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Differential methylation of the type 2 diabetes susceptibility locus KCNQ1 is associated with insulin sensitivity and is predicted by CpG site specific genetic variation

Lookup NU author(s): Ushma Shah, Professor Mark Walker, Professor Caroline Relton, Dr Hannah Elliott


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© 2019 The Authors Aims: Epigenetic 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. Methods: DNA 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. Results: DNA 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. Conclusion: Evidence indicates that genetic and epigenetic determinants at the KCNQ1 locus influence insulin sensitivity.

Publication metadata

Author(s): Shah UJ, Xie W, Flyvbjerg A, Nolan JJ, Hojlund K, Walker M, Relton CL, Elliott HR

Publication type: Article

Publication status: Published

Journal: Diabetes Research and Clinical Practice

Year: 2019

Volume: 148

Pages: 189-199

Print publication date: 01/02/2019

Online publication date: 11/01/2019

Acceptance date: 04/01/2019

ISSN (print): 0168-8227

ISSN (electronic): 1872-8227

Publisher: Elsevier Ireland Ltd


DOI: 10.1016/j.diabres.2019.01.008


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