5′ Insulin Gene Polymorphism Confers Risk to IDDM Independently of HLA Class II Susceptibility

Abstract

The polymorphic variable number of tandem repeats in the 5' upstream region of the human insulin gene is a well-known non-human leukocyte antigen locus contributing to genetic susceptibility to IDDM. Controversy exists about the question as to whether INS susceptibility haplotypes are or are not preferentially inherited together with HLA-DR4 haplotypes. We investigated whether genetic interaction between INS and the HLA complex can be better defined using DQ genotypic and phenotypic markers in addition to DR serology. The 5' INS 1/1 genotype was positively 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 patients 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 class II polymorphisms therefore provide independent risk markers, which may both contribute to the genetic screening of a high-risk population among nondiabetic individuals.

LADA and T1D in Estonian population — Two different genetic risk profiles

“…These authors noticed that in multiplex families, the diabetes-associated alleles of INS VNTR were transmitted preferentially to HLA-DR4-positive diabetic offspring from heterozygous parents. Future investigators, including us, stated that the association is not restricted to HLA-DR4-positive individuals and that the INS genotype confers T1D susceptibility independently of HLA-DR (Bain et al, 1992;Haller et al, 2007;Metcalfe et al, 1995;van der Auwera et al, 1993). The present study supports the idea of independent association of these two gene regions with diabetes.…”

TNFa microsatellite polymorphism modulates the risk of type 1 diabetes in the Belgian population, independent of HLA-DQ

“…So far, only four type 1 diabetes (T1D) susceptibility loci have been identified with convincing and reproducible statistical support: the HLA class II genes on chromosome 6p21-IDDM1 (DQA1, DQB1 and DRB1) [1,2], the insulin gene region at 11p15-IDDM2 [3,4], the CTLA4 locus at 2q33 [5,6] and the PTPN22 gene at 1p13 [7]. Recently, convincing statistical support has The first two authors contributed equally to this study.…”