No evidence for association of PTPN22 R620W functional variant C1858T with type 1 diabetes in Asian Indians

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Dear Editor, Type 1 diabetes (T1D) is a typical organ specific autoimmune disease with an annual incidence of 10.5/100,000 in Asian Indians [1]. It is characterized by T cell-mediated destruction of pancreatic beta cells influenced by multiple genetic factors, such as HLA-II locus on chromosome 6p21.3 [2], insulin gene on 11p15.5 [3] and the CTLA4 locus on 2q33 [4], all of these are involved in T cell activation, immune homeostasis and development of T cell receptor (TCR)-repertoire. Recently, we have shown a significant association of CTLA4 – 318, 1661 and tumour necrosis factor (TNF)-α -308 promoter polymorphism with T1D in Asian Indians [5, 6]. Another important gene currently under intense investigation is PTPN22 on chromosome 1p13.3–13.1, which encodes lymphoid-specific phosphatase (LYP), a protein of tyrosine phosphatase family. LYP is involved in the negative regulation of T cell signalling by interacting with C-terminal Src tyrosine kinases (Csk), Lck and Fyn [7]. A nonsynonymous single nuclestide polymorphism (SNP) at nucleotide 1858 in codon 620 of this gene results in amino acid substitution (Arg620Trp). It was hypothesized that 620Trp decreases the affinity of LYP to Csk. The C1858T SNP in the PTPN22 gene was found to be associated with several autoimmune disorders, including T1D in Caucasians [8-10]. In a recent survey and meta-analysis of T allele and T/T genotype, it was suggested that the PTPN22 C1858T SNP confers susceptibility to T1D and other subgroup of autoimmune diseases [11]. The PTPN22 R620W disease-associated variant was validated as a gain-of-function variant, with increased catalytic activity compared with the non-associated variant [12], in different ethnic groups of T1D patients [9, 10, 12]. However, there are no reports on its association with T1D in Asian Indians. We performed PCR-RFLP analysis to genotype PTPN22 R620W C1858T variant in 129 T1D patients and 109 age, sex and ethnicity matched normal individuals. The mean age at onset of the disease was 15.4±6.6 years, and sex (male: female) ratio was 78:51. The mean body mass index (BMI) of patients was 19.0±3.0 kg/m2, and HbA1c at the time of study was 9.0±2.5. All patients required insulin for glycaemic control, and 58% of them had ketosis at presentation. The local institutional ethics committee approved the study protocol, and written informed consent was obtained from the study subjects. Statistical analysis (chi-square test) was performed using EPI INFO version 6.04d (CDC, Atlanta, GA, USA). The frequency of wild type homozygous C/C genotype and C allele was higher (>95%), and the mutant C/T genotype and T allele was rare (<5%), but almost equally distributed in patients and in normal subjects. The mutant T/T genotype was very rare (0.8%) in patients, but absent in normal subjects (Table 1). With 2.75% prevalence of 1858T allele in Asian Indians, and with 129 patients and 109 controls, our study has 80% power at 95% confidence level. Thus, a larger cohort of 784 patients and 1270 controls would be required to detect the significant risk conferred by 1858T allele. However, C1858T SNP appears to be a rare variant, and seems to play no role in T1D susceptibility in Asian Indians. Similarly, C1858T SNP was not related to T1D susceptibility in other Asians such as Japanese and Koreans [13]. Moreover, −1123G>C SNP appeared to be more likely a causative variant in these populations but not in Caucasians [10]. Functionally, PTPN22 is a compelling candidate gene for T1D, as protein tyrosine phosphatases play important roles in TCR signalling. Since the polymorphism in PTPN22 gene maps to 293-kb linkage disequilibrium block [14], it seems reasonable to presume that some other potentially functional SNPs may be responsible for T1D susceptibility in Asian Indians.