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Association of PTPN22 Haplotypes with Graves’ Disease

Department of Medicine (J.M.H., O.J.B., J.D.C.-S., J.A.F., S.C.G.), Division of Medical Sciences, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom; and Wellcome Trust Centre for Human Genetics (J.C.B.), University of Oxford, Oxford OX3 7BN, United Kingdom

Address all correspondence and requests for reprints to: Dr. Joanne Heward, Department of Medicine, Division of Medical Sciences, Institute of Biomedical Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom. E-mail: j.m.king{at}bham.ac.uk.

Context: A recent study reported associations of a series of single nucleotide polymorphisms (SNPs) within PTPN22, including rs2476601, with rheumatoid arthritis.

Objective: Having previously reported significant association of the T allele of rs2476601 in a Graves’ disease (GD) cohort, we sought to determine whether novel rheumatoid arthritis-associated SNPs were also contributing to susceptibility to GD.

Design: Case control and family-based studies of five PTPN22 tag SNPs were performed.

Setting: An United Kingdom academic department of medicine was the setting for the study.

Patients or Other Participants: A total of 768 GD patients, 768 control subjects, and 313 families with autoimmune thyroid disease participated.

Main Outcome Measure: Tests for association with disease were the main outcome measure.

Results: No association with disease of any of the individual SNPs and no correlation between genotype and clinical phenotype were seen. However, haplotype analysis of the SNP markers with addition of rs2476601 did reveal a strong association of a haplotype containing the T allele, in both the case control (² = 29.13; P = 6.77 x 10^–8) and family data sets (² = 5.24; P = 0.02). Furthermore, a novel protective effect of a haplotype containing all six SNPs was observed (² = 17.02; P = 3.7 x 10^–5).

Conclusions: These data suggest that the association of SNPs within the PTPN22 region differs between autoimmune diseases, occurring individually and/or as part of a haplotype, indicating that the mechanisms by which PTPN22 confers susceptibility to GD may, in part, be disease specific.

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