**3. Autoimmune diseases**

The information on genetic polymorphisms facilitates to explain pathologic mechanisms and help in identifying individuals at risk. It also helps us to find novel targets for drug treatment. The protein tyrosine phosphatase non-receptor type 22 (*PTPN22*) gene is an important predisposing gene for human autoimmune diseases. The alterations in PTPN22 render a person susceptible and lead to the development of several autoimmune diseases. Many single nucleotide polymorphisms (SNPs) have been identified in PTPN22, but only one non-synonymous SNP has been intensively studied in relation to autoimmune diseases. This SNP C1858T

(rs2476601) in exon 14 of the PTPN22 gene has been associated with a number of autoimmune diseases and considered as a risk factor due to significant production

The PTPN22 C1858T variant has been studied in autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes mellitus, juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD) including Crohn's disease (CD) and ulcerative colitis (UC), antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, vitiligo, systemic sclerosis (SSc), Graves' disease (GD), myasthenia gravis (MG), Addison's disease, psoriasis, psoriatic arthritis (PsA), Behcet's disease (BD), endometriosis, autoimmune thyroid disease (AITD), giant cell arteritis (GCA), alopecia areata (AA), and Sjögren's syndrome. The association of PTPN22 C1858T genetic polymorphism is very significant and noteworthy in some autoimmune diseases, while in other it is less significant [3]. However, available literature on PTPN22 C1858T polymorphism and autoimmune diseases shows inconsistencies and ethnic

PTPN22 gene is located on chromosomes 1p13.3–p13.1 and encodes a lymphoidspecific tyrosine phosphatase (Lyp). Lyp is an intracellular protein tyrosine phosphatase, bound to the SH3 domain of the C-terminal Src kinase (Csk) through a proline-rich motif. It is believed to suppress kinases mediating T-cell activation [4]. Lyp plays an important role in B-cell signaling, besides functioning as a negative regulator of T cells. It works in signaling cascade at various levels and targets several signaling intermediates involved in T-cell receptor signaling [5, 6]. After HLA, PTPN22 gene is the second-most important predisposing gene for human autoim-

The minor allele 1858T in the *PTPN22* locus has a strong and consistent genetic association with autoimmune diseases. In PTPN22 C1858T (rs2476601), cytosine changes to thymidine at nucleotide 1858, resulting in an amino acid change from arginine to tryptophan at codon 620 (R620W), located in the polyproline-binding motif P1 [7, 8]. Yet there is no consensus whether C1858T polymorphism is a gainor loss-of-function variant. The C1858T has been reported as a susceptibility locus associated with several autoimmune diseases. It was first reported in type 1 diabetes

PTPN22 C1858T polymorphism has been suggested to increase Lyp protein activity which in turn inhibits T-cell signaling and results in a failure to delete autoreactive T cells during thymic selection. The association of this polymorphism is restricted to disorders that have a strong autoantibody component as it results in

With the advent of new genotyping and molecular biology techniques, a huge amount of data are available for analysis. A large number of genes associated with diseases have been identified by the GWAS, candidate gene, and epidemiological

of autoantibodies [2, 3].

*The Recent Topics in Genetic Polymorphisms*

variations exist.

**2.** *PTPN22* **gene**

mune diseases.

mellitus (T1DM) [7].

**82**

immune responses against autoantigens [8].

Autoimmune diseases are pathological conditions identified by abnormal autoimmune responses and characterized by autoantibodies and T-cell responses to self-molecules by immune system reactivity. Human autoimmune diseases occur frequently (affecting in aggregate more than 5% of the population worldwide) and impose a significant burden of morbidity and mortality on the human population [9].

The etiology of autoimmune diseases involves both genetic and environmental factors. Familial clustering is known in autoimmune diseases with higher rate of concordance in monozygotic twins as compared to dizygotic twins [10–12]. Most autoimmune diseases are multigenic, with multiple susceptibility genes working in concert to produce the disease; however, a few autoimmune diseases are caused by mutations in a single gene. Even in such cases other genes modify the severity of disease. On the other hand, some individuals with these mutations do not manifest the disease.

