Elsevier

Human Immunology

Volume 66, Issue 1, January 2005, Pages 60-64
Human Immunology

Association of the single nucleotide polymorphism C1858T of the PTPN22 gene with type 1 diabetes

https://doi.org/10.1016/j.humimm.2004.09.016Get rights and content

Abstract

The PTPN22 (protein tyrosine phosphatase N22) gene encodes the protein tyrosine phosphatase Lyp. One function of Lyp is downregulation of T-cell signaling through its interaction with the negative regulatory kinase C-terminal Src tyrosine kinase (Csk). A single nucleotide polymorphism in the PTPN22 gene, C1858T, encodes products with different Csk binding affinities. Disease association of the PTPN22 1858T allele has been reported in case-control studies of three different autoimmune disorders: type 1 diabetes (T1D), rheumatoid arthritis, and systemic lupus erythematosus. In this study, a set of 341 white, multiplex T1D families were genotyped for the C1858T single nucleotide polymorphism of PTPN22, and transmission disequilibrium test analysis revealed significant association (p = 0.005) of the T allele with T1D. No effects of parent of origin, sex of patient, or human leukocyte antigen genotype (high-risk human leukocyte antigen DR3/DR4 vs non-DR3/DR4) were observed. However, transmission of the T allele was significantly increased in the subset of patients who also carried at least one copy of the TCF7 883A allele, another allele that is important in regulating T-cell responses and that is associated with T1D. These results are consistent with the hypothesis that individuals lacking the C allele of PTPN22 may have reduced capacity to downregulate T-cell responses and may therefore be more susceptible to autoimmunity.

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.

References (19)

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