Replication of an Association Between the Lymphoid Tyrosine Phosphatase Locus (LYP/PTPN22) With Type 1 Diabetes, and Evidence for Its Role as a General Autoimmunity Locus

  1. Deborah Smyth1,
  2. Jason D. Cooper1,
  3. Joanne E. Collins2,
  4. Joanne M. Heward2,
  5. Jayne A. Franklyn2,
  6. Joanna M.M. Howson1,
  7. Adrian Vella1,
  8. Sarah Nutland1,
  9. Helen E. Rance1,
  10. Lisa Maier1,
  11. Bryan J. Barratt3,
  12. Cristian Guja4,
  13. Constantin Ionescu-Tı̂rgovişte4,
  14. David A. Savage5,
  15. David B. Dunger6,
  16. Barry Widmer6,
  17. David P. Strachan7,
  18. Susan M. Ring8,
  19. Neil Walker1,
  20. David G. Clayton1,
  21. Rebecca C.J. Twells1,
  22. Stephen C.L. Gough2 and
  23. John A. Todd1
  1. 1Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust (WT) Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge, U.K
  2. 2Division of Medical Sciences, University of Birmingham, Birmingham, U.K
  3. 3AstraZeneca, Macclesfield, U.K
  4. 4Clinic of Diabetes, Institute of Diabetes, Nutrition and Metabolic Diseases “N. Paulescu,” Bucharest, Romania
  5. 5Department of Medical Genetics, Queen’s University Belfast, Belfast City Hospital, Belfast, Northern Ireland
  6. 6Department of Paediatrics, Addenbrooke’s Hospital, University of Cambridge, Cambridge, U.K
  7. 7Department of Public Health Sciences, St. George’s Hospital Medical School, London, U.K
  8. 8Avon Longitudinal Study of Parents and Children (ALSPAC), University of Bristol, Bristol, U.K
  1. Address correspondence and reprint requests to Professor John A. Todd, Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust (WT) Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge, U.K. E-mail: john.todd{at}cimr.cam.ac.uk

Abstract

In the genetic analysis of common, multifactorial diseases, such as type 1 diabetes, true positive irrefutable linkage and association results have been rare to date. Recently, it has been reported that a single nucleotide polymorphism (SNP), 1858C>T, in the gene PTPN22, encoding Arg620Trp in the lymphoid protein tyrosine phosphatase (LYP), which has been shown to be a negative regulator of T-cell activation, is associated with an increased risk of type 1 diabetes. Here, we have replicated these findings in 1,388 type 1 diabetic families and in a collection of 1,599 case and 1,718 control subjects, confirming the association of the PTPN22 locus with type 1 diabetes (family-based relative risk (RR) 1.67 [95% CI 1.46–1.91], and case-control odds ratio (OR) 1.78 [95% CI 1.54–2.06]; overall P = 6.02 × 10−27). We also report evidence for an association of Trp620 with another autoimmune disorder, Graves’ disease, in 1,734 case and control subjects (P = 6.24 × 10−4; OR 1.43 [95% CI 1.17–1.76]). Taken together, these results indicate a more general association of the PTPN22 locus with autoimmune disease.

Footnotes

  • D.S. and J.D.C. contributed equally to this work.

    • Accepted August 17, 2004.
    • Received June 4, 2004.
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  1. doi: 10.2337/diabetes.53.11.3020 Diabetes November 2004 vol. 53 no. 11 3020-3023
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