60A) IFN-α 17 (551G) haplotype increased risk. CCR 2, a receptor for monocyte chemoattractant protein, plays an important role in recruiting monocytes, T-cells, natural killer cells and dendritic cells [54]. CCR2 knockout mice die rapidly when challenged with mycobacteria [55] and display decreased IFN-γ production when challenged with *Leishmania donovani* or *Cryptococcus neoformans* [56, 57]. A single nucleotide polymorphism (SNP) in CCR2 gene (G190A, Val64Ile) is associated with protection in Japanese patients [58]. Evaluation of eight SNPs in the CCR2 gene in 304 Dutch patients showed that haplotype 2 was associated with Lofgren's syndrome [59]. Underrepresentation of the Val64Ile variant was observed in 65 Czech patients and in 80 control subjects but did not achieve statistical significance [60]. Despite using case control–based and family-based study designs and a sample much larger than the previous three studies, Valentonyte and colleagues could not replicate the CCR2 association [61].

#### **C-C chemokine Receptor 5 (CCR5)**

CCR5 serves as a receptor for CCL3 (macrophage inflammatory protein 1-α), CCL4 (macro‐ phage inflammatory protein 1-β), CCL5 (RANTES [regulated upon activation, T-cell expressed and secreted]), and CCL8 (monocyte chemotactic protein 2) [62, 63]. A 32 bp deletion in the CCR5 gene results in a non-functional receptor unable to bind its ligands [64]. Petrek and colleagues reported that 32-bp deletion in CCR5 gene was significantly increased in Czech patients [60], whereas Spagnolo and colleagues, using haplotype analysis, found no association in evaluating 106 white British patients and 142 control subjects and 112 Dutch patients and 169 control subjects [65].

#### **Clara cell 10 kD protein gene**

Clara cells act as stem cells in bronchial epithelial repair, provides xenobiotic metabolism, and counter regulates inflammation [66]. Clara cell 10-kD protein (CC10) has been shown to inhibit IFN-γ, tumor necrosis factor (TNF)-α, and interleukin (IL)-1β. Murine and human CC10 gene promoter regions contain sites where inflammatory mediators, such as TNF-αand INF-α, -β, and –γ, alter transcriptional activity [67]. Increased level of CC10 in serum and BAL has been found in sarcoidosis patients whose disease had resolved compared with those whose disease had progressed [68]. The CC10 gene consists of three short exons separated by a long first and short second intron. An adenine to guanine substitution at position 38 (A38G) downstream from the transcription initiation site within the noncoding region of exon 1 has been the most studied CC10 polymorphism. The A/A genotype is believed to result in decreased CC10 levels [69]. The CC10A allele was found to be associated with sarcoidosis by Ohchi and colleague [70]. However association with the CC10 A38G polymorphism was not replicated in Dutch population or in Japanese subjects by Janssen and colleagues [71].

#### **Complement receptor 1**

Complement receptor 1 (CR1; CD35) is present on polymorphonuclear leukocytes, macro‐ phages, B lymphocytes, some T lymphocytes, dendritic cells, and erythrocytes [71]. Immune complexes bound to CR1 are transferred to phagocytes as erythrocytes traverse the liver and spleen [72]. Immune complex clearance rates correlate with CR1 density. Low expression of erythrocyte CR1 is associated with impaired immune complex clearance and deposition outside the reticuloendothelial system [73]. These extrareticuloendothelial immune com‐ plex deposits incite local inflammatory responses and presumably granuloma formation. That immune complexes may be involved in sarcoidosis was suggested in the early 1970s. In a series involving 3,676 patients from 11 cities around the world, James and coworkers [74] reported elevated serum γ-globulin levels above 3.5 g/100 ml in 23 to 96% of patients, with IgG being the most consistently and persistently elevated [75]. The different sensitivi‐ ties of the techniques used explain in part the wide range in γ-globulin levels. It is general‐ ly accepted that immune complexes are always present in sarcoidosis depending on when and how they are detected. Zorzetto and colleagues have been the only group to report a CR1 gene association with sarcoidosis [76]. The GG genotype for the Pro1827Arg (C507G) polymorphism was associated with sarcoidosis versus healthy control subjects (odds ratio [OR), 3.13; 95% CI, 1.49–6.69) and versus control subjects with chronic obstructive pulmona‐ ry disease (OR, 2.82; 95% CI, 1.27–6.39). The GG genotype was most strongly associated with disease in female patients (OR, 7.05; 95% CI, 3.10–1.61) versus healthy control sub‐ jects. No relationship with clinical variables was found.

ogy [92]. Abdallah and colleagues found the promoter -297T allele associated with sarcoidosis

Genetic Factors Involved in Sarcoidosis http://dx.doi.org/10.5772/55116 61

IL-1β produced mainly by macrophages maintains T-cell alveolitis and granuloma formation. Hunninghake and colleagues also demonstrated higher IL-1β activity in the BALF of patients with sarcoidosis compared with normal subjects [94]. Mikuniya and colleagues suggested that the ratio of IL-1 receptor antagonist to IL-1β in sarcoidal alveolar macrophage culture super‐ natants could predict disease chronicity [95]. The IL-1α 5' flanking –889 C allele was found nearly two times more commonly among Czech patients with sarcoidosis compared with

The inflammatory response in sarcoidosis is primarily Th1 mediated. IL-4 drives Th2 differ‐ entiation [97]. To test whether variation in the IL-4R gene confers susceptibility to sarcoidosis, Bohnert and colleagues typed 241 members of 62 families with 136 affected siblings and 304 healthy control subjects for three functional SNPs within the IL-4R gene and found no evidence

IL-18 produced by monocytes/macrophages induces IFN-γ and drives the Th1 response. BALF and serum IL-18 levels are increased in sarcoidosis [99]. An association between IL-18607 (A/ C) polymorphism and sarcoidosis has been reported and refuted in Japanese [100, 101] and

The increasing number of reported cases of IFN-α–induced sarcoidosis supports that IFN-α is important in sarcoidosis [104]. Akahoshi and colleagues found an IFN-α T551G (Ile184Arg) polymorphism associated with sarcoidosis susceptibility (OR, 3.27; 95% CI, 1.44–7.46; p=0.004) [105]. This allele is also associated with high IFN-α production and subsequent strong Th1

Polymorphisms for all three isoforms of transforming growth factor (TGF) – β (TGF- β1, TGFβ2, and TGF-β3) have been associated with protein expression variation or functionality changes [106]. TGF-β1 levels are increased in patients with sarcoidosis who have impaired pulmonary function [107]. Kruit and colleagues reported that the TGF-β2 59941Gallele and the TGF-β3 4875 A and 17369 C alleles were associated with chest X-ray evidence of pulmonary

Toll-like receptor 4 (TLR4), the first and best described of the many TLRs, plays a crucial role in detecting infection and inducing inflammatory and adaptive immune responses [109]. Pabst and colleagues examined 141 white German patients and control subjects for the TLR4

fibrosis [85]. The TFG-β3 15101 G allele was lower in patients with fibrosis [108].

**Toll-like receptor 4 (TLR4) and TLR10-TLR1-TLR6 cluster**

for linkage or association, thus excluding a significant role for IL-4R [98].

[93]. No other IκB studies in sarcoidosis have been reported.

**Interlukin-1(IL-1)**

control subjects [96].

**Interlukin-18 (IL-18)**

white subjects [102, 103].

**Transforming Growth Factor-β (TGF-β)**

**Interferon–α (IFN-α)**

polarization.

**Interleukin Receptor- 4 (IL-4R)**

#### **Cystic fibrosis transmembrane conductance regulator**

The R75Q mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) occurs in high frequency in patients with atypical mild cystic fibrosis [77], bronchiectasis, and allergic bronchopulmonary aspergillosis [78]. Bombieri and colleagues reported a R75Q association with sarcoidosis [79], but in followup using complete cystic fibrosis gene mutation screening they could not replicate their findings [80]. Schurmann and colleagues could not demonstrate a CFTR association with sarcoidosis [81].

#### **Heat shock protein A1L**

Heat shock proteins (HSPs) comprise a conserved group of proteins with an average weight of 70 kD. Intracellular HSPs serve as molecular chaperones [82], whereas extracellular HSPs induce cellular immune responses [83]. HSPs may also act as carrier molecules for the immunogenic peptides presented on antigen-presenting cells [84]. Polymorphisms in the HSPA1L (alias HSP70-hom) have been associated with susceptibility to rheumatoid arthritis [85]. Antibodies to HSP70 in sarcoidosis have been reported [86, 87]. To further evaluate the role of HSPs in sarcoidosis, the HSP70 +2437 C allele was evaluated and found to be associated with sarcoidosis and Lo° fgren's syndrome in Polish patients [88] but not in Japanese patients [89].

#### **Inhibitor κB-α**

Inhibitor κB (IκB) masks the nuclear factor (NF)- κB nuclear localization sequence, thus retaining NF-κB in the cytoplasm and preventing DNA binding. On phosphorylation, IκB degrades, allowing NF-kB's nuclear localization and initiation of transcription [90]. Terminat‐ ing the NF-κB response requires IκB-α. IκB-α knockout mice die 7 to 10 days after birth with increased levels of TNF-α mRNA in the skin and severe dermatitis [91]. NF-κB–dependent signaling in alveolar macrophage makes NF-κB and thus IκB central to sarcoid pathophysiol‐ ogy [92]. Abdallah and colleagues found the promoter -297T allele associated with sarcoidosis [93]. No other IκB studies in sarcoidosis have been reported.

#### **Interlukin-1(IL-1)**

erythrocyte CR1 is associated with impaired immune complex clearance and deposition outside the reticuloendothelial system [73]. These extrareticuloendothelial immune com‐ plex deposits incite local inflammatory responses and presumably granuloma formation. That immune complexes may be involved in sarcoidosis was suggested in the early 1970s. In a series involving 3,676 patients from 11 cities around the world, James and coworkers [74] reported elevated serum γ-globulin levels above 3.5 g/100 ml in 23 to 96% of patients, with IgG being the most consistently and persistently elevated [75]. The different sensitivi‐ ties of the techniques used explain in part the wide range in γ-globulin levels. It is general‐ ly accepted that immune complexes are always present in sarcoidosis depending on when and how they are detected. Zorzetto and colleagues have been the only group to report a CR1 gene association with sarcoidosis [76]. The GG genotype for the Pro1827Arg (C507G) polymorphism was associated with sarcoidosis versus healthy control subjects (odds ratio [OR), 3.13; 95% CI, 1.49–6.69) and versus control subjects with chronic obstructive pulmona‐ ry disease (OR, 2.82; 95% CI, 1.27–6.39). The GG genotype was most strongly associated with disease in female patients (OR, 7.05; 95% CI, 3.10–1.61) versus healthy control sub‐

The R75Q mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) occurs in high frequency in patients with atypical mild cystic fibrosis [77], bronchiectasis, and allergic bronchopulmonary aspergillosis [78]. Bombieri and colleagues reported a R75Q association with sarcoidosis [79], but in followup using complete cystic fibrosis gene mutation screening they could not replicate their findings [80]. Schurmann and colleagues could not demonstrate

Heat shock proteins (HSPs) comprise a conserved group of proteins with an average weight of 70 kD. Intracellular HSPs serve as molecular chaperones [82], whereas extracellular HSPs induce cellular immune responses [83]. HSPs may also act as carrier molecules for the immunogenic peptides presented on antigen-presenting cells [84]. Polymorphisms in the HSPA1L (alias HSP70-hom) have been associated with susceptibility to rheumatoid arthritis [85]. Antibodies to HSP70 in sarcoidosis have been reported [86, 87]. To further evaluate the role of HSPs in sarcoidosis, the HSP70 +2437 C allele was evaluated and found to be associated with sarcoidosis and Lo° fgren's syndrome in Polish patients [88] but not in

Inhibitor κB (IκB) masks the nuclear factor (NF)- κB nuclear localization sequence, thus retaining NF-κB in the cytoplasm and preventing DNA binding. On phosphorylation, IκB degrades, allowing NF-kB's nuclear localization and initiation of transcription [90]. Terminat‐ ing the NF-κB response requires IκB-α. IκB-α knockout mice die 7 to 10 days after birth with increased levels of TNF-α mRNA in the skin and severe dermatitis [91]. NF-κB–dependent signaling in alveolar macrophage makes NF-κB and thus IκB central to sarcoid pathophysiol‐

jects. No relationship with clinical variables was found.

**Cystic fibrosis transmembrane conductance regulator**

a CFTR association with sarcoidosis [81].

**Heat shock protein A1L**

60 Sarcoidosis

Japanese patients [89].

**Inhibitor κB-α**

IL-1β produced mainly by macrophages maintains T-cell alveolitis and granuloma formation. Hunninghake and colleagues also demonstrated higher IL-1β activity in the BALF of patients with sarcoidosis compared with normal subjects [94]. Mikuniya and colleagues suggested that the ratio of IL-1 receptor antagonist to IL-1β in sarcoidal alveolar macrophage culture super‐ natants could predict disease chronicity [95]. The IL-1α 5' flanking –889 C allele was found nearly two times more commonly among Czech patients with sarcoidosis compared with control subjects [96].