The genetic polymorphisms also occur in normal population and are compatible with a normal immune function. However, when these polymorphisms occur with


#### **Table 1.**

*Association of PTPN22 C1858T polymorphism with* vitiligo *susceptibility.*

other susceptibility genes, they develop autoimmunity [13, 14]. The extent of risk is not same for all such genes, and some of the genes confer a much higher level of risk than others [9].

**Population Case/**

*DOI: http://dx.doi.org/10.5772/intechopen.90836*

Australian 413/690

American (European

ancestry)

*\**

**85**

**Table 5.**

*Meta-analysis.*

**controls**

1608/9284

**Genotype/allele/ polymorphism**

Australian 324/568 C1858T Susceptible [70]

*The Protein Tyrosine Phosphatase Non-Receptor Type 22 (PTPN22) Gene Polymorphism…*

Greek 128/221 C1858T Susceptible [73] Egyptian 60/40 T-allele Susceptible [75] UK 661/595 C1858T Susceptible [65] Czechs 130/400 T-allele Susceptible [72] European 809/3535 C1858T Susceptible [69] Norwegian 320/555 C1858T Susceptible [74] Mixed\* 4552/10,161 C1858T Susceptible [77] Mixed\* 4238/6012 C1858T Susceptible [76] Finish 230 T-allele No association [78] Hungarian 150/200 T-allele No association [79]

*Association of PTPN22 C1858T polymorphism with* juvenile idiopathic arthritis *susceptibility.*

**Population Case/controls Genotype/allele/polymorphism Association References** Spanish 826/1036 T-allele Susceptible [96] Italian 396/477 T-allele Susceptible [92] Turkish 323/426 C1858T Susceptible [97] Colombian 298/308 T-allele Susceptible [86] Colombian 413/434 T-allele Susceptible [87] Egyptian 150/150 T-allele Susceptible [89] Egyptian 394/398 C1858T Susceptible [90] Egyptian 112/122 T-allele Susceptible [88] Egyptian 100/114 C1858T No association [100] Algerian 110/197 C1858T Susceptible [85] Mexican 315/315 C1858T Susceptible [95] Mexican 364/387 C1858T Susceptible [94] Mexican 309/347 T-allele Susceptible [93] UK 886/595 C1858T Susceptible [65] Iranian 120/120 C1858T Susceptible [91] Iranian 120/120 T-allele Susceptible [84] Iranian 405/467 C1858T No association [101] Chinese Han 358/564 C1858T No association [99] Chinese-Yunnan 192/288 C1858T No association [98]

647/751 C1858T Susceptible [67]

C1858T Susceptible in

females

**Association References**

[71]

The results of various association studies of PTPN22 C1858T variant with some of the autoimmune diseases are summarized in **Tables 1–18**.


#### **Table 2.**

*Association of PYPN22 C1858T polymorphism with* alopecia *susceptibility.*


#### **Table 3.**

*Association of PTPN22 C1858T polymorphism with* psoriasis *susceptibility.*


#### **Table 4.**

*Association of PTPN22 C1858T polymorphism with* psoriatic arthritis *susceptibility.*

**Population Case/ controls Genotype/allele/ polymorphism Association References** American (European ancestry) 647/751 C1858T Susceptible [67] Australian 324/568 C1858T Susceptible [70] Australian 413/690 1608/9284 C1858T Susceptible in females [71] Greek 128/221 C1858T Susceptible [73] Egyptian 60/40 T-allele Susceptible [75] UK 661/595 C1858T Susceptible [65] Czechs 130/400 T-allele Susceptible [72] European 809/3535 C1858T Susceptible [69] Norwegian 320/555 C1858T Susceptible [74] Mixed\* 4552/10,161 C1858T Susceptible [77] Mixed\* 4238/6012 C1858T Susceptible [76] Finish 230 T-allele No association [78] Hungarian 150/200 T-allele No association [79] *\* Meta-analysis.*

*The Protein Tyrosine Phosphatase Non-Receptor Type 22 (PTPN22) Gene Polymorphism… DOI: http://dx.doi.org/10.5772/intechopen.90836*

#### **Table 5.**

other susceptibility genes, they develop autoimmunity [13, 14]. The extent of risk is not same for all such genes, and some of the genes confer a much higher level of risk

