The development of Graves' disease and the CTLA-4 gene on chromosome 2q33

Case-control studies suggest that the CTLA-4 gene may be a susceptibility locus for Graves' disease. The previously reported A/G polymorphism at position 49 in exon 1 of the CTLA-4; gene was, therefore, investigated in a case-control (n = 743) and family-based (n = 179) dataset of white Caucasian subjects with Graves' disease. The relationship between CTLA-4 genotype and severity of thyroid dysfunction at diagnosis was also investigated. An increase in frequency of the G (alanine) allele was seen in Graves' patients compared with control subjects (42% vs. 31.5%, respectively; corrected P < 0.0002; odds ratio = 1.58), and a significant difference in the distribution of GG, GA, and AA genotypes was observed between the groups (chi(2) = 21.7; corrected P < 0.00003). Increased transmission of the G allele was seen from heterozygous parents to affected offspring compared to unaffected offspring (chi(2) = 5.7; P = 0.025). Circulating free T-4 concentrations at diagnosis were significantly associated with CTLA-4 genotype (P = 3.26; P = 0.04). These results support the hypothesis that CTLA-4 may play a role in regulating self-tolerance by the immune system and in the pathogenesis of autoimmune disorders such as Graves' disease.