#### **Interleukin Receptor- 4 (IL-4R)**

The inflammatory response in sarcoidosis is primarily Th1 mediated. IL-4 drives Th2 differ‐ entiation [97]. To test whether variation in the IL-4R gene confers susceptibility to sarcoidosis, Bohnert and colleagues typed 241 members of 62 families with 136 affected siblings and 304 healthy control subjects for three functional SNPs within the IL-4R gene and found no evidence for linkage or association, thus excluding a significant role for IL-4R [98].

#### **Interlukin-18 (IL-18)**

IL-18 produced by monocytes/macrophages induces IFN-γ and drives the Th1 response. BALF and serum IL-18 levels are increased in sarcoidosis [99]. An association between IL-18607 (A/ C) polymorphism and sarcoidosis has been reported and refuted in Japanese [100, 101] and white subjects [102, 103].

#### **Interferon–α (IFN-α)**

The increasing number of reported cases of IFN-α–induced sarcoidosis supports that IFN-α is important in sarcoidosis [104]. Akahoshi and colleagues found an IFN-α T551G (Ile184Arg) polymorphism associated with sarcoidosis susceptibility (OR, 3.27; 95% CI, 1.44–7.46; p=0.004) [105]. This allele is also associated with high IFN-α production and subsequent strong Th1 polarization.

#### **Transforming Growth Factor-β (TGF-β)**

Polymorphisms for all three isoforms of transforming growth factor (TGF) – β (TGF- β1, TGFβ2, and TGF-β3) have been associated with protein expression variation or functionality changes [106]. TGF-β1 levels are increased in patients with sarcoidosis who have impaired pulmonary function [107]. Kruit and colleagues reported that the TGF-β2 59941Gallele and the TGF-β3 4875 A and 17369 C alleles were associated with chest X-ray evidence of pulmonary fibrosis [85]. The TFG-β3 15101 G allele was lower in patients with fibrosis [108].

#### **Toll-like receptor 4 (TLR4) and TLR10-TLR1-TLR6 cluster**

Toll-like receptor 4 (TLR4), the first and best described of the many TLRs, plays a crucial role in detecting infection and inducing inflammatory and adaptive immune responses [109]. Pabst and colleagues examined 141 white German patients and control subjects for the TLR4 polymorphisms Asp299Gly and Thre399Ile and found no association with disease presence but did find a significant correlation with chronic disease [110].

colleagues' findings [131]. Rybicki and colleagues also could not confirm VDRs as candidate

Genetic Factors Involved in Sarcoidosis http://dx.doi.org/10.5772/55116 63

The B7 family of costimulatory molecules (CD80 and CD86) regulate T-cell activation. T-cell activation requires two signals: one mediated by T-cell receptor interaction with specific antigen in association with HLA molecules and an antigen-independent costimulatory signal provided by interaction between CD28 on T-cell surface and its ligands CD80 (B7-1) and CD86 (B7-2) on the antigen-presenting cells [146]. Handa and colleagues investigated CD80 and CD86 SNPs for sarcoidosis susceptibility in 146 Japanese patients and found no significant

Unfortunately none of candidate gene chosen based on its likely function in sarcoidosis pathophysiology has been confirmed using the family-based study design. Limitation to many of these studies likely resides in the case-control study design's susceptibility to a form of confounding known as population stratification which can be overcome by using a familybased design that involves recruiting patients 'siblings and parents if available. In this design, parental alleles not transmitted to affected offspring are used as the control alleles and thus control for genetic background. The transmission disequilibrium test, one of the statistical methods used, counts the number of parental gene variants transmitted to affected offspring. Deviation from expected transmission supports a predisposing effect of the more frequently

The first genome scan study related to sarcoidosis was conducted by Schurmann and collea‐ gues, in which they used 225 microsatellite markers spanning the genome in 63 German families to identify a linkage signal (D6S1666) on chromosome 6p21 [132]. This group then used a three-stage single-nucleotide polymorphism (SNP) scan of the 16-MB region surround‐ ing D6S1666 [133] and identified a single SNP, rs2076530, in the BTNL2 gene associated with sarcoidosis. This SNP (G/A) was found at the 3' boundary of the exon 5 coding region. The A allele at this position has been proposed to introduce an alternative splice site at the exon 5–3' intron boundary of the BTNL2 transcript that results in a premature truncation of the protein. BTNL2, also known as "butyrophilin-like 2" and "BTL-2," is a butyrophilin gene that belongs to the immunoglobulin gene superfamily related to the B7 family [134, 135]. Butyrophilin was initially cloned from cattle mammary epithelial cells [136]. This gene was localized to the MHC class II region in humans. To determine the consistency of the BTNL2 gene as a sarcoidosis risk factor across different populations, Rybicki and colleagues characterized variation in the BTNL2 exon/intron 5 region in an African-American family sample that consisted of 219 nuclear families (686 individuals) and in 2 case–control samples (295 African-American matched pairs and 366 white American matched pairs) [137].They confirmed that BTNL2 somewhat was less associated with sarcoidosis in African Americans compared with whites. BTNL2 appears to have moderate influence on individual disease risk (odds ratio of 1.6 in

genes in sarcoidosis [49].

difference compared with 157 control subjects [147].

**4.2. Genome scanning: Affected sib pair linkage analysis**

**Sarcoidosis genome scan in Germans**

**CD80 and CD86**

transmitted allele.

Recently Veltcamp and colleague found that genetic variation in TLR10-TLR1-TLR6 cluster is associated with increased risk of chronic disease [111].

#### **Tumor Necrosis Factor–α (TNF-α)**

TNF-α has a broad range of inflammatory and immunostimulatory actions, including orchestrating granuloma formation. TNF-α stimulates cytokine production, enhances expres‐ sion of adhesion molecules, and acts as a costimulator of T-cell activation. Alveolar macro‐ phages from patients with active sarcoidosis secrete more TNF-α than those with inactive disease [112]. TNF-α has been considered a target for therapy in sarcoidosis [113].

Although it is unclear whether TNF-α promoter polymorphisms are functionally signifi‐ cant, studies suggest that a small but significant effect of the TNF-α promoter -307 A/G polymorphism may exist, with the A allele being associated with slightly greater levels of TNF-α transcription [114, 115]. A higher frequency of TNF-307A allele has been found in patients presenting with Lofgren's syndrome and erythema nodosum [116–118]. In evaluat‐ ing five promoter polymorphisms, Grutters and colleagues found a significant increase in TNF -857T allele in white British and Dutch patients and confirmed the TNF -307A allele association with Lo° fgren's syndrome [119]. In these studies, it is not clear whether TNF-307A confers independent risk from HLA-DRB1 because TNF is in tight LD with HLA-DRBI [120]. Using a family-based approach, TNF-α was not found to be significantly associated with sarcoidosis [49].

#### **Vascular endothelial growth factor**

Dysregulated vascular endothelial growth factor (VEGF) expression has been implicated in several inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel diseases [121, 122]. VEGF modulates angiogenesis, enhances monocyte migration, a key event in granuloma formation [123]. Tolnay and colleagues reported increased VEGF transcription and protein production in activated alveolar macrophages in epithelioid cells and multinuclear giant cells of pulmonary sarcoidal granulomas [124]. Several polymorphisms have been associated with VEGF protein production [125, 126]. Morohashi and colleagues found that the VEGF+813T allele was underrepresented (associated with decreased risk) in patients with sarcoidosis. The +813 site is predicted to lie within a potential transcription factor binding site and could potentially reduce VEGF expression [126].

#### **Vitamin D receptors**

The active form of vitamin D, 1,25-dihydroxy vitamin D3, modulates the immune response through control of cytokine expression, including IFN-γ and IL-2 [127]. Increased expression of vitamin D receptors (VDRs) on sarcoidal BAL T cells and alveolar macrophage production of 1,25-dihydroxy vitamin D3 have been reported [128, 129]. Niimi and colleagues reported a VDR Bsm1 restriction site polymorphism in intron 8 to be associated with sarcoidosis [130]. Guleva and Seitzer examined a VDR Taq1 polymorphism in linkage disequilibrium with the BsmI polymorphism in 85 patients and 80 control subjects and could not confirm Niimi and colleagues' findings [131]. Rybicki and colleagues also could not confirm VDRs as candidate genes in sarcoidosis [49].

#### **CD80 and CD86**

polymorphisms Asp299Gly and Thre399Ile and found no association with disease presence

Recently Veltcamp and colleague found that genetic variation in TLR10-TLR1-TLR6 cluster is

TNF-α has a broad range of inflammatory and immunostimulatory actions, including orchestrating granuloma formation. TNF-α stimulates cytokine production, enhances expres‐ sion of adhesion molecules, and acts as a costimulator of T-cell activation. Alveolar macro‐ phages from patients with active sarcoidosis secrete more TNF-α than those with inactive

Although it is unclear whether TNF-α promoter polymorphisms are functionally signifi‐ cant, studies suggest that a small but significant effect of the TNF-α promoter -307 A/G polymorphism may exist, with the A allele being associated with slightly greater levels of TNF-α transcription [114, 115]. A higher frequency of TNF-307A allele has been found in patients presenting with Lofgren's syndrome and erythema nodosum [116–118]. In evaluat‐ ing five promoter polymorphisms, Grutters and colleagues found a significant increase in TNF -857T allele in white British and Dutch patients and confirmed the TNF -307A allele association with Lo° fgren's syndrome [119]. In these studies, it is not clear whether TNF-307A confers independent risk from HLA-DRB1 because TNF is in tight LD with HLA-DRBI [120]. Using a family-based approach, TNF-α was not found to be significantly

Dysregulated vascular endothelial growth factor (VEGF) expression has been implicated in several inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel diseases [121, 122]. VEGF modulates angiogenesis, enhances monocyte migration, a key event in granuloma formation [123]. Tolnay and colleagues reported increased VEGF transcription and protein production in activated alveolar macrophages in epithelioid cells and multinuclear giant cells of pulmonary sarcoidal granulomas [124]. Several polymorphisms have been associated with VEGF protein production [125, 126]. Morohashi and colleagues found that the VEGF+813T allele was underrepresented (associated with decreased risk) in patients with sarcoidosis. The +813 site is predicted to lie within a potential transcription factor binding site

The active form of vitamin D, 1,25-dihydroxy vitamin D3, modulates the immune response through control of cytokine expression, including IFN-γ and IL-2 [127]. Increased expression of vitamin D receptors (VDRs) on sarcoidal BAL T cells and alveolar macrophage production of 1,25-dihydroxy vitamin D3 have been reported [128, 129]. Niimi and colleagues reported a VDR Bsm1 restriction site polymorphism in intron 8 to be associated with sarcoidosis [130]. Guleva and Seitzer examined a VDR Taq1 polymorphism in linkage disequilibrium with the BsmI polymorphism in 85 patients and 80 control subjects and could not confirm Niimi and

disease [112]. TNF-α has been considered a target for therapy in sarcoidosis [113].

but did find a significant correlation with chronic disease [110].

associated with increased risk of chronic disease [111].

**Tumor Necrosis Factor–α (TNF-α)**

62 Sarcoidosis

associated with sarcoidosis [49].

**Vitamin D receptors**

**Vascular endothelial growth factor**

and could potentially reduce VEGF expression [126].

The B7 family of costimulatory molecules (CD80 and CD86) regulate T-cell activation. T-cell activation requires two signals: one mediated by T-cell receptor interaction with specific antigen in association with HLA molecules and an antigen-independent costimulatory signal provided by interaction between CD28 on T-cell surface and its ligands CD80 (B7-1) and CD86 (B7-2) on the antigen-presenting cells [146]. Handa and colleagues investigated CD80 and CD86 SNPs for sarcoidosis susceptibility in 146 Japanese patients and found no significant difference compared with 157 control subjects [147].

Unfortunately none of candidate gene chosen based on its likely function in sarcoidosis pathophysiology has been confirmed using the family-based study design. Limitation to many of these studies likely resides in the case-control study design's susceptibility to a form of confounding known as population stratification which can be overcome by using a familybased design that involves recruiting patients 'siblings and parents if available. In this design, parental alleles not transmitted to affected offspring are used as the control alleles and thus control for genetic background. The transmission disequilibrium test, one of the statistical methods used, counts the number of parental gene variants transmitted to affected offspring. Deviation from expected transmission supports a predisposing effect of the more frequently transmitted allele.

#### **4.2. Genome scanning: Affected sib pair linkage analysis**

#### **Sarcoidosis genome scan in Germans**

The first genome scan study related to sarcoidosis was conducted by Schurmann and collea‐ gues, in which they used 225 microsatellite markers spanning the genome in 63 German families to identify a linkage signal (D6S1666) on chromosome 6p21 [132]. This group then used a three-stage single-nucleotide polymorphism (SNP) scan of the 16-MB region surround‐ ing D6S1666 [133] and identified a single SNP, rs2076530, in the BTNL2 gene associated with sarcoidosis. This SNP (G/A) was found at the 3' boundary of the exon 5 coding region. The A allele at this position has been proposed to introduce an alternative splice site at the exon 5–3' intron boundary of the BTNL2 transcript that results in a premature truncation of the protein.