The results of various association studies of PTPN22 C1858T variant with some

**Population Case/controls Genotype/allele/polymorphism Association References** Mexican 64/225 T-allele Susceptible [41] Belgian-German 435/628 C1858T Susceptible [39] English 196/507 C1858T Susceptible [38] Mixed\* 1129/1702 T and CT Susceptible [43] Mixed\* 365/173 C1858T Susceptible [42] Egyptian 103/100 CT, TT Susceptible [40] Iranian 69/69 T-allele No association [44]

**Population Case/controls Genotype/allele/polymorphism Association References** Saudi 106/200 T-allele, CT Susceptible [53] German 375 + 418/376 + 561 C1858T No association [57] English 647/566 C1858T No association [58] Caucasian 1146 C1858T No association [59] Mixed\* 3334/5753 T-allele No association [56] Mixed\* 1448/1385 C1858T No association [55] Cretan (Greek) 173/348 T-allele No association [60]

**Population Case/controls Genotype/allele/polymorphism Association References** Toronto (admixed) 207/199 T-allele Susceptible [61] Swedish 291/725 T-allele Susceptible [62] Mixed# 1177/2155 C1858T Susceptible [63] UK 455/595 C1858T No association [65] Newfoundland 238/149 T-allele No association [61] German 375/376 T-allele No association [66]

of the autoimmune diseases are summarized in **Tables 1–18**.

*Association of PYPN22 C1858T polymorphism with* alopecia *susceptibility.*

*Association of PTPN22 C1858T polymorphism with* psoriasis *susceptibility.*

*Association of PTPN22 C1858T polymorphism with* psoriatic arthritis *susceptibility.*

than others [9].

*The Recent Topics in Genetic Polymorphisms*

*\**

*\**

*#*

**84**

**Table 4.**

*Genome-wide association study.*

**Table 3.**

*Meta-analysis.*

**Table 2.**

*Meta-analysis.*

*Association of PTPN22 C1858T polymorphism with* juvenile idiopathic arthritis *susceptibility.*



**Population Case/**

*DOI: http://dx.doi.org/10.5772/intechopen.90836*

*\**

*\**

*\**

*#*

**87**

**Table 9.**

*Meta-analysis.*

*Genome-wide association study.*

**Table 8.**

*Meta-analysis.*

**Table 7.**

*Meta-analysis.*

**controls**

*Association of PTPN22 C1858T polymorphism with* SLE *susceptibility.*

*Association of PTPN22 C1858T polymorphism with* AITD *susceptibility.*

*Association of PTPN22 C1858T polymorphism with* Graves' disease *susceptibility.*

**Genotype/allele/ polymorphism**

Mexican mestizos 150/150 C1858T No association [130] Turkish 158/155 C1858T No association [131] Turkish 137/160 C1858T No association [132] Chinese Han 713/672 C1858T No association [99] Chinese 40/20 C1858T No association [129]

*The Protein Tyrosine Phosphatase Non-Receptor Type 22 (PTPN22) Gene Polymorphism…*

**Population Case/controls Genotype/allele/polymorphism Association References** Egyptian 60/60 C1858T Susceptible [133] German 140/100 T-allele Susceptible [138] Mixed\* 3764/3328 C1858T Susceptible [139] Japanese 456/221 T-allele No association [143] Japanese 334/179 C1858T No association [144] Korean 212/225 T-allele No association [145] Polish 149/200 C1858T No association [147] Jordanian Arab 204/2016 C1858T No association [146]

**Population Case/controls Genotype/allele/polymorphism Association References** Latin-American 83/336 C1858T Susceptible [148] Polish 166/154 C1858T Susceptible [149] Polish 290/310 T-allele Susceptible [150] Polish 735/1216 C1858T No association [154] English 768/768 C1858T Susceptible [140] English 549/429 C1858T Susceptible [151] English 901/833 C1858T Susceptible [152] Mixed\* 3 studies T-allele Susceptible [2] Mixed\* 3764/3328 C1858T Susceptible [139] Indian Kashmiri 135/150 C1858T No association [155] Chinese Han# 5904/5866 C1858T No association [153]

**Association References**

#### **Table 6.**

*Association of PTPN22 C1858T polymorphism with* RA *susceptibility.*


*The Protein Tyrosine Phosphatase Non-Receptor Type 22 (PTPN22) Gene Polymorphism… DOI: http://dx.doi.org/10.5772/intechopen.90836*


