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To study interactions between the two most widely confirmed Graves' disease (GD) loci: HLA-DRB1 and CTLA-4. HLA-DRB1*03 (risk allele) and DRB1*07 (protective allele) were analyzed in this aspect, the linked TNF G(-308)A polymorphism was also considered.A case-control study of 429 patients with GD compared to 308 healthy subjects. The impact of genes and their interactions were analyzed by stepwise logistic regression.The independent effects of DRB1*03 and DRB1*07 were confirmed in our study both by stratification studies and logistic regression. CTLA-4 did not appear to be associated with GD when the interactions with other genes were considered. By logistic regression we observed a significant interaction between DRB1*07 and CTLA-4 and revealed that CTLA-4 49G attenuated the DRB1*07-related protection, the effect noticed also in three-way stratification studies. We confirmed that the TNF G(-308)A polymorphism is only a marker of the DRB1 status.Our results stress the importance of complex gene interactions in the multigene predisposition to GD. The interactions between two predisposing loci, DRB1 and CTLA-4, are exerted rather by DRB1*07 than DRB1*03 allele: CTLA-4 acts via switching off the protective DRB1*07 influence, whereas the effect of DRB1*03 is independent.

Recently, a functional polymorphism in the CD40 gene at position -1, C to T change (C-1T) has been identified and the C/C genotype has been reported to be associated with Graves' disease (GD).We performed a case-control, replication study on 556 patients with GD and 611 healthy subjects in a Polish population. Furthermore, we analyzed the distribution of CD40 genotypes in subgroups of patients with GD divided according to age of onset, gender, family history, tobacco smoking, ophthalmopathy, and genetic parameters (CTLA4 49G, PTPN22/LYP 1858T or HLA-DRB1*03 alleles).Although the frequency of C/C genotype was increased in GD compared to controls, the difference was not significant (60.5% versus 55.8%, p = 0.062, odds ratio [OR] = 1.21, 95% confidence interval [CI]: 0.96-1.53). Because our study was underpowered to detect such a modest association, we performed a meta-analysis with the data from previous studies. The combined OR for the C/C genotype as a risk factor for GD was 1.22 (95% CI: 1.08-1.38, p = 0.001). We failed to find an interaction between CD40 genotypes and other GD susceptibility alleles. No significant genotype-phenotype associations were found.Our results support the notion that CD40 C-1T polymorphism has a modest effect on genetic susceptibility to sporadic GD.