BTNL2, also known as "butyrophilin-like 2" and "BTL-2," is a butyrophilin gene that belongs to the immunoglobulin gene superfamily related to the B7 family [134, 135]. Butyrophilin was initially cloned from cattle mammary epithelial cells [136]. This gene was localized to the MHC class II region in humans. To determine the consistency of the BTNL2 gene as a sarcoidosis risk factor across different populations, Rybicki and colleagues characterized variation in the BTNL2 exon/intron 5 region in an African-American family sample that consisted of 219 nuclear families (686 individuals) and in 2 case–control samples (295 African-American matched pairs and 366 white American matched pairs) [137].They confirmed that BTNL2 somewhat was less associated with sarcoidosis in African Americans compared with whites. BTNL2 appears to have moderate influence on individual disease risk (odds ratio of 1.6 in heterozygotes and 2.8 in homozygotes). The population attributable risk of 23% for heterozy‐ gotes and homozygotes indicates a significant contribution at the population level.

**4.3. Genome-Wide Association Studies (GWAS)**

hedgehog signaling pathway.

**5. Counseling and screening**

gations in the absence of complaints.

**6. Genetic testing**

**7. Future directions**

In genome-wide association study high throughput genotyping methods are used to genotype a dense set of SNPs across the genome. A significant advantage of this approach is that association studies are more powerful than affected sib pair methods of linkage analysis. Hofmann and colleagues [144] conducted a genomewide association study of 499 German patients with sarcoidosis and 490 control subjects. The strongest signal mapped to the annexin A11 gene on chromosome 10q22.3. Validation in an independent sample confirmed the association. Annexin A11 has regulatory functions in calcium signaling, cell division, vesicle trafficking, and apoptosis. Depletion or dysfunction of annexin A11 may affect the apoptosis pathway in sarcoidosis. Later the same group [145] reported another associated locus 6p12.1 that comprises several genes, a likely candidate being RAB23. RAB23 is proposed to be involved in antibacterial defense processes and regulation of the sonic

Genetic Factors Involved in Sarcoidosis http://dx.doi.org/10.5772/55116 65

In the context of genetic family counseling, this generally is perceived as a small risk by the clients and should lead to enhanced awareness but does not justify specific medical investi‐

Genetic testing at present does not play a role in the diagnosis and treatment of sarcoidosis.

The cause of sarcoidosis remains unknown. It is thought to be caused by interaction between environmental and genetic factors. Genetic studies have revealed the HLA and other candidate genes associated with sarcoidosis susceptibility. Association studies have been motivated by the hopes that identifying alleles that affect risk and phenotype will help in understanding disease etiology. Unfortunately, many of the reported associations have not been replicated. Two genome scans have been reported and one has yielded a likely candidate gene, BTNL2 that has been replicated in large studies. Emerging technologies and advances in genomics and proteomics will help find the causes sarcoidosis, better understanding of pathogenesis of sarcoidosis and to test new therapy. Gene expression profiling in BALF and blood carried out at the time of presentation will likely help to better predict disease resolution or progression.

Whether BTNL2 as a sarcoidosis risk factor is independent of HLA-DRB risk alleles or not, still remains a question. HLADRB and BTNL2 are in linkage disequilibrium. Linkage disequilibrium is the nonrandom association of alleles physically closes on a chromosome. HLA-DRB lies about 180 kb centromeric to BTNL2. On the basis of regression models, BTNL2 appears to be an independent risk factor [133, 137]. In the case of blacks, in whom the BTNL2-conferred sarcoidosis risk is less significant than for whites, a negative interac‐ tion with HLA-DR appears to exist [137]. In one study, BTNL2 was found not to be associated with Wegener's granulomatosis [138].

Most recently Hofmann and colleagues [139] conducted a Genome-Wide Linkage Analysis in 181 German sarcoidosis families using clustered biallelic markers. This study revealed one region of suggestive linkage on chromosome 12p13.31 at 20 cM (LOD= 2.53; local *P* value =. 0003) and another linkage on 9q33.1 at 134 cM (LOD =2.12; local *P* value =.0009). It is proposed that these regions might harbor yet-unidentified, possibly subphenotype-specific risk factors for the disease (e.g. immune-related functions like the tumor necrosis factor receptor 1).

#### **Sarcoidosis genome scan in African Americans**

Eleven centers joined together in an NHLBI-sponsored effort (Sarcoidosis Genetic Analy‐ sis Consortium [SAGA]) to perform a genome scan in African American siblings. This group performed a 380-microsatellite genomewide scan across 22 autosomes in 519 African American sib pairs. The significant findings included 15 markers with p values < 0.05 with the strongest linkage signal on chromosome 5 [140]. Fine mapping studies indicated a sarcoidosis susceptibility gene on chromosome 5q11.2 and a gene protective effect for sarcoidosis on 5p15.2 [141].

The reason why African Americans were chosen to uncover sarcoidosis susceptibility genes was that African Americans are more commonly and severely affected and have affected family members more often than whites. But the disadvantage of doing so is that African Americans are admixed with white and other populations to varying degrees with possible admixture among their participating centers ranging from 12% in South Carolina to 20% in New York [142]. To address the possibility that admixed subpopulations existed in the SAGA sample and affected the power to detect linkage, the sample was stratified by genetically determined ancestry using the data from the 380 microsatellite markers genotyped in the genome scan. The African-American families were clustered into subpopulations based on ancestry similarity. Evidence of two genetically distinct groups was found: Stratified linkage results suggest that one subpopulation of families contributed to previously identified linkage signals at 1p22, 3p21-14, 11p15, and 17q21 and that a second subpopulation of families contributed to those found at 5p15-13 and 20q13 [143]. These findings support the presence of sarcoidosis susceptibility genes in regions previously identified but indicate that these genes are likely to be specific to ancestral groups that have combined to form modern-day African Americans.

#### **4.3. Genome-Wide Association Studies (GWAS)**

heterozygotes and 2.8 in homozygotes). The population attributable risk of 23% for heterozy‐

Whether BTNL2 as a sarcoidosis risk factor is independent of HLA-DRB risk alleles or not, still remains a question. HLADRB and BTNL2 are in linkage disequilibrium. Linkage disequilibrium is the nonrandom association of alleles physically closes on a chromosome. HLA-DRB lies about 180 kb centromeric to BTNL2. On the basis of regression models, BTNL2 appears to be an independent risk factor [133, 137]. In the case of blacks, in whom the BTNL2-conferred sarcoidosis risk is less significant than for whites, a negative interac‐ tion with HLA-DR appears to exist [137]. In one study, BTNL2 was found not to be

Most recently Hofmann and colleagues [139] conducted a Genome-Wide Linkage Analysis in 181 German sarcoidosis families using clustered biallelic markers. This study revealed one region of suggestive linkage on chromosome 12p13.31 at 20 cM (LOD= 2.53; local *P* value =. 0003) and another linkage on 9q33.1 at 134 cM (LOD =2.12; local *P* value =.0009). It is proposed that these regions might harbor yet-unidentified, possibly subphenotype-specific risk factors for the disease (e.g. immune-related functions like the tumor necrosis factor receptor 1).

Eleven centers joined together in an NHLBI-sponsored effort (Sarcoidosis Genetic Analy‐ sis Consortium [SAGA]) to perform a genome scan in African American siblings. This group performed a 380-microsatellite genomewide scan across 22 autosomes in 519 African American sib pairs. The significant findings included 15 markers with p values < 0.05 with the strongest linkage signal on chromosome 5 [140]. Fine mapping studies indicated a sarcoidosis susceptibility gene on chromosome 5q11.2 and a gene protective effect for

The reason why African Americans were chosen to uncover sarcoidosis susceptibility genes was that African Americans are more commonly and severely affected and have affected family members more often than whites. But the disadvantage of doing so is that African Americans are admixed with white and other populations to varying degrees with possible admixture among their participating centers ranging from 12% in South Carolina to 20% in New York [142]. To address the possibility that admixed subpopulations existed in the SAGA sample and affected the power to detect linkage, the sample was stratified by genetically determined ancestry using the data from the 380 microsatellite markers genotyped in the genome scan. The African-American families were clustered into subpopulations based on ancestry similarity. Evidence of two genetically distinct groups was found: Stratified linkage results suggest that one subpopulation of families contributed to previously identified linkage signals at 1p22, 3p21-14, 11p15, and 17q21 and that a second subpopulation of families contributed to those found at 5p15-13 and 20q13 [143]. These findings support the presence of sarcoidosis susceptibility genes in regions previously identified but indicate that these genes are likely to be specific to ancestral groups that have combined to form modern-day African

gotes and homozygotes indicates a significant contribution at the population level.

associated with Wegener's granulomatosis [138].

**Sarcoidosis genome scan in African Americans**

sarcoidosis on 5p15.2 [141].

64 Sarcoidosis

Americans.

In genome-wide association study high throughput genotyping methods are used to genotype a dense set of SNPs across the genome. A significant advantage of this approach is that association studies are more powerful than affected sib pair methods of linkage analysis. Hofmann and colleagues [144] conducted a genomewide association study of 499 German patients with sarcoidosis and 490 control subjects. The strongest signal mapped to the annexin A11 gene on chromosome 10q22.3. Validation in an independent sample confirmed the association. Annexin A11 has regulatory functions in calcium signaling, cell division, vesicle trafficking, and apoptosis. Depletion or dysfunction of annexin A11 may affect the apoptosis pathway in sarcoidosis. Later the same group [145] reported another associated locus 6p12.1 that comprises several genes, a likely candidate being RAB23. RAB23 is proposed to be involved in antibacterial defense processes and regulation of the sonic hedgehog signaling pathway.

#### **5. Counseling and screening**

In the context of genetic family counseling, this generally is perceived as a small risk by the clients and should lead to enhanced awareness but does not justify specific medical investi‐ gations in the absence of complaints.

#### **6. Genetic testing**

Genetic testing at present does not play a role in the diagnosis and treatment of sarcoidosis.

### **7. Future directions**

The cause of sarcoidosis remains unknown. It is thought to be caused by interaction between environmental and genetic factors. Genetic studies have revealed the HLA and other candidate genes associated with sarcoidosis susceptibility. Association studies have been motivated by the hopes that identifying alleles that affect risk and phenotype will help in understanding disease etiology. Unfortunately, many of the reported associations have not been replicated. Two genome scans have been reported and one has yielded a likely candidate gene, BTNL2 that has been replicated in large studies. Emerging technologies and advances in genomics and proteomics will help find the causes sarcoidosis, better understanding of pathogenesis of sarcoidosis and to test new therapy. Gene expression profiling in BALF and blood carried out at the time of presentation will likely help to better predict disease resolution or progression.

### **Author details**

Birendra P. Sah and Michael C. Iannuzzi

SUNY, Upstate Medical University, Syracuse, New York, USA

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**Chapter 4**

**Genetics of Sarcoidosis**

http://dx.doi.org/10.5772/55332

in sarcoidosis is yet unknown [3].

phenotype (Figure 1).

**1. Introduction**

Nabeel Y. Hamzeh and Lisa A. Maier

Additional information is available at the end of the chapter

Sarcoidosis is a multi-system, T-helper 1 (Th1) cell biased granulomatous disorder. The current hypothesis is that sarcoidosis develops in a genetically predisposed individual who is exposed to a yet unknown environmental trigger(s) [1]. Antigen presentation in the context of major histocompatibility complex II (MHC-II) activates Th1 cells with subse‐ quent production of various cytokines and chemokines including but not limited to IFNγ, TNF-α, TGF-β, IL-2, IL-12 and others leading to further immune cell recruitment and activation [2]. The immune response ultimately leads to the formation of granulomas which consist of a central core of mononuclear cells surrounded by CD4+ cells and a small number of CD8+ and B-cells [2]. A role for regulatory T-cells has been proposed but their exact role

The disparity in prevalence and variability of organ involvement between ethnic groups [1] and the familial clustering of sarcoidosis strongly support a genetic basis for sarcoido‐ sis [4]. Several genome wide associations studies (GWAS) have identified potential association between specific genetic loci and sarcoidosis [5-11] and several studies have also associated various human leukocyte antigen (HLA) markers and gene-specific single nucleotide polymorphisms (SNP) with the risk, disease course and organ involvement with sarcoidosis indicating that sarcoidosis is a polygenic disease. Adding to this complexity, certain genetic markers have shown an association based on ethnicity and gender and some have shown differential associations based on gender and ethnicity [34]. Genetic polymor‐ phisms that are functional can potentially influence the immune system's recognition of an antigen and the subsequent immune response to the antigen thus dictating disease

and reproduction in any medium, provided the original work is properly cited.

