CTLA-4 GENE POLYMORPHISM CONFERS SUSCEPTIBILITY TO INSULIN-DEPENDENT DIABETES-MELLITUS (IDDM) INDEPENDENTLY FROM AGE AND FROM OTHER GENETICOR IMMUNE DISEASE MARKERS

Apart from genes in the HLA complex (IDDM1) and the variable number of tandem repeats in the 5' region of the insulin gene (INS VNTR, IDDM2) , several other loci have been proposed to contribute to IDDM suscepti bility, Recently, linkage and association have been shown between the cytotoxic T lymphocyte-associated protein 4(CTLA-4) gene on chromosome 2q and IDDM. In a registry-based group of 525 recent-onset IDDM patie nts < 40 years old we investigated the possible interactions of a CTLA -4 gene A-to-G transition polymorphism with age at clinical disease on set and with the presence or absence of established genetic (HLA-DQ, I NS VNTR) and immune disease markets (autoantibodies against islet cell cytoplasm (ICA); insulin (IAA); glutamate decarboxylase (GAD65-Ab); I A-2 protein tyrosine phosphatase (IA-2-Ab)) determined within the firs t week of insulin treatment. In new-onset IDDM patients, G-allele-cont aining CTLA-4 genotypes (relative risk (RR) = 1.5; 95% confidence inte rval (CI) = 1.2-20; P < 0.005) were nor preferentially associated with age at clinical presentation or with the presence of other genetic (H LA-DR3 or DR4 alleles; HLA-DQA10301-DQB1*0302 and/or DQA1*0501-DQB1*0 201 risk haplotypes; INS VNTR I/I risk genotype) or immune (ICA, IAA, IA-2-Ab, GAD65-Ab) markers of diabetes. For 151 patients, thyrogastric autoantibodies (anti-thyroid peroxidase, anti-thyroid-stimulating hor mone (TSH) receptor, anti-parietal cell, anti-intrinsic factor) were d etermined, but association between CTLA-4 risk genotypes and markers o f polyendocrine autoimmunity could not be demonstrated before or after stratification for HLA-or INS-linked risk. In conclusion, the presenc e of a G-containing CTLA-4 genotype confers a moderate but significant RR for IDDM that is independent of age and genetic or immune disease markers.