Association of the single nucleotide polymorphism C1858T of the PTPN22 gene with type 1 diabetes
Introduction
Insulin-dependent type 1 diabetes mellitus (T1D), an autoimmune disease, is characterized by the destruction of insulin-producing pancreatic β-cells by cytotoxic T cells. Although both genetic and environmental factors appear to be associated with the development of the disease, a clear genetic susceptibility to T1D has been established in the human leukocyte antigen (HLA) region of chromosome 6 (see, e.g., [1]). In addition to the HLA region, other genetic susceptibility regions have been identified by whole-genome screens on large numbers of affected sib pairs [2, 3]. Recently, single nucleotide polymorphisms (SNPs) in several genes have manifested an association with T1D, thus expanding the repertoire of genetic factors that influence its development. Reinforcing the fact that T1D is an autoimmune disease, SNPs in genes involved in the T-cell–mediated immune response have been demonstrated to be associated with its development (e.g.,TCF7, CTLA4, IL6) [4, 5, 6].
The PTPN22 (protein tyrosine phosphatase N22) gene maps to chromosome 1p13.3–p13.1 and encodes a lymphoid-specific phosphatase known as Lyp. Lyp dephosphorylates the kinases Lck, Fyn, and ZAP-70, all known to be important in T-cell signaling. An additional function of Lyp is to downregulate activation of T cells by binding to C-terminal Src tyrosine kinase (Csk). Csk is an important suppressor of kinases that mediate T-cell activation [7]. In addition, Lyp has been demonstrated to bind to the adaptor molecule Grb2 (growth factor receptor-bound protein 2), and this interaction is thought to play a negative regulatory role in T-cell signaling [8]. Recently, an allelic variation of the PTPN22 gene, C1858T, was revealed to be associated with T1D in a non-Hispanic, white population from North America and an Italian population [9]. The infrequent 1858T allele changes the amino acid at position 620 from an arginine (R) to a tryptophan (W), disrupting the proline-rich binding motif PxxPxR that is important for Lyp binding to both Csk and Grb2 [8, 9, 10]. The 1858T allele has also been reported to be associated with both rheumatoid arthritis and systemic lupus erythematosis [10, 11]. In the present study, we genotyped the PTPN22 C1858T SNP in 341 families with at least two siblings affected with T1D. This set includes 282 families previously genotyped for all HLA loci.
Section snippets
Subjects
Data were collected from genomic DNA from 1711 individuals from 341 families in the Human Biological Data Interchange (HBDI) repository (Philadelphia, PA). The HBDI was established, in part, for the discovery of T1D susceptibility loci. Samples from the HBDI repository are commercially available to approved researchers. All families had at least two children with T1D. Twenty-two families had one additional affected child, one family had two additional affected children, and one family had three
Results
The allele frequencies for the C1858T SNP in the parents were 0.873 for the C allele and 0.127 for the T allele. Although the parents do not represent an unbiased control group, these observed frequencies agree closely with those observed by Bottini et al. [9] for 395 North American white healthy controls [f(C) = 0.884, f(T) = 0.116]. The two alleles were in Hardy-Weinberg’s equilibrium in the parents. Allele frequency for the T allele was slightly higher in the affected sibs [f(T) = 0.142].
Discussion
The PTPN22 gene product Lyp is an important downregulator of T-cell activation, in part through its physical interaction with Csk and probably through its interaction with the adaptor molecule Grb2 [8, 19]. Csk, when bound to Lyp, suppresses the kinases Lck and Fyn, which mediate T-cell signaling. The binding of Lyp to Csk is dramatically reduced when the Lyp protein has Trp at amino acid residue 620 (allele 1858T) rather than Arg (allele 1858C), as demonstrated by coimmunoprecipitation
Acknowledgments
We thank Eunji Cho for excellent technical assistance. This work was supported by NIH grant DK61722 to J.A.N. and by a generous donation from the W.G. Green family.
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