© 2013 Hamzeh and Maier; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

### **Chapter 4**

## **Genetics of Sarcoidosis**

Nabeel Y. Hamzeh and Lisa A. Maier

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/55332

### **1. Introduction**

Sarcoidosis is a multi-system, T-helper 1 (Th1) cell biased granulomatous disorder. The current hypothesis is that sarcoidosis develops in a genetically predisposed individual who is exposed to a yet unknown environmental trigger(s) [1]. Antigen presentation in the context of major histocompatibility complex II (MHC-II) activates Th1 cells with subse‐ quent production of various cytokines and chemokines including but not limited to IFNγ, TNF-α, TGF-β, IL-2, IL-12 and others leading to further immune cell recruitment and activation [2]. The immune response ultimately leads to the formation of granulomas which consist of a central core of mononuclear cells surrounded by CD4+ cells and a small number of CD8+ and B-cells [2]. A role for regulatory T-cells has been proposed but their exact role in sarcoidosis is yet unknown [3].

The disparity in prevalence and variability of organ involvement between ethnic groups [1] and the familial clustering of sarcoidosis strongly support a genetic basis for sarcoido‐ sis [4]. Several genome wide associations studies (GWAS) have identified potential association between specific genetic loci and sarcoidosis [5-11] and several studies have also associated various human leukocyte antigen (HLA) markers and gene-specific single nucleotide polymorphisms (SNP) with the risk, disease course and organ involvement with sarcoidosis indicating that sarcoidosis is a polygenic disease. Adding to this complexity, certain genetic markers have shown an association based on ethnicity and gender and some have shown differential associations based on gender and ethnicity [34]. Genetic polymor‐ phisms that are functional can potentially influence the immune system's recognition of an antigen and the subsequent immune response to the antigen thus dictating disease phenotype (Figure 1).

© 2013 Hamzeh and Maier; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

In this review, we will attempt to summarize the current literature on the association of genetic markers with sarcoidosis from a functional perspective and highlight differences that might

**Gene Polymorphism Population OR CI p Ref**

HLA DRB1\*03 White UK/Dutch 7.97 4.16-15.26 <0.0001 [26]

MHC2TA rs3087456G White Swedish 1.31† 1.04-1.65† .019 [31]

BTNL2 rs3117099T White UK/Dutch 3.05 2.01-4.62 <0.0001 [26] CCR2 Haplotype 2\* White Dutch 4.4 1.9-9.7 <0.0001 [41]

CCR5 rs2040388A German/Female 1.93 1.35-2.77 0.0003 [53]

TNF# TNF-α 308AA rs1800629 US White 8.182 2.45-27.34 0.027 [73]

ANXA11 rs1049550TT Czech 0.31 0.11-0.84 0.02 [95]

HLA DQB1\*0602-DRB1\*15 White Dutch 2.27 1.46-3.54† 0.0032 [32]

DRB1\*0301 White Spanish 3.52 1.83-6.79 0.0004 [27] DRB1\*0301 White Swedish 7.71 4.63-12.84 <0.0001 [27] DRB1\*03 White Swedish 6.71 NR <0.0001 [28] DRB1\*03-DQB1\*0201 White Dutch 12.5 5.69-27.52 <0.0001 [29] DRB1\*0301 Finnish 2.46 1.11-5.45 0.044 [33] DRB1\*1501 Finnish 2.16 1.06-4.41 0.037 [33]

Genetics of Sarcoidosis

81

http://dx.doi.org/10.5772/55332

rs11074932C White Swedish 1.27† 1.02-1.58† .026 [31]

Haplotype 2\* Spanish 2.03 1.11-3.73 0.041 [27] Haplotype 2\* Swedish 3.02 1.65-5.52 0.0027 [27]

rs2856757C German/Female 1.65 1.17-2.33 0.004 [53]

DRB1\*12 White UK/Dutch 2.5 1.26-4.96 0.003 [26] DRB1\*12 UK 3.7 1.73-7.94 0.001 [29] DRB1\*12 Japanese 2.5 1.17-5.21 0.03 [29] DRB1\*1201 US White/AA 2.13 1.14-4.12 0.015 [34] DRB1\*10 White UK/Dutch 2.4 1.00-5.88 0.01 [26] DRB1\*14 White UK/Dutch 3.1 1.7-5.57 0.0003 [26] DRB1\*14 White Swedish 1.79 NR 0.017 [28] DRB1\*1401 US White/AA 2.29 1.21-4.34 0.011 [34]

TNF-α 308A rs1800629 Polish 2.3 1.23-4.32 <0.01 [77] TNF-α 308A UK/Dutch 3.1† 1.33-7.20† 0.006 [78] TNF-α 308A German NR NR 0.0078 [79] LTA-252G rs909253 Polish 2.98 1.67-5.29 <0.001 [77] LTA-252GG rs909253 US White females 11.33 3.18-40.37 0.027 [73]

exist between different racial groups.

Lofgren's Syndrome

Increased risk of non-Lofgren's

Genetic markers and risk of disease (Table 1):

**Figure 1.** Functional genetic polymorphisms dictate immune response and disease phenotype

Genetic studies have played an important role in revealing new pathways and mechanisms involved in the pathogenesis of immune mediated diseases such as rheumatoid arthritis, inflammatory bowel disease, psoriasis, systemic lupus erythematosus, type 1 diabetes and others [12]. Genome-wide association studies investigate the potential association of a disease with genetic markers across the entire genome without a mechanistic hypothesis [13]. Thou‐ sands of representative SNPs (tagging SNPs) that span the whole genome are assayed for potential association with a specific disease. In contrast, a candidate-gene approach is hypoth‐ esis driven and investigates the potential association of disease with polymorphisms in a specific gene(s) that encode molecule(s) (receptor, cytokine, signal transduction…) that are involved in the pathogenesis of a disease [13]. Familial-genetic studies investigate the associ‐ ation of genetic markers with a rare disease. Family members of an affected individual are studied for genetic markers that are present in affected members but absent in others [13].

Several environmental and infectious agents have been proposed to be associated with sarcoidosis but none proven yet. The ACCESS (A Case Controlled Etiological Study in Sarcoidosis) study group identified 5 occupations and 5 exposures that were more prevalent in sarcoidosis patients [14]. These exposures included agricultural employment, physicians, jobs raising birds, jobs in automotive manufacturing and middle/secondary school teachers, insecticides, employment in pesticide-using industries, occupational exposure to mold and mildew, occupational exposure to musty odors and use of home central air-conditioning [14]. In contrast, smoking appears to be protective against sarcoidosis [14, 15]. Infectious agents, particularly Mycobateria, are re-emerging as a potential antigen in sarcoidosis with studies detecting Mycobacteria proteins in tissues from sarcoidosis patients and T-cells from sarcoi‐ dosis patients responding to stimulation by Mycobacterial antigens [16-23]. Recent studies have also demonstrated an interaction between genetic markers and in vitro immune respons‐ es to Mycobacterial antigens further supporting the gene-environment interaction theory. [22] In this review, we will attempt to summarize the current literature on the association of genetic markers with sarcoidosis from a functional perspective and highlight differences that might exist between different racial groups.


Genetic markers and risk of disease (Table 1):

**Figure 1.** Functional genetic polymorphisms dictate immune response and disease phenotype

80 Sarcoidosis

Genetic studies have played an important role in revealing new pathways and mechanisms involved in the pathogenesis of immune mediated diseases such as rheumatoid arthritis, inflammatory bowel disease, psoriasis, systemic lupus erythematosus, type 1 diabetes and others [12]. Genome-wide association studies investigate the potential association of a disease with genetic markers across the entire genome without a mechanistic hypothesis [13]. Thou‐ sands of representative SNPs (tagging SNPs) that span the whole genome are assayed for potential association with a specific disease. In contrast, a candidate-gene approach is hypoth‐ esis driven and investigates the potential association of disease with polymorphisms in a specific gene(s) that encode molecule(s) (receptor, cytokine, signal transduction…) that are involved in the pathogenesis of a disease [13]. Familial-genetic studies investigate the associ‐ ation of genetic markers with a rare disease. Family members of an affected individual are studied for genetic markers that are present in affected members but absent in others [13].

Several environmental and infectious agents have been proposed to be associated with sarcoidosis but none proven yet. The ACCESS (A Case Controlled Etiological Study in Sarcoidosis) study group identified 5 occupations and 5 exposures that were more prevalent in sarcoidosis patients [14]. These exposures included agricultural employment, physicians, jobs raising birds, jobs in automotive manufacturing and middle/secondary school teachers, insecticides, employment in pesticide-using industries, occupational exposure to mold and mildew, occupational exposure to musty odors and use of home central air-conditioning [14]. In contrast, smoking appears to be protective against sarcoidosis [14, 15]. Infectious agents, particularly Mycobateria, are re-emerging as a potential antigen in sarcoidosis with studies detecting Mycobacteria proteins in tissues from sarcoidosis patients and T-cells from sarcoi‐ dosis patients responding to stimulation by Mycobacterial antigens [16-23]. Recent studies have also demonstrated an interaction between genetic markers and in vitro immune respons‐ es to Mycobacterial antigens further supporting the gene-environment interaction theory. [22]


**Gene Polymorphism Population OR CI p Ref**

CCR2

UK: United Kingdom AA: African American.

TLR: Toll-like receptor NR: Not reported.

**2. Receptors**

**2.1. HLA region**

US: United States of America

HLA: Human Leukocyte Antigen.

£Allele 2: T(GT)5AC(GT)5AC(GT)10 ¥Allele 3: T(GT)5AC(GT)5AC(GT)9

#TNF association with erythema nodosum

\*haplotype 2: (A at -6752,A at 3000, T at 3547 and T at 4385)

and provide new potential therapeutic targets.

† Values calculated by authors from raw data provided in original manuscript.

**Table 1.** Association of genetic markers with risk of developing sarcoidosis.

Numerous studies have been published investigating the association of genetic markers with the risk of developing sarcoidosis or the risk of disease severity, disease course or specific organ involvement [5-11]. Genetic polymorphisms, that are functional, can influence the immune system's response or function leading to active, progressive dis‐ ease or self-resolving, limited disease. Although it is yet unknown if, and how, many of the genetic polymorphisms detected can influence the immune response, they do provide new insight on pathways that are potentially involved in the pathogenesis of sarcoidosis

The HLA system plays an important role in the immune response and has been associated with various autoimmune diseases [24]. The HLA genes are encoded on chromosome 6 and

DRB1\*0401 US White/AA 0.48 0.28-0.8 0.003 [34] DRB1\*04 UK 0.54 0.35-0.84 0.008 [29] DQB1\*0301 UK 0.69 0.51-0.94 0.02 [29] DQB1\*0603 US Males 0.5 NR NR [34] DRB1\*1503 US AA 0.56 0.3-0.99 0.44 [34] DRB1\*0401 Us white 0.44 0.25-0.77 0.003 [34] DRB1\*07 Czech 0.40† 0.21-0.76† 0.0031 [74]

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CCR2-64I Japanese 0.37 0.21-0.67 0.0007 [43]


HLA: Human Leukocyte Antigen.

TLR: Toll-like receptor

NR: Not reported.

**Gene Polymorphism Population OR CI p Ref**

BTNL-2 rs2076530A German 2.31 1.27-4.23 <0.006 [37]

TNF LTA-252G rs909253 Czech 2.63 1.63-4.25 <0.00001 [74]

TLR-10 rs1109695C Dutch NR NR 0.002 [68]

TLR-1 rs5743604G Dutch NR NR 0.003 [68]

ANXA11 rs1049550C German 1.54 1.23-1.92 0.00014 [94]

HLA DRB1\*01 White Swedish 0.61 NR 0.003 [28]

TLR

82 Sarcoidosis

SLC11A1

Decreased risk

DRB1\*14 UK 2.54 1.47-4.41 0.001 [29] DQB1\*0503/4 Dutch 2.4 1.11-5.18 0.04 [29] DRB1\*15 Finnish 1.67 1.12-2.5 0.011 [33] DRB1\*1501 US White/AA 1.7 1.18-2.46 0.003 [34] DRB1\*1101 US White/AA 1.98 1.37-2.9 <0.001 [34] DRB3\*0101 US White/AA 1.6 1.16-2.2 0.004 [34] DRB1\*1201 US AA 2.67 1.2-6.52 0.014 [34] DPB1\*0101 US AA 1.72 1.14-2.62 0.008 [34] DRB1\*0402 US white 2.57 1.02-7.28 0.043 [34] DRB1\*1501 US White 2.08 1.39-3.15 <0.001 [34] DRB1\*13 Czech 2.4 1.43-4.03 <0.02 [74]

rs2076530A White UK/Dutch 1.49 1.20-1.86 0.002 [26] rs2076530A White Dutch 1.85 1.19-2.88 0.007 [38] rs2076530A White US 2.03 1.32-3.12 NR [39] rs2294878C White UK/Dutch 1.54 1.24-1.92 0.001 [26]

TNF-α 308A rs1800629 Polish 2.167 1.17-4.01 <0.05 [77] TNF-α -857T UK/Dutch NR NR 0.002 [78]

rs7658893A Dutch NR NR 0.001 [68]

rs5743594G Dutch NR NR 0.049 [68]

Allele 2£ US AA 0.48 0.28-0.81 0.014 [69] Allele 3¥ Polish 1.68 1.01-2.81 0.04 [71] Allele 3¥ Turkish 2.69 1.61-4.47 <0.001 [70] Allele 3¥ Greek 1.52 1.08-4.52 0.015 [72] INT4 Turkish 2.75 1.68-4.52 <0.001 [70]

rs1049550T Czech 0.77 NR 0.04 [95] rs2573346C German 1.55 1.24-1.92 0.00008 [94]

DRB1\*01 White UK/Dutch 0.5 0.35-0.82 0.001 [26] DRB1\*01 UK 0.5 0.34-0.76 0.001 [29] DRB1\*01 Dutch 0.4 0.23-0.76 0.006 [29] DRB1\*01 Japanese 0.12 0.03-0.52 0.001 [29] DRB1\*01 Finnish 0.43 0.26-0.72 0.001 [109] DRB1\*04 White UK/Dutch 0.6 0.46-0.92 0.02 [26]

£Allele 2: T(GT)5AC(GT)5AC(GT)10

¥Allele 3: T(GT)5AC(GT)5AC(GT)9

\*haplotype 2: (A at -6752,A at 3000, T at 3547 and T at 4385)

#TNF association with erythema nodosum

† Values calculated by authors from raw data provided in original manuscript.

