A C/T single-nucleotide polymorphism in the region of the CD40 gene is associated with Graves' disease.

Graves' disease (GD) develops as a result of an interaction between susceptibility genes and environmental factors. We have previously mapped a susceptibility locus for GD on chromosome 20q11 (GD-2), which has recently been independently replicated. Among the genes mapped to 20q11 was the CD40 gene, an important costimulatory molecule and a good positional candidate gene for GD. We investigated whether the CD40 gene was the GD susceptibility gene on 20q11. Linkage analysis in a subset of Caucasian families showed a maximum multipoint logarithm of odds (LOD) score of 3.3 at the CD40 locus. We then sequenced all 9 exons of the CD40 gene in 8 probands and 10 controls and identified a new C/T single-nucleotide polymorphism (SNP) in the Kozak sequence of the CD40 gene at position -1. Case control association analysis of the CD40 C/T(-1) SNP in 154 Caucasian patients with GD and 118 Caucasian controls showed an association between the CC genotype and GD (p = 0.048, relative risk [RR] = 1.6). Furthermore, the association was stronger when only the probands from the linked families (n = 20) were used (p = 0.009, RR = 4.8). Transmission disequilibrium test (TDT) analysis also showed preferential transmission of the C allele of the CD40 C/T(-1) SNP to affected individuals (p = 0.02). In conclusion, our results suggested that the CD40 gene was a new susceptibility gene for GD within certain families because it was both linked and associated with GD.