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

Ushma J. Shah; Weijia Xie; Allan Flyvbjerg; John J. Nolan; Kurt Højlund; Mark Walker; Caroline L. Relton; Hannah R. Elliott; for the RISC consortium

doi:10.1016/j.diabres.2019.01.008

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

Ushma J. Shah, Weijia Xie, Allan Flyvbjerg, John J. Nolan, Kurt Højlund, Mark Walker, Caroline L. Relton, Hannah R. Elliott^*, for the RISC consortium

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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Abstract

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.

Original language	English
Pages (from-to)	189-199
Number of pages	11
Journal	Diabetes Research and Clinical Practice
Volume	148
Early online date	11 Jan 2019
DOIs	https://doi.org/10.1016/j.diabres.2019.01.008
Publication status	Published - Feb 2019

Keywords

insulin sensitivity
KCNQ1
Methylation
SNP
Type 2 diabetes

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Shah, U. J., Xie, W., Flyvbjerg, A., Nolan, J. J., Højlund, K., Walker, M., Relton, C. L., Elliott, H. R., & for the RISC consortium (2019). Differential methylation of the type 2 diabetes susceptibility locus KCNQ1 is associated with insulin sensitivity and is predicted by CpG site specific genetic variation. Diabetes Research and Clinical Practice, 148, 189-199. https://doi.org/10.1016/j.diabres.2019.01.008

@article{4ffa9e53552544dd9a890c5cfc4737b5,

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

abstract = "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 {\textquoteleft}Relationship between Insulin Sensitivity and Cardiovascular disease{\textquoteright} (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.",

keywords = "insulin sensitivity, KCNQ1, Methylation, SNP, Type 2 diabetes",

author = "Shah, {Ushma J.} and Weijia Xie and Allan Flyvbjerg and Nolan, {John J.} and Kurt H{\o}jlund and Mark Walker and Relton, {Caroline L.} and Elliott, {Hannah R.} and {for the RISC consortium}",

year = "2019",

month = feb,

doi = "10.1016/j.diabres.2019.01.008",

language = "English",

volume = "148",

pages = "189--199",

journal = "Diabetes Research and Clinical Practice",

issn = "0168-8227",

publisher = "Elsevier Science Ireland",

}

Shah, UJ, Xie, W, Flyvbjerg, A, Nolan, JJ, Højlund, K, Walker, M, Relton, CL, Elliott, HR & for the RISC consortium 2019, 'Differential methylation of the type 2 diabetes susceptibility locus KCNQ1 is associated with insulin sensitivity and is predicted by CpG site specific genetic variation', Diabetes Research and Clinical Practice, vol. 148, pp. 189-199. https://doi.org/10.1016/j.diabres.2019.01.008

Differential methylation of the type 2 diabetes susceptibility locus KCNQ1 is associated with insulin sensitivity and is predicted by CpG site specific genetic variation. / Shah, Ushma J.; Xie, Weijia; Flyvbjerg, Allan et al.
In: Diabetes Research and Clinical Practice, Vol. 148, 02.2019, p. 189-199.

Research output: Contribution to journal › Article (Academic Journal) › peer-review

TY - JOUR

T1 - Differential methylation of the type 2 diabetes susceptibility locus KCNQ1 is associated with insulin sensitivity and is predicted by CpG site specific genetic variation

AU - Shah, Ushma J.

AU - Xie, Weijia

AU - Flyvbjerg, Allan

AU - Nolan, John J.

AU - Højlund, Kurt

AU - Walker, Mark

AU - Relton, Caroline L.

AU - Elliott, Hannah R.

AU - for the RISC consortium

PY - 2019/2

Y1 - 2019/2

N2 - 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.

AB - 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.

KW - insulin sensitivity

KW - KCNQ1

KW - Methylation

KW - SNP

KW - Type 2 diabetes

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U2 - 10.1016/j.diabres.2019.01.008

DO - 10.1016/j.diabres.2019.01.008

M3 - Article (Academic Journal)

C2 - 30641161

AN - SCOPUS:85060452346

SN - 0168-8227

VL - 148

SP - 189

EP - 199

JO - Diabetes Research and Clinical Practice

JF - Diabetes Research and Clinical Practice

ER -

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

Abstract

Keywords

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