Genetic Association of PTPN22 Polymorphisms with Autoimmune Hepatitis and Primary Biliary Cholangitis in Japan.

Takeji Umemura,Eiji Tanaka,Yoshihiko Katsuyama,Masao Ota,Satoru Joshita,Michiharu Komatsu,Tomoo Yamazaki,Kaname Yoshizawa

doi:10.1038/srep29770

Abstract

Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) are liver-specific autoimmune conditions that are characterized by chronic hepatic damage and often lead to cirrhosis and hepatic failure. Specifically, the protein tyrosine phosphatase N22 (PTPN22) gene encodes the lymphoid protein tyrosine phosphatase, which acts as a negative regulator of T-cell receptor signaling. A missense single nucleotide polymorphism (SNP) (rs2476601) in PTPN22 has been linked to numerous autoimmune diseases in Caucasians. In the present series, nine SNPs in the PTPN22 gene were analyzed in 166 patients with AIH, 262 patients with PBC, and 322 healthy controls in the Japanese population using TaqMan assays. Although the functional rs3996649 and rs2476601 were non-polymorphic in all subject groups, the frequencies of the minor alleles at rs1217412, rs1217388, rs1217407, and rs2488458 were significantly decreased in AIH patients as compared with controls (all Pc < 0.05). There were no significant relationships with PTPN22 SNPs in PBC patients. Interestingly, the AAGTCCC haplotype was significantly associated with resistance to both AIH (odds ratio [OR] = 0.58, P = 0.0067) and PBC (OR = 0.58, P = 0.0048). SNPs in the PTPN22 gene may therefore play key roles in the genetic resistance to autoimmune liver disease in the Japanese.

Highlights

The protein tyrosine phosphatase N22 gene (PTPN22) located on chromosome 1p13.3-13.1 encodes a lymphoid-specific protein tyrosine phosphatase (Lyp) that is important in the negative control of T-cell activation and in T-cell development
In recent studies on the PTPN22 gene, the rs2476601 missense substitution single nucleotide polymorphism (SNP) has been associated with multiple autoimmune diseases in Caucasians, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Graves’ disease, and Addison’s disease. rs2476601 was proposed to be functionally involved in interactions between Lyp and Csk kinase[13,14,27]
Another functional SNP that is located in the catalytic domain of Lyp, rs33996649, leads to reduced phosphatase activity and has been highlighted as an important genetic risk factor for RA and SLE26

Summary

Introduction

The protein tyrosine phosphatase N22 gene (PTPN22) located on chromosome 1p13.3-13.1 encodes a lymphoid-specific protein tyrosine phosphatase (Lyp) that is important in the negative control of T-cell activation and in T-cell development. A missense single nucleotide polymorphism (SNP) known as rs2476601 in PTPN22 has been consistently associated with a variety of autoimmune diseases in populations of European ancestry, including rheumatoid arthritis (RA), type I diabetes, and systemic lupus erythematosus (SLE)[14,15,16,17,18], but this functional SNP was non-polymorphic and no relationships were found in studies from Japan[19,20,21,22]. Two SNPs, rs2488457 in the promoter region of PTPN22 and rs1217412 in the 3′-untranslated region, have been linked to the onset of acute type 1 diabetes in Japanese and Korean populations[18], and another amino acid substitution, rs33996649 within the catalytic domain of the enzyme, was related to the development www.nature.com/scientificreports/. We hypothesized that PTPN22 SNPs may be associated with autoimmune liver disease and investigated for relationships between PTPN22 SNPs and AIH or PBC in Japanese patients

Methods

Results

Conclusion