5' INSULIN GENE POLYMORPHISM CONFERS RISK TO IDDM INDEPENDENTLY OF HLA CLASS-II SUSCEPTIBILITY

The polymorphic variable number of tandem repeats in the 5' upstream r egion of the human insulin gene is a well-known non-human leukocyte an tigen locus contributing to genetic susceptibility to IDDM. Controvers y exists about the question as to whether INS susceptibility haplotype s are or are not preferentially inherited together with HLA-DR4 haplot ypes. We investigated whether genetic interaction between INS and the HLA complex can be better defined using DQ genotypic and phenotypic ma rkers in addition to DR serology. The 5' INS 1/1 genotype was positive ly associated with IDDM both in non-DR4 subjects (relative risk = 4.3; 95% confidence interval, 1.6-11.5) and DR4 subjects (relative risk = 4.2; 95% confidence interval, 1.9-9.0). Further subdivision of IDDM pa tients and matched control subjects according to HLA-DQA1 and HLA-DQB1 genotype or phenotype also failed to show any association between 5' INS and HLA class II genes in diabetic patients. The 5' INS and HLA cl ass II polymorphisms therefore provide independent risk markers, which may both contribute to the genetic screening of a high-risk populatio n among nondiabetic individuals.