**11. Autoimmune thyroid disease**

Autoimmune thyroid disease (AITD) is a complex disease which includes GD and Hashimoto's thyroiditis (HT). Its susceptibility is influenced by both genetic and environmental factors. The interaction of specific susceptibility genes and environmental exposures have been associated with AITD [135]. Both GD and HT are characterized by the production of thyroid autoantibodies and the invasion of thyroid lymphocytes. AITD is found in 5% of the general population and is one of the most prevalent autoimmune diseases. The incidence of GD and HT is influenced by genetic factors as well as environmental factors including geographical locations [136]. Approximately 37% of families with AITD exhibit either of these two disorders [137].

Previous molecular studies on genetic etiology of AITD have expanded the field of thyroid autoimmunity. Previous studies have shown that PTPT22 C1858T is associated with AITD [138, 139] (**Table 8**). Some reports have indicated a positive correlation [140–142], while others have indicated no correlation between PTPN22 C1858T and AITD in Japanese [143, 144], Korean [145], Jordanian, [146], and Polish populations [147].

PTPN22 C1858T polymorphism has been associated with GD (**Table 9**). It is susceptible to GD in Latin-American [148], Polish [149, 150], and English Caucasian populations [140, 151, 152]. Two separate meta-analyses confirmed the association of PTPN22 + 1858C/T polymorphism with Graves' disease [2, 139]. However, some reports have indicated no correlation between PTPN22 + 1858C/T and Graves' disease in Chinese Han, Polish, and Indian Kashmiri populations [153–155].

Jacobson et al. [156] reported that the PTPN22 + 1858C/T is related to the occurrence of HT. Another variant in PTPN22 gene has been found to be associated

non-HLA genetic variants also play a role in JIA susceptibility and have increasingly been identified by genome-wide and candidate gene studies [68, 69]. Many of the

Immunochip consortium, and several novel loci have also been identified showing a

Several reports indicate that PTPN22 C1858T polymorphism has been consistently associated with JIA (**Table 5**). PTPN22 C1858T polymorphism is associated with JIA in Australians [70, 71], Americans of European ancestry [67], Czech [72], Europeans [69], Greek [73], Norwegians [74], UK population [65], and Egyptians [75]. Two separate meta-analyses also indicated that PTPN22 C1858T is associated with susceptibility to JIA [76, 77]. However, it is not associated with JIA in Finish and Hungarian patients [78, 79]. These variations may be due to ethnic variations;

RA is a chronic autoimmune disorder of bone joints caused by the complex interplay between several factors like body physiology and the environment with genetic background [80, 81]. RA is characterized by synovial inflammation, hyperplasia, cartilage and bone destruction, autoantibody production (rheumatoid factor), anticyclic citrullinated peptide (CCP), and the decreased quality of life [82]. Its prevalence is approximately 0.51% worldwide and afflicts people of all races. RA shares a number of pathogenic mechanisms with other autoimmune disorders. More than 100 loci have been associated with RA as shown in a meta-analysis of GWAS. Out of these majority (97%) are located in the noncoding region, and the remaining 3% are in various non-HLA genes including PTPN22 (Trp620Arg) [83]. Several studies have been performed on the association of PTPN22 C1858T variants with RA susceptibility in different ethnic populations (**Table 6**). Various studies have demonstrated that allelic heterogeneity distribution has an increasing north-south gradient in the frequencies of the 1858T alleles in different European populations [84]. PTPN22 C1858T polymorphism has been associated with susceptibility to RA in Algerian [85], Colombian [86, 87], Egyptian [88–90], Iranian [84, 91], Italian [92], Mexican [93–95], Spanish [96], Turkish [97], and UK Cauca-

On the other hand, some studies reported that it is not associated with RA in Chinese [98, 99], Egyptian [100], and Iranian populations [101]. A number of meta-analyses have also shown that T-allele of PTPN22 C1858T is associated with RA susceptibility in Caucasians but not in Asians and Africans (**Table 6**) [102–104]. The different allele frequency of T-allele is very important in determining the population attributable risk of this allele for the autoimmune diseases in different populations. It also affects any suggested screening or predictive testing protocol for these diseases [101]. The absence of this association in Asians undermines the importance of this locus as a susceptibility locus for the RA and other autoimmune

SLE is a heterogeneous autoimmune inflammatory disease characterized by loss of self-tolerance with hyperactivation of autoreactive T and B cells with a predominance of Th2 inflammatory response [109]. The SLE incidence rate varies from 1 to 10 per 100,000 person/years, and the prevalence varies from 20 to 70 per 100,000

genetic associations have been confirmed recently by the International JIA

however, methodological error in genotyping cannot be ruled out.

genome-wide association.

