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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

Deborah Smyth¹, Jason D. Cooper¹, Joanne E. Collins², Joanne M. Heward², Jayne A. Franklyn², Joanna M.M. Howson¹, Adrian Vella¹, Sarah Nutland¹, Helen E. Rance¹, Lisa Maier¹, Bryan J. Barratt³, Cristian Guja⁴, Constantin Ionescu-Tîrgovite⁴, David A. Savage⁵, David B. Dunger⁶, Barry Widmer⁶, David P. Strachan⁷, Susan M. Ring⁸, Neil Walker¹, David G. Clayton¹, Rebecca C.J. Twells¹, Stephen C.L. Gough², and John A. Todd¹

¹ Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust (WT) Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge, U.K
² Division of Medical Sciences, University of Birmingham, Birmingham, U.K
³ AstraZeneca, Macclesfield, U.K
⁴ Clinic of Diabetes, Institute of Diabetes, Nutrition and Metabolic Diseases "N. Paulescu," Bucharest, Romania
⁵ Department of Medical Genetics, Queen’s University Belfast, Belfast City Hospital, Belfast, Northern Ireland
⁶ Department of Paediatrics, Addenbrooke’s Hospital, University of Cambridge, Cambridge, U.K
⁷ Department of Public Health Sciences, St. George’s Hospital Medical School, London, U.K
⁸ Avon Longitudinal Study of Parents and Children (ALSPAC), University of Bristol, Bristol, U.K

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 x 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 x 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.

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