CTLA-4 PROMOTER VARIANTS IN PATIENTS WITH GRAVES-DISEASE AND HASHIMOTOS-THYROIDITIS

Graves' disease (GD) and Hashimoto's thyroiditis (HT) are T-cell media ted organ-specific autoimmune disorders with a genetic predisposition, The cytotoxic T-lymphocyte antigen 4 (CTLA-4) molecule is the predomi nant receptor for B7 on activated T cells and represents a negative re gulator for T-cell function. Since the CTLA-4-guanine at position 49 o f exon 1 is associated with susceptibility to GD as well as to HT and IDDM, we investigated a recently detected cytosine/thymine substitutio n at position -318 within the CTLA-4 promoter region in patients with GD and HT. 125 patients with GD were significantly more often homozygo us 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 p atients with HT, the distribution was similar but not significant (81% homozygous for cytosine and 16% heterozygous). When correlating the p romoter and the exon 1 polymorphism we found the strongest linkage bet ween thy-mine (promoter) and adenine (exon 1). In conclusion, a promot er 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.