#### **Table 7.**

**Population Case/controls Genotype/allele/polymorphism Association References**

Mixed\* 11,727/12,640 T-allele Susceptible [105] Mixed\* 3209/3692 C1858T Susceptible [106] Mixed\* 20,344/21,828 C1858T Susceptible [76] Mixed\* 13 studies T-allele Susceptible [107] Mixed\* 17,961/18,611 C1858T Susceptible [102] Mixed\* 34 studies C1858T Susceptible [108] Mixed\* 36 studies T-allele Susceptible [2]

C1858T

C1858T

**Genotype/allele/ polymorphism**

Spanish 338/1036 T-allele Susceptible [96] Swedish 571/1042 C1858T Susceptible [120] American 525/1961 C1858T Susceptible [116] Crete 328/427 C1858T Susceptible [119] Colombian 94/434 T-allele Susceptible [87] Colombian 143/308 T-allele Susceptible [86] Polish 135/201 CT, T-allele Susceptible [122] Polish 150/300 C1858T Susceptible [121] Mixed\* 6 studies T-allele susceptible [107] Mixed\* 772/1092 C1858T Susceptible [126] Mixed\* 9120/11724 C1858T Susceptible [128] Mixed\* 11 studies CT, TT Susceptible [125] Mixed\* 14 studies T-allele Susceptible [2] Mixed\* 3868/7458 T-allele, TT Susceptible [127] European-Americans 3936/3491 C1858T Susceptible [118] Hispanics 1492/807 C1858T No association [118] African-Americans 1527/1811 C1858T No association [118] Asians 1265/1260 C1858T No association [118] Egyptian 170/241 C1858T Susceptible [124] Egyptian 40/20 CT Susceptible [123] Egyptian 60/60 C1858T No association [133] European-American 1680/1467 T-allele Susceptible [117] Mexican 500/355 T-allele Susceptible [134]

Susceptible No association

Susceptible No association [103]

[104]

**Association References**

27,205/27,677 C1858T

29 studies C1858T

*Association of PTPN22 C1858T polymorphism with* RA *susceptibility.*

**controls**

Caucasian\* Asian\*

*The Recent Topics in Genetic Polymorphisms*

European\* Asian and African

*\**

**86**

**Table 6.**

*Meta-analysis.*

**Population Case/**

*Association of PTPN22 C1858T polymorphism with* SLE *susceptibility.*


#### **Table 8.**

*Association of PTPN22 C1858T polymorphism with* AITD *susceptibility.*


*# Genome-wide association study.*

#### **Table 9.**

*Association of PTPN22 C1858T polymorphism with* Graves' disease *susceptibility.*


**Population Case/controls Genotype/allele/**

*DOI: http://dx.doi.org/10.5772/intechopen.90836*

International children

*\**

*Meta-analysis.*

**Table 11.**

**polymorphism**

257 C1858T Associated with

**Genotype/allele/ polymorphism**

1120/716 C1858T Susceptible [217]

French 659/504 T-allele Susceptible [216]

Caucasian 3422/3638 C1858T Susceptible [214] Mixed\* 4367/4771 C1858T Susceptible [107]

Mixed\* 6 studies C1858T Susceptible [107] Mixed\* 19,495/25,341 C1858T Susceptible [204]

Mixed\* 11 studies T-allele Susceptible in European [206] Mixed\* 16,240/17,997 C1858T Susceptible [207] Mixed\* 8869/20,829 C1858T Susceptible [208] Mixed\* 10 studies C1858T Susceptible [209] Indian 145/210 T-allele Susceptible [210] Indian 129/109 C1858T No association [180] Greek 130/135 C1858T No association [179]

Mixed\* 22,485/35,292 C1858T Susceptible in

*Association of PTPN22 C1858T polymorphism with* T1DM *susceptibility.*

**controls**

French 121/103 C1858T No

Columbian 101/434 T-allele No

Spanish 54/55 C1858T No

*Association of PTPN22 C1858T polymorphism with* systemic sclerosis *susceptibility.*

