PTPN22 Trp620 explains the association of chromosome 1p13 with type 1 diabetes and shows a statistical interaction with HLA class II genotypes

  1. Deborah J. Smyth,
  2. Jason D. Cooper,
  3. Joanna M. M. Howson,
  4. Neil M. Walker,
  5. Vincent Plagnol,
  6. Helen Stevens,
  7. David Clayton and
  8. John A. Todd (John.Todd{at}cimr.cam.ac.uk)
  1. 1Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK

    Abstract

    Objective: The disease association of the common 1858C>T Arg620Trp (rs2476601) nonsynonymous single nucleotide polymorphism (SNP) of protein tyrosine phosphatase; non-receptor type 22 (PTPN22) on chromosome 1p13 has been confirmed in type 1 diabetes, and also in other autoimmune diseases including rheumatoid arthritis and Graves' disease. Some studies have reported additional associated SNPs independent of rs2476601/Trp620, suggesting that it may not be the sole causal variant in the region; and that the relative risk of rs2476601/Trp620 is greater in lower risk by HLA class II genotypes than in the highest risk class II risk cateogory.

    Research design and Methods: We resequenced PTPN22, and used these and other data to provide over 150 SNPs to evaluate the association of the PTPN22 gene and its flanking chromosome region with type 1 diabetes in a minimum of 2,000 cases and 2,400 controls.

    Results: Owing to linkage disequilibrium we were unable to distinguish between rs2476601/Trp620 (P = 2.11 x10−87) and rs6679677 (P = 3.21 x10−87), an intergenic SNP between the genes PHTF1and RSBN1. None of the previously reported disease associated SNPs proved to be independent of rs2476601/Trp620. We did not detect any interaction with age-at-diagnosis or sex. However, we found rs2476601/Trp620 has a higher relative risk in type 1 diabetes cases carrying lower risk HLA class II genotypes than in those carrying higher risk ones (P =1.36 x 10−4 in a test of interaction).

    Conclusions: In our datasets there was no evidence for allelic heterogeneity at the PTPN22 locus in type 1 diabetes, indicating that the SNP rs2476601/Trp620 remains the best candidate for the sole causal variant in this chromosome region in European populations. The heterogeneity of rs2476601/Trp620 disease risk by HLA class II genotype is consistent with previous studies, and, therefore, we now have a convincing example of a non-multiplicative, gene-gene interaction involving a non-HLA gene in type 1 diabetes.

    Footnotes

      • Received August 13, 2007.
      • Accepted February 23, 2008.

    This Article

    1. Diabetes
    1. Online-Only Appendix
    2. adfcda
    3. All Versions of this Article:
      1. db07-1131v1
      2. db07-1131v2
      3. 57/6/1730 most recent