CTLA4 ALANINE-17 CONFERS GENETIC SUSCEPTIBILITY TO GRAVES-DISEASE ANDTO TYPE-1 DIABETES-MELLITUS

The genetic susceptibility to Graves' disease and type 1 (insulin-depe ndent) diabetes mellitus is conferred by genes in the human leukocyte antigen region on the short arm of chromosome 6, but several other gen es are presumed to determine disease susceptibility. Among those candi date genes is the cytotoxic T lymphocyte antigen 4 (CTLA4) located on chromosome 2q33 in man. We investigated the distribution of the CTLA4 exon 1 polymorphism (49 A/G) in Graves' disease and IDDM. This dimorph ism at codon 17 results in an amino acid exchange (Thr/Ala) in the lea der peptide of the expressed protein and was analyzed by PCR, single s trand conformation polymorphism, and restriction fragment length polym orphism analysis in 305 patients with Graves' disease, 293 patients wi th IDDM, and 325 controls. Patients with Graves' disease had significa ntly more Ala alleles than controls, both as homozygotes (21% vs. 13%) and as heterozygotes (53% vs. 46%), and less Thr as homozygotes (26% vs. 42%; P < 2 x 10(-4)). The phenotypic frequency of Ala-positive pat ients (73%) was significantly higher than of controls (58%; P = 10(-4) ; relative risk = 2). Patients with IDDM also had significantly more A la alleles as homozygotes (19%) or heterozygotes (50%; P = 0.01). In c onclusion, an alanine at codon 17 of CTLA4 is associated with genetic susceptibility to Graves' disease as well as to IDDM.