**Table 1.** Association of genetic markers with risk of developing sarcoidosis.

Numerous studies have been published investigating the association of genetic markers with the risk of developing sarcoidosis or the risk of disease severity, disease course or specific organ involvement [5-11]. Genetic polymorphisms, that are functional, can influence the immune system's response or function leading to active, progressive dis‐ ease or self-resolving, limited disease. Although it is yet unknown if, and how, many of the genetic polymorphisms detected can influence the immune response, they do provide new insight on pathways that are potentially involved in the pathogenesis of sarcoidosis and provide new potential therapeutic targets.

#### **2. Receptors**

#### **2.1. HLA region**

The HLA system plays an important role in the immune response and has been associated with various autoimmune diseases [24]. The HLA genes are encoded on chromosome 6 and consist of over 200 genes [25]. HLA class I molecules, HLA-A, B and C, are expressed by most somatic cells and are important in the immune response [25]. They are composed of an α polypeptide chain, which is coded by the class I genes, and a β chain which is coded by the β2-microglobulin gene on chromosome 15 [25]. The HLA class II genes code for the α and β polypeptides of the class II molecule [25]. The HLA class II molecules are designated by 3 letters, the first (D) represents the class, the second (M,O,P,Q or R) represent the family and the third (A or B) represent the α or β chains [25]. The numbers that precedes the asterisk indicates the gene and the numbers following the asterisk represent the allelic variant of that gene [25]. HLA class II molecules are primarily expressed on immune cells. The HLA class II molecules play an important role in the immune response presenting antigens to the effector cells and induce activation of the immune cells [25].

Overall, HLA-DRB1 molecules appear to play an important role in the pathogenesis of sarcoidosis either by recognizing specific antigen(s) or mounting different immune responses to different antigen(s). A better understanding of the role of HLA molecules in the pathogenesis of sarcoidosis could move us a step closer to potentially identifying the antigen(s) that trigger

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The butyrophilin like 2 gene (BTNL2) belongs to the immunoglobulin gene superfamily and is related to the CD80 and CD86 co-stimulatory receptors. [7] In a mouse model, it was shown that BTNL2 binds to activated T-cells and inhibits their proliferation. [36] BTNL-2 was first linked to sarcoidosis when a GWAS in 63 German families with sarcoidosis identified a linkage to chromosome 6p21. [5] Further investigation found an association between SNP rs2076530A in the BTNL2 gene and sarcoidosis. [7] rs2076530A produces an alternative splice site that results in an early stop codon and a truncated, non-functional protein as a final product. [7] These findings were replicated in another German sarcoidosis cohort [37]. In a white British and Dutch cohorts, the SNPs rs2076530A and rs2294878C both showed an association with increased risk of sarcoidosis whereas haplotype 4 (which included rs2076530G and rs2294878A) had a protective association [26]. The SNP rs2076530A was associated with non-Lofgren's sarcoidosis and a gene dose effect was detected (AG vs GG OR 1.98, AA vs GG OR 2.63) [26]. There was strong linkage disequilibrium (LD) between BTNL2 haplotype 2 and HLA-DRB1\*03 and between BTNL2 haplotype 4 and HLA-DRB1\*01. [26] When the association of rs2076530A with the risk of sarcoidosis was analyzed in the context of HLA-DRB1, the rs2076530A association no longer held whereas the association of HLA-DRB1\*12 and \*14 with the risk of sarcoidosis persisted. [26] In a Dutch cohort, BTNL2 rs2076530A was associated with increased risk of sarcoidosis and a strong LD was found with HLA-DRB1\*15. [38] rs2076530A was also associated with an increased risk of sarcoidosis in an American Caucasian cohort whereas in an African American cohort, the BTNL2 gene risk and the HLA-DRB1 gene risk negated each other. [39] In the same cohort, BTNL2 rs3117099T was associated with Lofgren's syndrome, similar but stronger association was also detected for haplotype 2 which contains rs3117099T. [26] The association of both haplotype 2 and HLA-DRB1\*03 with Lofgren's syndrome remained significant after adjusting for each other and was stronger when

both were present and protective against sarcoidosis when both were absent [26].

CCR2 is a receptor for the chemokines CCL5, CCL2 and CCL3 that play an important role in recruiting monocytes, T-cells and other inflammatory cells. [40, 41] The association of 8 SNPs in the CCR2 gene with sarcoidosis was investigated in a white Dutch sarcoidosis population, a haplotype that consisted of 4 unique alleles (A at -6752,A at 3000, T at 3547 and T at 4385) was associated with LS, this association remained significant after adjustment for HLA-DRB1\*0301-DQB1\*0201 and female gender (both of which have been associated with LS). [41] No difference was seen between non-LS and controls. [41] This association and independence from HLA-DRB1 was confirmed in Swedish and Spanish sarcoidosis cohorts. [27] Similar

sarcoidosis [35].

**2.2. BTNL2**

**2.3. CCR2**

Sarcoidosis can present insidiously (non-Lofgren's syndrome) or present acutely with systemic symptoms, acute arthritis, erythema nodosum and bilateral hilar lymphadenopathy, more commonly known as Lofgren's syndrome (LS) [1]. Several HLA alleles have been associated with LS. HLA-DRB1 is the most common and has been reported in a white Dutch and UK cohorts [26], Spanish and Swedish cohorts (HLA-DRB1\*0301) [27], a Scandinavian cohort (HLA-DRB1\*03) [28] and a Dutch cohort (HLA-DRB1\*03-DQB1\*0201) [29]. In addition, HLA-DQB1\*0201 has been reported In White UK and Dutch cohorts [30]. HLA-DRB1\*03 and HLA-DQB1\*02 are in strong LD [30]. In addition, 2 SNPs (rs3087456 and rs11074932) in the major histocompatibility complex class II transactivator (MHC2TA) gene, which acts as a master regulator for the expression of MHC class II molecules, were found to be associated with LS independent of HLA-DRB1\*03 [31].

Several HLA alleles have also been associated with increased risk of developing non-LS sarcoidosis. HLA-DQB1\*0602 has been associated with increased risk of non-LS sarcoidosis in a Dutch cohort [32]. HLA-DRB1\*14, \*12 and \*10 have been associated with increased risk of sarcoidosis in a white Dutch and British cohort [26], and HLA-DRB1\*12 and DRB1\*14 in cohorts from the UK, Netherlands and Japan [29] whereas HLA-DRB1\*1501 was associated with risk of sarcoidosis in a Finnish cohort [33]. HLA-DRB1\*1201, \*1401, \*1501, \*1101 and HLA-DRB3\*0101 were associated with sarcoidosis in the ACCESS cohort in the USA [34].

In contrast, HLA alleles that have been associated with decreased risk (protective) for sarcoi‐ dosis included HLA-DRB1\*01 and \*04 in white Dutch and UK cohorts [26] and HLA-DRB1\*01 in cohorts from the UK, Netherlands and Japan [29] and HLA-DRB1\*0101 was protective in a Finnish cohort [33]. In the ACCESS cohort, HLA-DRB1\*0401 was protective for the overall cohort (African Americans and Caucasians) [34].

Some HLA markers are gender or ethnic specific in their association with sarcoidosis. In the ACCESS cohort, HLA-DRB1\*1101 was associated with increased risk more in males than females whereas HLA-DRB1\*0401 was associated with decreased risk more in males than females, [34] HLA-DQB1\*0603 was a risk factor for females but a protective factor for males. [34] For blacks in the ACCESS cohort, HLA-DRB1\*1201 and HLA-DPB1\*1503 were associated with increased risk of sarcoidosis and HLA-DRB1\*1503 was associated with decreased risk of sarcoidosis [34] whereas in whites, HLA-DRB1\*0402 and DRB1\*1501 were associated with increased risk whereas HLA-DRB1\*0401 was protective against sarcoidosis [34].

Overall, HLA-DRB1 molecules appear to play an important role in the pathogenesis of sarcoidosis either by recognizing specific antigen(s) or mounting different immune responses to different antigen(s). A better understanding of the role of HLA molecules in the pathogenesis of sarcoidosis could move us a step closer to potentially identifying the antigen(s) that trigger sarcoidosis [35].

#### **2.2. BTNL2**

consist of over 200 genes [25]. HLA class I molecules, HLA-A, B and C, are expressed by most somatic cells and are important in the immune response [25]. They are composed of an α polypeptide chain, which is coded by the class I genes, and a β chain which is coded by the β2-microglobulin gene on chromosome 15 [25]. The HLA class II genes code for the α and β polypeptides of the class II molecule [25]. The HLA class II molecules are designated by 3 letters, the first (D) represents the class, the second (M,O,P,Q or R) represent the family and the third (A or B) represent the α or β chains [25]. The numbers that precedes the asterisk indicates the gene and the numbers following the asterisk represent the allelic variant of that gene [25]. HLA class II molecules are primarily expressed on immune cells. The HLA class II molecules play an important role in the immune response presenting antigens to the effector

Sarcoidosis can present insidiously (non-Lofgren's syndrome) or present acutely with systemic symptoms, acute arthritis, erythema nodosum and bilateral hilar lymphadenopathy, more commonly known as Lofgren's syndrome (LS) [1]. Several HLA alleles have been associated with LS. HLA-DRB1 is the most common and has been reported in a white Dutch and UK cohorts [26], Spanish and Swedish cohorts (HLA-DRB1\*0301) [27], a Scandinavian cohort (HLA-DRB1\*03) [28] and a Dutch cohort (HLA-DRB1\*03-DQB1\*0201) [29]. In addition, HLA-DQB1\*0201 has been reported In White UK and Dutch cohorts [30]. HLA-DRB1\*03 and HLA-DQB1\*02 are in strong LD [30]. In addition, 2 SNPs (rs3087456 and rs11074932) in the major histocompatibility complex class II transactivator (MHC2TA) gene, which acts as a master regulator for the expression of MHC class II molecules, were found to be associated with LS

Several HLA alleles have also been associated with increased risk of developing non-LS sarcoidosis. HLA-DQB1\*0602 has been associated with increased risk of non-LS sarcoidosis in a Dutch cohort [32]. HLA-DRB1\*14, \*12 and \*10 have been associated with increased risk of sarcoidosis in a white Dutch and British cohort [26], and HLA-DRB1\*12 and DRB1\*14 in cohorts from the UK, Netherlands and Japan [29] whereas HLA-DRB1\*1501 was associated with risk of sarcoidosis in a Finnish cohort [33]. HLA-DRB1\*1201, \*1401, \*1501, \*1101 and HLA-

In contrast, HLA alleles that have been associated with decreased risk (protective) for sarcoi‐ dosis included HLA-DRB1\*01 and \*04 in white Dutch and UK cohorts [26] and HLA-DRB1\*01 in cohorts from the UK, Netherlands and Japan [29] and HLA-DRB1\*0101 was protective in a Finnish cohort [33]. In the ACCESS cohort, HLA-DRB1\*0401 was protective for the overall

Some HLA markers are gender or ethnic specific in their association with sarcoidosis. In the ACCESS cohort, HLA-DRB1\*1101 was associated with increased risk more in males than females whereas HLA-DRB1\*0401 was associated with decreased risk more in males than females, [34] HLA-DQB1\*0603 was a risk factor for females but a protective factor for males. [34] For blacks in the ACCESS cohort, HLA-DRB1\*1201 and HLA-DPB1\*1503 were associated with increased risk of sarcoidosis and HLA-DRB1\*1503 was associated with decreased risk of sarcoidosis [34] whereas in whites, HLA-DRB1\*0402 and DRB1\*1501 were associated with

DRB3\*0101 were associated with sarcoidosis in the ACCESS cohort in the USA [34].

increased risk whereas HLA-DRB1\*0401 was protective against sarcoidosis [34].

cells and induce activation of the immune cells [25].

independent of HLA-DRB1\*03 [31].

84 Sarcoidosis

cohort (African Americans and Caucasians) [34].

