Lymphoid tyrosine phosphatase (PTPN22/LYP) variant and Graves' disease in a Polish population: association and gene dose-dependent correlation with age of onset.

Objective: Susceptibility to Graves' disease (GD) is to a significant extent determined by genetic factors of which the best known are those associated with the HLA and the CTLA4 locus. Recently, two studies on British Caucasians reported that a single nucleotide polymorphism, 1858 C > T in PTPN22, encoding Arg620Trp in the lymphoid protein tyrosine phosphatase (LYP), which is a negative regulator of T-cell activation, increases the risk of GD. The purpose of our study was to investigate whether the PTPN22 'T' allele is associated with GD and/or its subsets, defined by clinical or genetic parameters, in a Polish population.

Subjects And Design: A cohort of 290 patients and 310 controls was genotyped using a PCR-RFLP method. The distribution of PTPN22 alleles and genotypes among patients and controls was compared, and correlation was sought between PTPN22 'T' and sex, tobacco smoking status, family history of GD, age of disease onset, presence (and severity) of ophthalmopathy, and presence of the CTLA4 A49G or DRB1*03 alleles.

Results: Association between GD and the PTPN22 'T' allele was confirmed (OR 1.7, P < 0.0008). Furthermore, a significant correlation between the PTPN22 genotype and the age of GD onset was demonstrated (r = -0.18, P = 0.0019). The PTPN22 'TT' and 'CC' genotypes defined groups characterized by more than twofold difference in median age of disease onset (20.8 years vs. 42 years, P < 0.003) whereas the 'CT' genotype was associated with an intermediate value (35 years). There were no statistically significant correlations with other analysed clinical or genetic parameters.

Conclusions: We replicated the association between Graves' disease and PTPN22 'T' reported in British Caucasians. We also found a gene dose-dependent effect of PTPN22 'T' on the age of onset of Graves' disease.