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The Codon 620 Tryptophan Allele of the Lymphoid Tyrosine Phosphatase (LYP) Gene Is a Major Determinant of Graves’ Disease

Institute of Human Genetics (M.R.V., V.W., C.E.J., C.J.O., S.H.S.P.) and School of Clinical Medical Sciences (C.J.O., S.H., P.T.D., R.A.J., R.Q., S.G.B., P.P., S.H.S.P.), University of Newcastle, Newcastle upon Tyne, United Kingdom

Address all correspondence and requests for reprints to: Simon Pearce, Institute of Human Genetics, Central Parkway, Newcastle upon Tyne NE1 3BZ, United Kingdom. E-mail: s.h.s.pearce{at}ncl.ac.uk

Abstract

The lymphoid tyrosine phosphatase (LYP), encoded by the protein tyrosine phosphatase-22 (PTPN22) gene, is a powerful inhibitor of T cell activation. Recently, a single nucleotide polymorphism (SNP), encoding a functional arginine to tryptophan residue change at LYP codon 620 has been shown to be associated with type 1 diabetes and other autoimmune disorders. We have used a PCR-restriction fragment (XcmI) assay to examine genotypes at the codon 620 polymorphism in 549 unrelated probands with Graves’ disease, 104 unrelated subjects with autoimmune Addison’s disease and 429 controls. The T nucleotide at the SNP, encoding the tryptophan 620 residue, was present in 151 of 1098 (13.8%) Graves’ disease alleles compared to 67 of 858 (7.8%) control alleles (² = 17.2, p = 3.4 x 10^–5’ odds ratio = 1.88, 5–95% confidence intervals [CI] 1.39 to 2.55). Similarly, the T nucleotide at the codon 620 SNP was present in 26 of 208 (12.5%) Addison’s disease alleles vs 7.8% of controls (² = 4.63, p = 0.031; odds ratio = 1.69, 5–95% CI 1.04 to 2.73). These data suggest that this LYP polymorphism is a susceptibility allele for Graves’ disease with a major effect, and which is likely to have a role in many other autoimmune conditions.

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