The butyrophilin like 2 gene (BTNL2) belongs to the immunoglobulin gene superfamily and is related to the CD80 and CD86 co-stimulatory receptors. [7] In a mouse model, it was shown that BTNL2 binds to activated T-cells and inhibits their proliferation. [36] BTNL-2 was first linked to sarcoidosis when a GWAS in 63 German families with sarcoidosis identified a linkage to chromosome 6p21. [5] Further investigation found an association between SNP rs2076530A in the BTNL2 gene and sarcoidosis. [7] rs2076530A produces an alternative splice site that results in an early stop codon and a truncated, non-functional protein as a final product. [7] These findings were replicated in another German sarcoidosis cohort [37]. In a white British and Dutch cohorts, the SNPs rs2076530A and rs2294878C both showed an association with increased risk of sarcoidosis whereas haplotype 4 (which included rs2076530G and rs2294878A) had a protective association [26]. The SNP rs2076530A was associated with non-Lofgren's sarcoidosis and a gene dose effect was detected (AG vs GG OR 1.98, AA vs GG OR 2.63) [26]. There was strong linkage disequilibrium (LD) between BTNL2 haplotype 2 and HLA-DRB1\*03 and between BTNL2 haplotype 4 and HLA-DRB1\*01. [26] When the association of rs2076530A with the risk of sarcoidosis was analyzed in the context of HLA-DRB1, the rs2076530A association no longer held whereas the association of HLA-DRB1\*12 and \*14 with the risk of sarcoidosis persisted. [26] In a Dutch cohort, BTNL2 rs2076530A was associated with increased risk of sarcoidosis and a strong LD was found with HLA-DRB1\*15. [38] rs2076530A was also associated with an increased risk of sarcoidosis in an American Caucasian cohort whereas in an African American cohort, the BTNL2 gene risk and the HLA-DRB1 gene risk negated each other. [39] In the same cohort, BTNL2 rs3117099T was associated with Lofgren's syndrome, similar but stronger association was also detected for haplotype 2 which contains rs3117099T. [26] The association of both haplotype 2 and HLA-DRB1\*03 with Lofgren's syndrome remained significant after adjusting for each other and was stronger when both were present and protective against sarcoidosis when both were absent [26].

#### **2.3. CCR2**

CCR2 is a receptor for the chemokines CCL5, CCL2 and CCL3 that play an important role in recruiting monocytes, T-cells and other inflammatory cells. [40, 41] The association of 8 SNPs in the CCR2 gene with sarcoidosis was investigated in a white Dutch sarcoidosis population, a haplotype that consisted of 4 unique alleles (A at -6752,A at 3000, T at 3547 and T at 4385) was associated with LS, this association remained significant after adjustment for HLA-DRB1\*0301-DQB1\*0201 and female gender (both of which have been associated with LS). [41] No difference was seen between non-LS and controls. [41] This association and independence from HLA-DRB1 was confirmed in Swedish and Spanish sarcoidosis cohorts. [27] Similar findings were found in a Czech cohort although the difference did not reach statistical significance. [40] No association was detected between 3 SNPs in CCR2 and sarcoidosis in a German cohort. [42] CCR2-64I mutation (A substitution mutation where isoleucine replaces valine in the transmembrane region) was found it to be protective against sarcoidosis in a Japanese cohort. [43]

**2.7. SLC11A1 (NRAMP1, Natural Resistance-Associated Macrophage Protein Gene)**

**3. Cytokines/Chemokines**

compared to controls. [78]

disease in an Indian cohort. [83]

the TNF-α 308 and TNF-β (intron 1) genotypes. [84]

**3.1. TNF-α and lymphotoxin-A (LTA, TNF-β)**

The SLC11A1 gene encodes a macrophage-specific, membrane protein whose function involves transport and appears to be important in the early stages of macrophage activation. [69] In US African Americans, a repeat polymorphism in 5' region (allele 2) of the gene was protective against sarcoidosis. [69] This finding was replicated in Polish, Turkish and Greek cohorts where the opposite polymorphism (allele 3) was associated with increased risk of sarcoidosis. [70-72] In the Turkish cohort, polymorphism in INT4 was also associated with increased risk of sarcoidosis but this association was not noted in the other cohorts. [70]

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TNF-α and LTA genes are located within the MHC class III region on chromosome 6p21.3 [73-75]. TNF-α plays a pivotal role in sarcoidosis [76]. It is produced by alveolar macrophages and high levels of spontaneous and stimulated release of TNF-α by macrophages from sarcoidosis patients correlates with disease severity. [76] Several Loci in the TNF-α gene have

LTA-252G (rs909253) allele was associated with sarcoidosis in Czech and Polish cohorts [77] and TNF-α-308A (rs1800629) allele was associated with sarcoidosis in Polish and Czech sarcoidosis cohorts [77]. There was a strong LD between the TNF-α 308A, LTA252G alleles and HLA-DRB1\*03 which has been associated with LS [74]. An association between TNFα 308A (rs1800629) allele and LS and between TNF-α -857T allele and non-LS sarcoidosis was also found in a British and Dutch cohort [78] and German cohorts [79-81]. An association was found between the TNF-α -308 (rs1800629) and LTA252G(rs909253) SNPs and erythema nodosum in US white women [73] but no association between polymor‐ phisms in the TNF-α gene and sarcoidosis in African Americans was detected. [82] There was also an increased frequency of the -857T allele in British and Dutch sarcoidosis patients

The relationship between serum TNF-α levels and genotypes is unclear, one study found an increased serum TNF-α levels with the TNF-α-307(8)G and the TNF-α -238A alleles in a sarcoidosis population but not normal controls, [83] whereas another study did not detect any association in the spontaneous or stimulated release of TNF-α from BAL and PBMC cells with

The TNF-α-863 position lies further upstream in the promoter region. It influences the binding of NF-kB p50-p50 to the promoter region and inhibiting TNF-α production. The A allele variant inhibits the binding of NF-kB p50-p50 and thus leading to a higher production of TNF-α. [85] There was a marginal association of the allele TNF-1031A with the risk of sarcoidosis and an association of TNF-1031A and TNF-α-863A with chronic

been studied including -307 (previously mislabeled as -308), -857, -863.

#### **2.4. CCR5**

The CCR5 gene is located on the short arm of chromosome 3 [44] and codes for a receptor for several chemokines including CCL3, CCL4, CCL5 and CCL8. [45] These chemokines play an important role in lymphocyte and monocyte recruitment and activation in sarcoidosis. [46, 47] In Sarcoidosis, CCR5 expression is up-regulated in Bronchoalveolar lavage (BAL) macro‐ phages and lymphocytes [48, 49] and levels of the CCR5 ligands, CCL3 and CCL5, correlate with risk of disease progression. [50-52] The CCR5Δ32 null allele results a 32bp deletion in the CCR5 gene and produces a non-functional receptor that is unable to bind to its ligand [53]. The A allele at position -5663 (rs2040388) and the C allele at position -3900 (rs2856757), both of which are part of the HHC haplotype, were associated with LS in a German cohort, particularly in females [53]. No association between 8 SNPs in the CCR5 gene and risk of sarcoidosis was detected in a white Dutch and UK cohorts but an association was noted with severity of lung disease. [54]

#### **2.5. CARD15**

CARD15/NOD2 is an intracellular molecule that is part of the innate immunity which recog‐ nizes muramyl dipeptide, a component of gram-positive and gram-negative bacteria cell wall [55]. It was first identified in association with the risk of Crohn's disease. [55] No significant association was detected between CARD15 polymorphisms and risk of sarcoidosis in German [56, 57], Japanese [58], Danish [59, 60] cohorts. In contrast, an association was noted with risk of disease in a Greek cohort [61].

#### **2.6. Toll-Like receptors**

Toll-like receptors (TLR) are transmembrane proteins that are critical in the innate immune system. [62] They are also known as pattern recognition receptors as they recognize specific microbial structures. [62] So far, 11 TLRs have been recognized. [62] Several studies in German and Dutch cohorts have investigated the potential association of polymorphisms in the TLR4, TLR2 and TLR9 genes with sarcoidosis but found no association with the risk of sarcoidosis. [63-67] One study in a German cohort suggested an association with chronic sarcoidosis. [63] In a Dutch cohort, SNPs rs1109695 and rs7658893 in the TLR-10 gene and rs57436004 and rs5743594 in the TLR-1 gene were associated with the risk of sarcoidosis. [68] None of the 4 SNPs were significantly different between remitting and chronic disease but they did differ significantly between healthy controls and sarcoidosis patients with chronic/progressive disease. [68]

#### **2.7. SLC11A1 (NRAMP1, Natural Resistance-Associated Macrophage Protein Gene)**

The SLC11A1 gene encodes a macrophage-specific, membrane protein whose function involves transport and appears to be important in the early stages of macrophage activation. [69] In US African Americans, a repeat polymorphism in 5' region (allele 2) of the gene was protective against sarcoidosis. [69] This finding was replicated in Polish, Turkish and Greek cohorts where the opposite polymorphism (allele 3) was associated with increased risk of sarcoidosis. [70-72] In the Turkish cohort, polymorphism in INT4 was also associated with increased risk of sarcoidosis but this association was not noted in the other cohorts. [70]

### **3. Cytokines/Chemokines**

findings were found in a Czech cohort although the difference did not reach statistical significance. [40] No association was detected between 3 SNPs in CCR2 and sarcoidosis in a German cohort. [42] CCR2-64I mutation (A substitution mutation where isoleucine replaces valine in the transmembrane region) was found it to be protective against sarcoidosis in a

The CCR5 gene is located on the short arm of chromosome 3 [44] and codes for a receptor for several chemokines including CCL3, CCL4, CCL5 and CCL8. [45] These chemokines play an important role in lymphocyte and monocyte recruitment and activation in sarcoidosis. [46, 47] In Sarcoidosis, CCR5 expression is up-regulated in Bronchoalveolar lavage (BAL) macro‐ phages and lymphocytes [48, 49] and levels of the CCR5 ligands, CCL3 and CCL5, correlate with risk of disease progression. [50-52] The CCR5Δ32 null allele results a 32bp deletion in the CCR5 gene and produces a non-functional receptor that is unable to bind to its ligand [53]. The A allele at position -5663 (rs2040388) and the C allele at position -3900 (rs2856757), both of which are part of the HHC haplotype, were associated with LS in a German cohort, particularly in females [53]. No association between 8 SNPs in the CCR5 gene and risk of sarcoidosis was detected in a white Dutch and UK cohorts but an association was noted with severity of lung

CARD15/NOD2 is an intracellular molecule that is part of the innate immunity which recog‐ nizes muramyl dipeptide, a component of gram-positive and gram-negative bacteria cell wall [55]. It was first identified in association with the risk of Crohn's disease. [55] No significant association was detected between CARD15 polymorphisms and risk of sarcoidosis in German [56, 57], Japanese [58], Danish [59, 60] cohorts. In contrast, an association was noted with risk

Toll-like receptors (TLR) are transmembrane proteins that are critical in the innate immune system. [62] They are also known as pattern recognition receptors as they recognize specific microbial structures. [62] So far, 11 TLRs have been recognized. [62] Several studies in German and Dutch cohorts have investigated the potential association of polymorphisms in the TLR4, TLR2 and TLR9 genes with sarcoidosis but found no association with the risk of sarcoidosis. [63-67] One study in a German cohort suggested an association with chronic sarcoidosis. [63] In a Dutch cohort, SNPs rs1109695 and rs7658893 in the TLR-10 gene and rs57436004 and rs5743594 in the TLR-1 gene were associated with the risk of sarcoidosis. [68] None of the 4 SNPs were significantly different between remitting and chronic disease but they did differ significantly between healthy controls and sarcoidosis patients with chronic/progressive

Japanese cohort. [43]

**2.4. CCR5**

86 Sarcoidosis

disease. [54]

**2.5. CARD15**

of disease in a Greek cohort [61].

**2.6. Toll-Like receptors**

disease. [68]

#### **3.1. TNF-α and lymphotoxin-A (LTA, TNF-β)**

TNF-α and LTA genes are located within the MHC class III region on chromosome 6p21.3 [73-75]. TNF-α plays a pivotal role in sarcoidosis [76]. It is produced by alveolar macrophages and high levels of spontaneous and stimulated release of TNF-α by macrophages from sarcoidosis patients correlates with disease severity. [76] Several Loci in the TNF-α gene have been studied including -307 (previously mislabeled as -308), -857, -863.

