Endocrine Abstracts (2009) 19 P387

PTPN22 genotype is a determinant of age of onset of Graves' disease

MA Karamat, MJ Simmonds, PR Newby, JM Heward, JA Franklyn, SC Gough & OJ Brand


University of Birmingham, Birmingham, West Midlands, UK.


PTPN22, encodes lymphoid tyrosine phosphatise (LYP), an important inhibitor of T lymphocyte activation and has been associated with numerous autoimmune diseases including type 1 diabetes, rheumatoid arthritis, and Graves’ disease (GD). Consistent association has been reported between disease and a non-synonymous SNP +1858 C>T (rs2476601) encoding an Arginine to Tryptophan substitution at amino acid 620 of LYP. Our group was the first to show strong evidence of association at SNP +1858 with GD and also demonstrated disease specific PTPN22 haplotype effects in a cohort of 901 GD patients and 833 controls. Due to low frequency of the T allele it has not previously been possible to comprehensively investigate the +1858 SNP with specific GD sub-phenotypes. In the present study, we have now screened PTPN22+1858 in an extended case–control cohort of 2366 GD patients and 2578 matched controls. In support of our previous studies, we observed strong association of the T allele of +1858 with GD (OR=1.53), with a high degree of statistical confidence (P=1.25×10−11). We subsequently investigated clinical correlations between genotype and specific GD features, including autoantibody status, ophthalmopathy, presence of goitre, gender and age of diagnosis. The associated T allele occurred more frequently in GD patients exhibiting early onset of GD (≤30 years of age) compared to a later age of onset (>30 years of age), (P=0.011). Moreover, patients homozygous for the predisposing T allele developed disease 5 years younger at an average of 38.5 years of age compared to homozygous C patients (average age 43.53 years). No further evidence of association with any other clinical feature was identified. These results confirm our previous findings of association in the T allele of +1858 SNP with GD and for the first time have shown presence of the T allele to decrease GD age of onset.

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