*The Recent Topics in Genetic Polymorphisms*

**9. Rheumatoid arthritis**

sian populations [65].

**10. Systemic lupus erythematosus**

diseases.

**94**

with HT using whole-exome sequencing [157] indicating the role of *PTPN22* in autoimmune thyroid disease. However, the functional mechanism involved in the association remains to be found out.

to rise to 592 million by 2035 [176]. Most people with diabetes live in low- and middle-income countries, where rapid changes in lifestyle have increased the prevalence of diabetes, cardiovascular diseases, and cancer, and these countries are expected to experience the greatest increase in cases of diabetes in the next 20 years. The global prevalence of diabetes was reported as 8.8% of the world's population (95% confidence interval 7.2–11.3%) in 2017, and it is expected to increase to 9.9% in 2045 [177]. At present in every seventh second, someone dies from diabetes or its complications. Fifty percent of these deaths are under the age of 60 years. According to a report, 424.9 million people were having diabetes worldwide in 2017 which is expected to increase to 628.6 million people in 2045. The prevalence of diabetes is continuously increasing since the IDF Diabetes Atlas first was launched in 2000, and about 50% of the diabetes cases remain undiagnosed espe-

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

A positive association between PTPN22 C1858 T polymorphism and susceptibility to the development of T1DM has been reported in a large number of studies from several populations (**Table 11**) with the exception of a few such as a single study from Chinese [178], Greek [179], Indian [180], and Iranian populations [181]

The review by Prezioso et al. [182] evaluated the role of the PTPN22 C1858 T in the prognosis of disease. On the basis of the potential role of C1858 T as a target for tertiary prevention trials and new therapeutic strategies, such as the Lyp inhibitors, they suggested that PTPN22 can be a promising target for therapeutic interventions and identification of at-risk subjects in autoimmune diseases such as T1DM.

It has been shown that several SNPs could potentially contribute to susceptibility to various autoimmune disorders including T1DM. However, 1858C/T SNP is the most stable, where T-allele correlates with T1DM (**Table 11**) [7, 142, 152, 183]. Habib et al. [211] demonstrate a role of PTPN22 1858T in signaling defects in both transitional and naïve B cells in healthy subjects resulting in an increased resistance to BCRdriven apoptosis in these cells and peripheral reservoir of autoreactive cells [212].

SSc is a complex disease with an autoimmune origin in which extensive fibrosis, vascular alterations, and autoantibodies against various cellular antigens are among the principal features [213]. Although the etiopathogenesis is not yet well understood, the results of numerous genetic association studies support genetic contribu-

SSc occurs in persons who are genetically predisposed and have faced specific

In spite of these findings, the complete genetic background of SSc, the nature of its genetic determinants, and how they contribute to SSc susceptibility and clinical manifestations are poorly understood. Interestingly, PTPN22 has emerged as an important genetic risk factor for human autoimmunity. The PTPN22 C1858T polymorphism in SSc has also been investigated and shows a trend of association (**Table 12**). It has been associated with SSc susceptibility in French [216], Caucasian [214], and White, Black, and Hispanic American [217]. A meta-analysis showed that PTPN22 1858T is susceptible to SSc [107]. Some other report shows the absence of any association between this polymorphism and SSc in French [218], Columbian

environmental factors with or without other randomly distributed factors [214, 215]. It has been consistently associated with the major histocompatibility complex variants. Non-HLA genes associated with immunity have also been associ-

cially in developing countries which is a matter of concern [177].

where no association was found.

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

**14. Systemic sclerosis**

tions as an important factor to SSc.

ated with SSc susceptibility [214].

[87], and Spanish [219].

**97**