LTA-252G (rs909253) allele was associated with sarcoidosis in Czech and Polish cohorts [77] and TNF-α-308A (rs1800629) allele was associated with sarcoidosis in Polish and Czech sarcoidosis cohorts [77]. There was a strong LD between the TNF-α 308A, LTA252G alleles and HLA-DRB1\*03 which has been associated with LS [74]. An association between TNFα 308A (rs1800629) allele and LS and between TNF-α -857T allele and non-LS sarcoidosis was also found in a British and Dutch cohort [78] and German cohorts [79-81]. An association was found between the TNF-α -308 (rs1800629) and LTA252G(rs909253) SNPs and erythema nodosum in US white women [73] but no association between polymor‐ phisms in the TNF-α gene and sarcoidosis in African Americans was detected. [82] There was also an increased frequency of the -857T allele in British and Dutch sarcoidosis patients compared to controls. [78]

The relationship between serum TNF-α levels and genotypes is unclear, one study found an increased serum TNF-α levels with the TNF-α-307(8)G and the TNF-α -238A alleles in a sarcoidosis population but not normal controls, [83] whereas another study did not detect any association in the spontaneous or stimulated release of TNF-α from BAL and PBMC cells with the TNF-α 308 and TNF-β (intron 1) genotypes. [84]

The TNF-α-863 position lies further upstream in the promoter region. It influences the binding of NF-kB p50-p50 to the promoter region and inhibiting TNF-α production. The A allele variant inhibits the binding of NF-kB p50-p50 and thus leading to a higher production of TNF-α. [85] There was a marginal association of the allele TNF-1031A with the risk of sarcoidosis and an association of TNF-1031A and TNF-α-863A with chronic disease in an Indian cohort. [83]

### **3.2. TGF-β**

TGF-β is a growth factor with 3 isoforms: TGF-β1, TGF-β2 and TGF-β3. They have nearly identical biological properties but the functional properties are usually attributed to TGF-β1. [86] TGF-β induces the synthesis of extracellular matrix and decreases matrix degradation, has immunomodulatory properties acting as a mediator regulating chemotaxis and fibroblasts and has been implicated in pulmonary fibrosis. [86, 87] The variant allele C of -509T/C and C of codon 10 are associated with higher TGF-β1 protein levels in the serum and the codon 10 variant is associated with increased mRNA levels in PBMC. [88, 89] TGF-β1 levels in the BAL and alveolar macrophage supernatant are higher in patients with active sarcoidosis and especially in those with pulmonary function changes, [90] there was also a positive correlation with BAL lymphocytosis. [90]

associated with increased risk of sarcoidosis in their female patients. [96] No association was detected in a US Caucasian cohort [101]. Otherwise, no association between polymorphisms in the ACE gene and risk of sarcoidosis was detected in German, Dutch, Italian, British, Finnish

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The angiotensin II receptor 1 genotype AA and CC potentially increase the risk of sarcoidosis in males in a German cohort but these findings were not replicated in a Dutch cohort. [97, 98] No association existed between the angiotension II receptor 1 and 2 genotypes and sarcoidosis

No association between polymorphisms in the IL-10 or the CD40 gene and risk of sarcoidosis

**Gene Polymorphism Population OR CI p Ref**

HLA DQB1\*0602 AA NR NR 0.032 [107]

BTNL 2 rs2076530 Dutch 1.84 1.06-3.21 0.03 [38]

CCR5 HHC haplotype British 6.8\* 2.5-18.0 0.0045 [54]

CARD15/NOD2 rs2066844T British 4.1 1.0-15.5 0.04 [110]

IL23 Rs11209026A German 0.63 0.5-0.79 <0.001 [117]

DRB1\*07 Scandinavian 0.44 NR 0.009 [28]

DRB1\*14 Scandinavian 2.14 NR 0.005 [28]

DRB1\*15 Scandinavian 1.55 NR 0.011 [28]

DRB1\*01 Scandinavian 0.41 NR <0.001 [28]

DRB1\*03 Scandinavian 5.42 NR <0.001 [28]

DRB1\*03 Finnish 2.22 1.20-4.1 0.011 [33]

HHC haplotype Dutch 9\* 3.5-23.1 0.0009 [54]

TNF-α 308A Dutch 0.43 0.31-0.61 <0.001 [75]

and Czech sarcoidosis cohorts. [97-100, 102, 103]

in Japanese cohorts was detected. [105, 106]

Genetic markers and disease course / organ involvement (Table 2):

in a Japanese cohort. [104]

**5.2. IL-10 and CD40**

Progressive Pulmonary disease

TNF

No association was found between sarcoidosis and 2 polymorphisms (codon 10, T869C) in the TGF-β1 gene in a Japanese sarcoidosis cohort and no relationship with Scadding chest x-ray stage was found either. [91] Codon 10 was also not associated with sarcoidosis in a German cohort [92]. No association between polymorphisms in the TGF-β1, TGF-β2 and TGF-β3 genes and sarcoidosis was detected in a white Dutch cohort. [93]

### **4. Signaling molecules**

#### **4.1. Annexin A11**

The ANXA11 gene plays a role in the apoptosis pathway and depletion or dysfunction of the Annexin A11 protein may impair cell apoptosis and the down-regulation of the immune response [8]. A GWAS analysis in a German sarcoidosis cohort found a strong association between several SNPs in the annexin A11 (ANXA11) gene on chromosome 10 (10q22.3) and the risk of sarcoidosis. [8] This association was confirmed in a separate German cohort were the C allele of both rs1049550 and rs2573346 were associated with the development of sarcoi‐ dosis. [94] The association of rs1049550 with risk of sarcoidosis was also confirmed in a Czech cohort [95].

### **5. Others**

#### **5.1. Angiotensin Converting Enzyme (ACE)**

Serum ACE is one of the biochemical markers that reflect disease activity in sarcoidosis. [1] Serum ACE levels do correlate with ACE genotype, with genotype D/D having the highest levels and I/I the lowest. [96-100] Several studies have investigated the association of ACE genotypes with sarcoidosis. In an African American cohort, the DD genotype was associated with increased risk of sarcoidosis, but not extent or severity, and the association was stronger when a family history of sarcoidosis was taken into account. [101] This association was not noted in a later study in African Americans. [82] In a Japanese cohort, the DD genotype was associated with increased risk of sarcoidosis in their female patients. [96] No association was detected in a US Caucasian cohort [101]. Otherwise, no association between polymorphisms in the ACE gene and risk of sarcoidosis was detected in German, Dutch, Italian, British, Finnish and Czech sarcoidosis cohorts. [97-100, 102, 103]

The angiotensin II receptor 1 genotype AA and CC potentially increase the risk of sarcoidosis in males in a German cohort but these findings were not replicated in a Dutch cohort. [97, 98] No association existed between the angiotension II receptor 1 and 2 genotypes and sarcoidosis in a Japanese cohort. [104]

#### **5.2. IL-10 and CD40**

**3.2. TGF-β**

88 Sarcoidosis

with BAL lymphocytosis. [90]

**4. Signaling molecules**

**5.1. Angiotensin Converting Enzyme (ACE)**

**4.1. Annexin A11**

cohort [95].

**5. Others**

and sarcoidosis was detected in a white Dutch cohort. [93]

TGF-β is a growth factor with 3 isoforms: TGF-β1, TGF-β2 and TGF-β3. They have nearly identical biological properties but the functional properties are usually attributed to TGF-β1. [86] TGF-β induces the synthesis of extracellular matrix and decreases matrix degradation, has immunomodulatory properties acting as a mediator regulating chemotaxis and fibroblasts and has been implicated in pulmonary fibrosis. [86, 87] The variant allele C of -509T/C and C of codon 10 are associated with higher TGF-β1 protein levels in the serum and the codon 10 variant is associated with increased mRNA levels in PBMC. [88, 89] TGF-β1 levels in the BAL and alveolar macrophage supernatant are higher in patients with active sarcoidosis and especially in those with pulmonary function changes, [90] there was also a positive correlation

No association was found between sarcoidosis and 2 polymorphisms (codon 10, T869C) in the TGF-β1 gene in a Japanese sarcoidosis cohort and no relationship with Scadding chest x-ray stage was found either. [91] Codon 10 was also not associated with sarcoidosis in a German cohort [92]. No association between polymorphisms in the TGF-β1, TGF-β2 and TGF-β3 genes

The ANXA11 gene plays a role in the apoptosis pathway and depletion or dysfunction of the Annexin A11 protein may impair cell apoptosis and the down-regulation of the immune response [8]. A GWAS analysis in a German sarcoidosis cohort found a strong association between several SNPs in the annexin A11 (ANXA11) gene on chromosome 10 (10q22.3) and the risk of sarcoidosis. [8] This association was confirmed in a separate German cohort were the C allele of both rs1049550 and rs2573346 were associated with the development of sarcoi‐ dosis. [94] The association of rs1049550 with risk of sarcoidosis was also confirmed in a Czech

Serum ACE is one of the biochemical markers that reflect disease activity in sarcoidosis. [1] Serum ACE levels do correlate with ACE genotype, with genotype D/D having the highest levels and I/I the lowest. [96-100] Several studies have investigated the association of ACE genotypes with sarcoidosis. In an African American cohort, the DD genotype was associated with increased risk of sarcoidosis, but not extent or severity, and the association was stronger when a family history of sarcoidosis was taken into account. [101] This association was not noted in a later study in African Americans. [82] In a Japanese cohort, the DD genotype was

No association between polymorphisms in the IL-10 or the CD40 gene and risk of sarcoidosis in Japanese cohorts was detected. [105, 106]

Genetic markers and disease course / organ involvement (Table 2):



**6.3. CCR5**

involvement with Sarcoidosis [54].

**7. Cytokines/Chemokines**

**7.1. TNF-α 308, LTA252 (TNF-β)**

**7.2. TGFβ**

**7.3. IL-23**

associated with disease remission. [77]

**6.4. CARD15/NOD2**

CCR5Δ32 null allele was associated with the need for immunosuppressive therapy in a Czech cohort [40]. The haplotype HHC (-5663A, -3900C, -3458T, -2459G, -2135T, -2086G, -1835C, Δ32 wt) was strongly associated with the presence of parenchymal disease in British and Dutch cohorts at presentation, 2 and 4 years of follow up [54]. The haplotype HHC was also associated with lower forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), bronchoalveolar lavage neutrophilia (>4%) but not other organ

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In a British cohort, there was an association between allele T at loci 2104 (rs2066844) and the risk of radiographic Scadding stage IV at year 4 of follow up and an association between the allele G at loci 1761 with better lung function, defined by DLCO, at presentation, 2 and 4 years of follow up. [110] Interestingly, in a study in Crohn's disease patients, variants in loci 2104, 2722 and 3020 were associated with decreased number of T-regulatory cells in the lamina propria. [111] T-regulatory cells have been implicated to have a role in the immune pathogen‐

A higher representation of the TNF-α308A allele was found in a Dutch cohort with nonpersistent disease compared to persistent disease. [75] In a Polish cohort, TNF-α308 A/A was

In a white Dutch cohort, there was an increased frequency of the A allele in rs3917165 in the TGF-β3 gene in the fibrotic group compared to the acute/chronic groups [93], in addition, the C allele in rs3917200 was more frequent in the fibrotic group compared to the acute/chronic groups. [93] In another study, white American sarcoidosis patients who had CC homozygosity

IL-23 is a pro-inflammatory cytokine that stimulate Th-17 cells to produce IL-17 and other cytokines and has a role in a number of autoimmune diseases [114, 115]. Polymorphisms in rs11209026 can affect serum IL-17A levels in rheumatoid arthritis patients [116]. In a German

at position -509 (rs1800469) were more likely to have parenchymal disease [118].

cohort, rs11209026A was protective against chronic sarcoidosis [117].

esis of sarcoidosis but their exact role is yet unknown. [3, 112, 113]

HLA : Human Leukocyte Antigen

**Table 2.** Association of genetic markers with sarcoidosis disease course, severity and/or organ invovlement.

### **6. Receptors**

#### **6.1. HLA region**

HLA genetic markers were also investigated for their association with sarcoidosis disease course, severity and/or organ involvement. HLA-DQB1\*0602 was associated with radiograph‐ ic progression in an African American cohort [107], advanced pulmonary disease and uveitis in Dutch cohorts [30, 108] whereas in a Scandinavian cohort, HLA-DRB1\*07,\*14 and \*15 were associated with progressive pulmonary disease whereas \*01 and \*03 were associated with nonprogressive disease [28]. In a Finnish cohort, HLA-DRB1\*03 was associated with resolving disease [109].

#### **6.2. BTNL-2**

In a Dutch cohort, BTNL2 16071A variant was associated with increased risk of progressive or persistent pulmonary sarcoidosis [38].

### **6.3. CCR5**

**Gene Polymorphism Population OR CI p Ref**

TGF-β1 rs1800469 US white 2.5 1.3-4.5 0.005 [118]

TGF- β3 rs3917165A US White 7.9 2.1-30.9 P=0.01 [118]

TGF- β3 rs3917200C US White 5.1 1.6-17.7 P=0.05 [118]

GREM1 rs1919364CC Dutch 6.37 2.89-14.1 <0.001 [120]

ANXA11 rs1049550T Czech 0.61 0.41-0.89 0.01 [95]

HLA DRB1\*0401 AA/White 3.49 1.62-7.54 <0.0008 [34]

Hypercalcemia PBB1-0101 US white 4.28 1.45-12.6 0.005 [34]

HLA genetic markers were also investigated for their association with sarcoidosis disease course, severity and/or organ involvement. HLA-DQB1\*0602 was associated with radiograph‐ ic progression in an African American cohort [107], advanced pulmonary disease and uveitis in Dutch cohorts [30, 108] whereas in a Scandinavian cohort, HLA-DRB1\*07,\*14 and \*15 were associated with progressive pulmonary disease whereas \*01 and \*03 were associated with nonprogressive disease [28]. In a Finnish cohort, HLA-DRB1\*03 was associated with resolving

In a Dutch cohort, BTNL2 16071A variant was associated with increased risk of progressive or

**Table 2.** Association of genetic markers with sarcoidosis disease course, severity and/or organ invovlement.

DRB1\*0401-DQB10301 UK 3.4 1.64-7.08 0.001 [29]

DRB1\*03-DQB1\*0201 UK 0.21 0.08-0.54 <0.0001 [29]

TGF- β

90 Sarcoidosis

Ophthalmic

\* OR at 4 years

**6. Receptors**

**6.1. HLA region**

disease [109].