**Population Case/**

Mixed White, Black,

Hispanic

*Meta-analysis.*

**Table 12.**

*\**

**89**

Iranian 99/100 C1858T Susceptible [84] Iranian 144/197 C1858T No association [181] Estonian 170/230 T-allele Susceptible [198] Italian 271/89 C1858T Susceptible [199] Spanish 316/554 T-allele Susceptible [200] Colorado 753/662 CT, TT Susceptible [201] Colombian 110/308 T-allele Susceptible [86] Colombian 197 families C1858T Susceptible [202]

*The Protein Tyrosine Phosphatase Non-Receptor Type 22 (PTPN22) Gene Polymorphism…*

**Association References**

[203]

[205]

**Association References**

[218]

[87]

[219]

association

association

association

proinsulin levels

Caucasian

#### **Table 10.**

*Association of PTPN22 C1858T polymorphism with* IBD (CD + UC) *susceptibility.*



*The Protein Tyrosine Phosphatase Non-Receptor Type 22 (PTPN22) Gene Polymorphism… DOI: http://dx.doi.org/10.5772/intechopen.90836*

#### **Table 11.**

**Population Case/controls Genotype/allele/**

3111

Spanish 1903CD, 1677UC/

*The Recent Topics in Genetic Polymorphisms*

New Zealanders

*\*Meta-analysis.*

**Table 10.**

**88**

**polymorphism**

315/4081 C1858T No association with

Tunisian 164/100 C1858T Susceptible [163] Moroccan 195/311 C1858T No association [167]

Czech 345/501 C1858T No association [169]

British 514/374 C1858T No association [172] Spanish 1113/812 C1858T No association [173]

Mixed\* 8182/13356 C1858T Susceptible to CD [164] Meta-analysis C1858T Protective to CD [2] Italian 649/256 C1858T No association [175]

**polymorphism**

Saudi 372/372 T-allele Susceptible [184] German 220/239 C1858T Susceptible [185] Egyptian 150/165 T-allele Susceptible [186] Egyptian 120/120 T-allele Susceptible [187] Kuwaiti Arabs 253/2014 T-allele Susceptible [188] Chinese 202/240 C1858T Susceptible [189] Chinese 364/719 C1858T No association [178] Brazilian 612/792 C1858T Susceptible [190] Brazilian 205/308 C1858T Susceptible [191] Polish 215/236 C1858T Susceptible [192] Polish 147/327 C1858T Susceptible [193] Russian 27/62 families C1858T Susceptible [194] Croatian 102/193 T-allele Susceptible [195] Caucasian 140/100 T-allele Susceptible [138] Caucasian 8677 C1858T Susceptible [196] Caucasian 113 C1858T Susceptible [197] Czechs 372/400 T-allele Susceptible [72] Iranian (Azeri) 160/271 T-allele Susceptible [72]

Canadian 455/190 C1858T No association with

Canadian 249/207 T-allele No association with

German 146 C1858T No association with

*Association of PTPN22 C1858T polymorphism with* IBD (CD + UC) *susceptibility.*

**Population Case/controls Genotype/allele/**

**Association Reference**

[168]

[170]

[171]

[174]

C1858T Protective to CD [165]

CD

CD

CD

CD

**Association References**

*Association of PTPN22 C1858T polymorphism with* T1DM *susceptibility.*


#### **Table 12.**

*Association of PTPN22 C1858T polymorphism with* systemic sclerosis *susceptibility.*


*# Genome-wide association study.*

#### **Table 13.**

*Association of PTPN22 C1858T polymorphism with* myasthenia gravis *susceptibility.*


#### **Table 14.**

*Association of PTPN22 (C1858T) polymorphism with* Behcet's disease *susceptibility.*


**4. Vitiligo**

*Meta-analysis.*

**Table 18.**

*\**

**91**

other autoimmune diseases [18–20].

