CTLA4 gene polymorphisms are associated with, and linked to, insulin-dependent diabetes mellitus in a Russian population

The Ala17 allele of the CTLA4 gene was preferentially transmitted from parents to diabetic offspring (p < 0.0001) as shown by the combined transmission/disequlibrium test (TDT) and sib TDT (S-TDT) analysis. A significant difference between diabetic and non-diabetic offspring was also observed for the transmission of alleles 17, 20, and 26 of the dinucleotide microsatellite. Allele 17 was transmitted significantly more frequently to affected offspring than to other children (p = 0.0112) whereas alleles 20 and 26 were transmitted preferentially to non-diabetic sibs (p = 0.045 and 0.00068 respectively). A nonrandom excess of the Ala17 CTLA4 molecular variant (maximum logarithm of odds score (MLS) of 3.26) and allele 17 of the dinucleotide marker (MLS = 3.14) was observed in IBD-affected sibling pairs.The CTLA4 gene is strongly associated with, and linked to IDDM in a Russian population.The cytotoxic T lymphocyte-associated antigen 4 gene (CTLA4) encodes the T cell receptor involved in the control of T cell proliferation and mediates T cell apoptosis [1]. The receptor protein is a specific T lymphocyte surface antigen that is detected on cells only after antigen presentation. Thus, CTLA4 is directly involved in both immune and autoimmune responses and may be involved in the pathogenesis of multiple T cell-mediated autoimmune disorders.The human CTLA4 gene was mapped to chromosome 2q33 [2]. It consists of three exons. The first encodes a V-like domain of 116 amino acids. An A-to-G substitution at nucleotide 49 in exon 1 results in an amino acid substitution (Thr/Ala) in the leader peptide of the protein [3]. The Ala allele has been shown to predispose the individual carrying it to the development of various immune diseases including Graves' disease [3,4], Hashimoto's thyroiditis [5], Addison's disease [5], rheumatoid arthritis [6,7], celiac disease [8,9], and others [10].The Thr17Ala dimorphism and the polymorphic (AT)n microsatellite starting at position 642 of the 3' u