CTLA‐4 promoter variants in patients with Graves' disease and Hashimoto's thyroiditis

Abstract

Graves' disease (GD) and Hashimoto's thyroiditis (HT) are T‐cell mediated organ‐specific autoimmune disorders with a genetic predisposition. The cytotoxic T‐lymphocyte antigen 4 (CTLA‐4) molecule is the predominant receptor for B7 on activated T cells and represents a negative regulator for T‐cell function. Since the CTLA‐4‐guanine at position 49 of exon 1 is associated with susceptibility to GD as well as to HT and IDDM, we investigated a recently detected cytosine/thymine substitution at position ‐318 within the CTLA‐4 promoter region in patients with GD and HT. 125 patients with GD were significantly more often homozygous for cytosine (86% vs. 73% in controls, P=0.006) and less frequently heterozygous for cytosine and thymine (14% vs. 27%, P=0.008). In 64 patients with HT, the distribution was similar but not significant (81% homozygous for cytosine and 16% heterozygous). When correlating the promoter and the exon 1 polymorphism we found the strongest linkage between thymine (promoter) and adenine (exon 1). In conclusion, a promoter variant of the CTLA‐4 gene represents an additional risk marker for GD and HT, but their predisposition is linked to the exon 1 alleles.