**Population Case/**

(ANCA)-associated vasculitis *susceptibility.*

*DOI: http://dx.doi.org/10.5772/intechopen.90836*

European 1651/

Spanish, German, Norwegian

**Table 17.**

*\**

*Meta-analysis.*

**Table 16.**

**Controls**

15,306

*Association of PTPN22 C1858T polymorphism with* giant cell arteritis *susceptibility.*

*Association of PTPN22 C1858T polymorphism with* Addison's disease *susceptibility.*

Spanish 95/229 C1858T No

*Association of PTPN22 C1858T polymorphism with* antineutrophil cytoplasmic antibody

Australian 209/455 T-allele Susceptible [267]

**Population Case/controls Genotype/allele/polymorphism Association References** Norwegian 332/990 T-allele Susceptible [269] UK and Polish 338/665 T-allele Susceptible [270] English 104/429 C1858T Susceptible [151] Mixed\* 6 studies T-allele Susceptible [2] German 121/239 C1858T No association [185] Mixed\* 2 studies C1858T No association [107]

**Genotype/allele/ polymorphism**

**Population Case/controls Genotype/allele/polymorphism Association References** Mixed\* 1399/9934 C1858T Susceptible in White [262] Mixed\* 1922/11,505 C1858T Susceptible [76]

*The Protein Tyrosine Phosphatase Non-Receptor Type 22 (PTPN22) Gene Polymorphism…*

911/8136 C1858T Susceptible [265]

**Association References**

[263]

association

C1858T Susceptible [266]

Vitiligo is an acquired, autoimmune skin disorder characterized by melanocyte loss resulting into progressive depigmentation of the skin and hair [15, 16]. The prevalence of vitiligo varies considerably with ethnicity and it affects 0.1–2% of the population worldwide [15, 17]. Vitiligo is associated with an elevated risk of several

Vitiligo commonly shows familial aggregation and multifactorial mode of inheritance. It is a polygenic disease, and several genes related to autoimmunity have

Various published reports on PTPN22 C1858T polymorphism support the association of the T-allele and vitiligo susceptibility in different ethnic populations (**Table 1**). However, available literature on the PTPN22 C1858T polymorphism and

been reported to be associated with the pathogenesis of vitiligo [20–25].

#### **Table 15.**

*Association of PTPN22 C1858T polymorphism with* endometriosis *susceptibility.*


*The Protein Tyrosine Phosphatase Non-Receptor Type 22 (PTPN22) Gene Polymorphism… DOI: http://dx.doi.org/10.5772/intechopen.90836*


#### **Table 16.**

**Population Case/controls Genotype/allele/polymorphism Association References** Swedish 409/1557 C1858T Susceptible [228] German 125/301 C1858T Susceptible [229] European 649/ C1858T Susceptible [230] Mixed\* 2802/3730 C1858T Susceptible [221] Hungarian, German 282/379 T-allele Susceptible [231] French 470/296 C1858T Susceptible [232] European# 532/2128 C1858T Susceptible [235] Chinese 79/50 C1858T No association [2] Turkish 416/293 C1858T No association [234] Italian 356/439 C1858T No association [233]

*Association of PTPN22 C1858T polymorphism with* myasthenia gravis *susceptibility.*

*Association of PTPN22 (C1858T) polymorphism with* Behcet's disease *susceptibility.*

*Association of PTPN22 C1858T polymorphism with* endometriosis *susceptibility.*

**Population Case/controls Genotype/allele/polymorphism Association References** Spanish 404/1517 C1858T No association [243] Turkish 134/177 C1858T No association [242] UK and Middle East 270/203 C1858T Protective [241] Mixed\* 1922/11,505 C1858T No association [76]

**Population Case/controls Genotype/allele/polymorphism Association Reference** Italian 132/232 C1858T Susceptible [252] Italian 132/359 T-allele Susceptible [253] Italian 130/250 C1858T Susceptible [254] Brazilian 140/180 C1858T Susceptible [255] Mixed\* 971/1181 T-allele Susceptible [246] Polish 171/310 C1858T No association [248]

**Population Case/controls Genotype/allele/polymorphism Association References** German 199/399 T-allele Susceptible [259] British 641/9115 C1858T Susceptible [260] Italian 344/945 C1858T Susceptible [261]

*\**

*#*

*\**

*\**

**90**

*Meta-analysis.*

**Table 15.**

*Meta-analysis.*

**Table 14.**

*Meta-analysis.*

**Table 13.**

*Genome-wide association study.*

*The Recent Topics in Genetic Polymorphisms*

*Association of PTPN22 C1858T polymorphism with* antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis *susceptibility.*


#### **Table 17.**

*Association of PTPN22 C1858T polymorphism with* giant cell arteritis *susceptibility.*


#### **Table 18.**

*Association of PTPN22 C1858T polymorphism with* Addison's disease *susceptibility.*
