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

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.