RAGE polymorphisms and the heritability of insulin resistance: The Leeds Family Study

Abstract

Activation of the receptor for advanced glycation end-products (RAGE) leads to a cascade of pro-inflammatory and pro-coagulant responses which are important in the pathogenesis of the vascular complications of diabetes mellitus. It is known that pro-inflammatory mechanisms underpin the development of type 2 diabetes. Our hypothesis is that RAGE may be involved in the evolution of insulin resistance in addition to mediating glucotoxic complications of diabetes mellitus. Methods: To investigate the relationship between RAGE allelic variation and insulin resistance, the Gly82Ser variant and three promoter variants (-429, -374, 63 bp deletion) were studied in 480 subjects of known relationship from 89 families characterised for insulin resistance (using homeostasis model assessment [HOMA]) and for atherothrombotic risk. Carriage of the -429 C allele was weakly associated with increased insulin resistance (p=0.02) when pedigree analysis was performed using SOLAR software. Results: Insulin resistance was estimated to have a heritability of 25.8% before the addition of covariates. Analysis of the relationship between RAGE and insulin resistance indicated that the -429 polymorphism reduced the unexplained heritability of insulin resistance after adjusting for covariates (age, sex, body mass index) from 17.5% of the total variance to 15.6% of the total variance. Conclusions: These preliminary results indicate that the RAGE gene may affect the development of insulin resistance or be in linkage disequilibrium with a locus involved in this process.