Synergistic combined effect between CD40-1C > T and CTLA-4 + 6230G > A polymorphisms in Graves' disease

• The combined effect between CD40 and CTLA-4 SNPs was evaluated by crossover analysis.
• Both CD40-1C > T and CTLA-4 + 6230G > A polymorphisms were related to GD.
• CD40-1C > T and CTLA-4 + 6230G > A SNPs confer to lower risk of GD with additive effect.
• Neither single SNP nor their combined effect was associated with TRAb concentration.

The aim of this study was to investigate whether a genetic combined effect exists between CD40-1C > T and CTLA-4 + 6230G > A (CT60) polymorphisms and whether the combined effect renders susceptibility to Graves' disease (GD). We recruited 260 patients with GD and 248 healthy controls. Single nucleotide polymorphisms were genotyped by polymerase chain reaction-high resolution melting. Genetic polymorphisms related to GD were identified, levels of thyroid stimulating hormone receptor antibodies (TRAb) were measured, and genetic interactions were assessed by logistic regression analysis. Significant difference in allele and genotype frequency of CD40-1C > T polymorphism was observed between the patients and control subjects (P < 0.001, 0.002 respectively). As for CTLA-4 + 6230G > A polymorphism, significant difference was observed only in allele frequencies between the patient and control groups (P = 0.014). Moreover, a significant combined effect was presented in CD40-1C > T and CTLA-4 + 6230G > A polymorphism (P = 0.020), and all, but one, combination CC-genotype of CD40-1C > T and GG-genotype of CTLA-4 + 6230G > A polymorphism has 54% lower risk of GD development than subjects with the CC and GG genotypes (OR = 0.46, 95% CI = 0.25–0.84). In newly onset GD group, neither single SNP (CD40-1C > T or CTLA-4 + 6230G > A polymorphism) nor their combined effect was showed a significant association with TRAb concentration (all P > 0.05). Our findings suggest a possible additive combined effect between CD40-1C > T and CTLA4 + 6230G > A polymorphisms in the development of GD.