**6.2. BTNL-2**

persistent pulmonary sarcoidosis [38].

HLA : Human Leukocyte Antigen

TNF-α 308T Italian 3.53 1.66-7.5 <0.001 [77]

CCR5Δ32 null allele was associated with the need for immunosuppressive therapy in a Czech cohort [40]. The haplotype HHC (-5663A, -3900C, -3458T, -2459G, -2135T, -2086G, -1835C, Δ32 wt) was strongly associated with the presence of parenchymal disease in British and Dutch cohorts at presentation, 2 and 4 years of follow up [54]. The haplotype HHC was also associated with lower forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), bronchoalveolar lavage neutrophilia (>4%) but not other organ involvement with Sarcoidosis [54].

#### **6.4. CARD15/NOD2**

In a British cohort, there was an association between allele T at loci 2104 (rs2066844) and the risk of radiographic Scadding stage IV at year 4 of follow up and an association between the allele G at loci 1761 with better lung function, defined by DLCO, at presentation, 2 and 4 years of follow up. [110] Interestingly, in a study in Crohn's disease patients, variants in loci 2104, 2722 and 3020 were associated with decreased number of T-regulatory cells in the lamina propria. [111] T-regulatory cells have been implicated to have a role in the immune pathogen‐ esis of sarcoidosis but their exact role is yet unknown. [3, 112, 113]

### **7. Cytokines/Chemokines**

#### **7.1. TNF-α 308, LTA252 (TNF-β)**

A higher representation of the TNF-α308A allele was found in a Dutch cohort with nonpersistent disease compared to persistent disease. [75] In a Polish cohort, TNF-α308 A/A was associated with disease remission. [77]

#### **7.2. TGFβ**

In a white Dutch cohort, there was an increased frequency of the A allele in rs3917165 in the TGF-β3 gene in the fibrotic group compared to the acute/chronic groups [93], in addition, the C allele in rs3917200 was more frequent in the fibrotic group compared to the acute/chronic groups. [93] In another study, white American sarcoidosis patients who had CC homozygosity at position -509 (rs1800469) were more likely to have parenchymal disease [118].

#### **7.3. IL-23**

IL-23 is a pro-inflammatory cytokine that stimulate Th-17 cells to produce IL-17 and other cytokines and has a role in a number of autoimmune diseases [114, 115]. Polymorphisms in rs11209026 can affect serum IL-17A levels in rheumatoid arthritis patients [116]. In a German cohort, rs11209026A was protective against chronic sarcoidosis [117].

### **8. Signaling**

#### **8.1. GREM1**

Gremlin, encoded by GREM1, is a secreted glycoprotein and antagonizes bone morphogenetic protein (BMP) by forming heterodimers with BMP-2, BMP-4 and BMP-7 preventing BMP from interacting with its ligand and subsequent downstream signaling. [119] Dutch sarcoidosis patients with the CC genotype for rs1919364 in GREM1 had a 6 fold increased risk of devel‐ oping fibrotic lung disease. [120]

**11. Conclusions**

peutic targets.

mended [4].

dulatory therapy.

strong LD with HLA markers [26].

Sarcoidosis is a complex disease with variable presentations, course and organ involvement, as such, it is no surprise that research into the genetic basis of the disease yields complex and variable results. This is supported by the variability in presentation, course and organ involvement between various ethnic groups. To add to this complexity, linkage disequilibrium (LD) occurs when alleles at two loci are not independent of each other. As such, when one genetic marker is identified as associated with a disease or trait, then any allele in strong LD with that marker could be the actual link to the disease. For example, BTNL-2 has been associated with increased risk of sarcoidosis [5, 7, 8, 26, 37] but has also been shown to be in

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93

http://dx.doi.org/10.5772/55332

HLA molecules play an important role in antigen presentation and immune stimulation [24, 25]. The association of HLA markers with increased risk of sarcoidosis or specific organ involvement could potentially lead to identification of a causative agent(s), as seen in chronic beryllium disease [125], and a recent study has shown an interaction between genetics and immune response to certain environmental antigens [22]. Chronic beryllium disease, a granulomatous disorder that is caused by exposure to beryllium and resembles sarcoidosis, has been associated with HLA-DP-βGLu69 as a genetic risk factor [126]. Studies have shown that HLA-DP-βGlu69 interacts with beryllium with subsequent stimulation of the immune response [125]. In addition, the identification of genetic markers that are associated with sarcoidosis might uncover novel pathways not previously identified or suspected as contrib‐ utors to disease pathogenesis, which could subsequently lead to identification of new thera‐

Further research is still needed to clarify the associations of the various genetic markers with risk and prognosis of disease and large validation studies will be needed to confirm these associations. Proper phenotyping of cases and stratification according to ethnicity and gender when analyzing genetic studies is extremely important. Several studies have shown opposite associations between gender and/or ethnicity and genetic markers when the analysis was stratified by gender and/or ethnicity [53]. In addition, the interaction between two or more

So what role does genetic testing have in the clinical care of sarcoidosis patients? At this stage, genetic testing has no identifiable role in the clinical arena. The odds of a first or second degree relative of a sarcoidosis patient also having sarcoidosis are 4.6 and the familial relative risk was larger in sibs than in parents and higher in Whites than African Americans [4]. This said, the absolute risk and attributable risk for a sib or parent of a sarcoidosis patients is approxi‐ mately 1% and as such, screening family members, clinically or genetically, is not recom‐

Potential future applications of genetic testing in the clinical arena include prognostication on disease course which will aid in determining intensity of follow up, prognostication on potential organ involvement which will influence frequency and intensity of screening for sarcoidosis involvement, and potentially a role for pharmacogenetics in guiding immunomo‐

distinct SNPs or haplotypes in sarcoidosis has yet to be studied [127].

#### **8.2. Annexin A11**

In a Czech cohort, rs1049550 T-allele was protective against parenchymal disease (Scadding stages II-IV) [95].

### **9. Other**

#### **9.1. COX2**

In a Spanish cohort, there was an association between the CC genotype of the COX2.8473 polymorphism and increased risk of sarcoidosis [121] and an association of the C-allele of the COX2.3050 with systemic sarcoidosis versus non-systemic sarcoidosis [122].

#### **9.2. IL-10 and CD40**

There were no associations between polymorphisms in the IL-10 and CD40 gene in Japanese cohorts and the risk of sarcoidosis. [105, 106]

### **10. Organ involvement**

A few genetic markers have also been associated with organ involvement in sarcoidosis. In the ACCESS study, HLA-DRB3 was associated with bone marrow involvement in blacks, HLA-DPB1\*0101 with hypercalcemia in whites, HLA-DRB1\*0401 with parotid and salivary gland involvement in blacks and HLA-DRB1\*0401 was found to have possible association with eye involvement [34]. In a cohort from the UK, HLA-DRB1\*0401-DQB1\*0301 was associated with increased risk of uveitis whereas HLA-DRB1\*03 and DQB1\*0201 were protective for uveitis. [29] In a Japanese cohort, HLA-DRB1\*15 and DQB1\*0602 were associated with skin disease and HLA-DRB1\*0803 with neurosarcoidosis. [29] In a Japanese cohort, polymorphisms in the CTLA-4 gene were associated with BAL lymphocytosis, ocular involvement and multi-organ involvement. [123, 124]

### **11. Conclusions**

**8. Signaling**

**8.2. Annexin A11**

stages II-IV) [95].

**9. Other**

**9.1. COX2**

**9.2. IL-10 and CD40**

**10. Organ involvement**

involvement. [123, 124]

cohorts and the risk of sarcoidosis. [105, 106]

oping fibrotic lung disease. [120]

Gremlin, encoded by GREM1, is a secreted glycoprotein and antagonizes bone morphogenetic protein (BMP) by forming heterodimers with BMP-2, BMP-4 and BMP-7 preventing BMP from interacting with its ligand and subsequent downstream signaling. [119] Dutch sarcoidosis patients with the CC genotype for rs1919364 in GREM1 had a 6 fold increased risk of devel‐

In a Czech cohort, rs1049550 T-allele was protective against parenchymal disease (Scadding

In a Spanish cohort, there was an association between the CC genotype of the COX2.8473 polymorphism and increased risk of sarcoidosis [121] and an association of the C-allele of the

There were no associations between polymorphisms in the IL-10 and CD40 gene in Japanese

A few genetic markers have also been associated with organ involvement in sarcoidosis. In the ACCESS study, HLA-DRB3 was associated with bone marrow involvement in blacks, HLA-DPB1\*0101 with hypercalcemia in whites, HLA-DRB1\*0401 with parotid and salivary gland involvement in blacks and HLA-DRB1\*0401 was found to have possible association with eye involvement [34]. In a cohort from the UK, HLA-DRB1\*0401-DQB1\*0301 was associated with increased risk of uveitis whereas HLA-DRB1\*03 and DQB1\*0201 were protective for uveitis. [29] In a Japanese cohort, HLA-DRB1\*15 and DQB1\*0602 were associated with skin disease and HLA-DRB1\*0803 with neurosarcoidosis. [29] In a Japanese cohort, polymorphisms in the CTLA-4 gene were associated with BAL lymphocytosis, ocular involvement and multi-organ

COX2.3050 with systemic sarcoidosis versus non-systemic sarcoidosis [122].

**8.1. GREM1**

92 Sarcoidosis

Sarcoidosis is a complex disease with variable presentations, course and organ involvement, as such, it is no surprise that research into the genetic basis of the disease yields complex and variable results. This is supported by the variability in presentation, course and organ involvement between various ethnic groups. To add to this complexity, linkage disequilibrium (LD) occurs when alleles at two loci are not independent of each other. As such, when one genetic marker is identified as associated with a disease or trait, then any allele in strong LD with that marker could be the actual link to the disease. For example, BTNL-2 has been associated with increased risk of sarcoidosis [5, 7, 8, 26, 37] but has also been shown to be in strong LD with HLA markers [26].

HLA molecules play an important role in antigen presentation and immune stimulation [24, 25]. The association of HLA markers with increased risk of sarcoidosis or specific organ involvement could potentially lead to identification of a causative agent(s), as seen in chronic beryllium disease [125], and a recent study has shown an interaction between genetics and immune response to certain environmental antigens [22]. Chronic beryllium disease, a granulomatous disorder that is caused by exposure to beryllium and resembles sarcoidosis, has been associated with HLA-DP-βGLu69 as a genetic risk factor [126]. Studies have shown that HLA-DP-βGlu69 interacts with beryllium with subsequent stimulation of the immune response [125]. In addition, the identification of genetic markers that are associated with sarcoidosis might uncover novel pathways not previously identified or suspected as contrib‐ utors to disease pathogenesis, which could subsequently lead to identification of new thera‐ peutic targets.

Further research is still needed to clarify the associations of the various genetic markers with risk and prognosis of disease and large validation studies will be needed to confirm these associations. Proper phenotyping of cases and stratification according to ethnicity and gender when analyzing genetic studies is extremely important. Several studies have shown opposite associations between gender and/or ethnicity and genetic markers when the analysis was stratified by gender and/or ethnicity [53]. In addition, the interaction between two or more distinct SNPs or haplotypes in sarcoidosis has yet to be studied [127].

So what role does genetic testing have in the clinical care of sarcoidosis patients? At this stage, genetic testing has no identifiable role in the clinical arena. The odds of a first or second degree relative of a sarcoidosis patient also having sarcoidosis are 4.6 and the familial relative risk was larger in sibs than in parents and higher in Whites than African Americans [4]. This said, the absolute risk and attributable risk for a sib or parent of a sarcoidosis patients is approxi‐ mately 1% and as such, screening family members, clinically or genetically, is not recom‐ mended [4].

Potential future applications of genetic testing in the clinical arena include prognostication on disease course which will aid in determining intensity of follow up, prognostication on potential organ involvement which will influence frequency and intensity of screening for sarcoidosis involvement, and potentially a role for pharmacogenetics in guiding immunomo‐ dulatory therapy.

### **Author details**

Nabeel Y. Hamzeh1,2 and Lisa A. Maier1,2

1 Division of Environmental and Occupational Health Sciences, National Jewish Health, Denver, CO, USA

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**Section 3**

**Clinical Features**

**Section 3**
