Abstract
AimsEpigenetic mechanisms regulate gene expression and may influence the pathogenesis of type 2 diabetes through the loss of insulin sensitivity. The aims of this study were to measure variation in DNA methylation at the type 2 diabetes locus KCNQ1 and assess its relationship with metabolic measures and with genotype. MethodsDNA methylation from whole blood DNA was quantified using pyrosequencing at 5 CpG sites at the KCNQ1 locus in 510 individuals without diabetes from the ‘Relationship between Insulin Sensitivity and Cardiovascular disease’ (RISC) cohort. Genotype data was analysed at the same locus in 1119 individuals in the same cohort. Insulin sensitivity was assessed by euglycaemic-hyperinsulinaemic clamp. ResultsDNA methylation at the KCNQ1 locus was inversely associated with insulin sensitivity and serum adiponectin. This association was driven by a methylation-altering Single Nucleotide Polymorphism (SNP) (rs231840) which ablated a methylation site and reduced methylation levels. A second SNP (rs231357), in weak Linkage Disequilibrium (LD) with rs231840, was also associated with insulin sensitivity and DNA methylation. These SNPs have not been previously reported to be associated with type 2 diabetes risk or insulin sensitivity. ConclusionEvidence indicates that genetic and epigenetic determinants at the KCNQ1 locus influence insulin sensitivity.
Highlights
Decreased insulin sensitivity is associated with a wide range of common disorders including type 2 diabetes, obesity, hypertension and cardiovascular disease
Methylation data were generated in 510 individuals randomly selected from the overall group (n = 1319) who had undertaken a euglycaemic-hyperinsulinaemic clamp and had fasting glucose levels of 7 mmol/L measured by clamp or oral glucose tolerance test. 459 of 510 individuals assayed for KCNQ1 methylation had genotyping, methylation and metabolic data
In this study we identify an association between variation in KCNQ1 and whole-body insulin sensitivity determined using the gold-standard euglycaemic-hyperinsulinaemic clamp
Summary
Decreased insulin sensitivity is associated with a wide range of common disorders including type 2 diabetes, obesity, hypertension and cardiovascular disease. DNA methylation has been associated with type 2 diabetes in a number of case-control studies, conducted on both genome wide and locus specific methylation data in various tissues [4,5,6,7]. In addition to its association with type 2 diabetes, evidence suggests DNA methylation is associated with insulin sensitivity measured by HOMA-IR [9,10]. In this study we explore locus-specific DNA methylation patterns in the gene KCNQ1, which has established links to type 2 diabetes aetiology [7]. The primary aim was to assess the relationship between DNA methylation at the KCNQ1 locus and measures of insulin sensitivity and b-cell function in a cohort of healthy individuals without diabetes. We describe the DNA methylation-phenotype relationship at this locus and consider the role of the underlying genetic architecture on the determination of DNA methylation and in turn the potential influence of these factors on phenotype in this healthy population
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