Investigation of the genetic basis of insulin resistance and cardiovascular disease

Abstract

Introduction: Cardiovascular disease (CVD) is the major cause of morbidity and premature mortality in type 2 diabetes (T2DM). Carotid artery intima-media thickness (cIMT) is a marker of cardiovascular disease. Carotid artery IMT heritability estimates are increased in both healthy and type 2 diabetic families, providing support for the role of genetic factors. This close link between CVD and T2DM raises the possibility that common gene variants might increase susceptibility to both conditions, the "common soil" hypothesis. Common variants of the genes encoding PPARy and adiponectin have been found to increase susceptibility to type 2 diabetes. The hypothesis to be investigated is that these susceptibility genes exhibit pleiotropy and increase the risk of CVD. Methods/Results: Subjects aged 30-60 years were recruited at 19 centres in 14 European countries. Each subject underwent anthropometric and metabolic assessment including euglycaemic hyperinsulinaemic clamp to study insulin sensitivity and β-mode ultrasound scan for the measurement of carotid IMT.The study cohort consists of 1278 subjects. Pro12 Ala was genotyped by restriction fragment length polymorphism (RFLP-PCR). SNP T-45G and SNPs (A-11426G, G-11391A and C-I 1377G) of the ADIPOQ gene were detected by Sequenom and TaqMan assay respectively. Results/Conclusions: In this study we confirmed that the Pro 12Ala of the PPARy variant influences insulin sensitivity in the healthy population. Specifically, subjects homozygous for the Ala allele are more insulin sensitive compared to the rest of the population independent of measures of adiposity. However in this cross sectional data, there was no significant association between cIMT and the genetic variation of the Pro 12 Ala variant. We also found that SNP +45 of the ADIPOQ gene influences insulin sensitivity independent of serum adiponectin in this healthy population. Subjects homozygous for the G allele are less insulin sensitive compared to the T allele carriers, have high waist circumference and fasting NEF As. However, there was no association of this polymorphism and c IMT, a measure of CVD. However, it was established that variation in the ADIPOQ gene promoter was directly associated with carotid IMT, and this was independent of circulating adiponectin levels and classical CVD risk factors. This observation needs to be replicated in other cohorts, and further evidence is needed to explore the potential mechanisms by which variation in adiponectin influence IMT and CVD.