Targeted allelic expression profiling in human islets identifies cis-regulatory effects for multiple variants identified by type 2 diabetes genome-wide association studies.
American Diabetes Association
This is an author-created, uncopyedited electronic version of an article accepted for publication in Diabetes. The American Diabetes Association (ADA), publisher of Diabetes, is not responsible for any errors or omissions in this version of the manuscript or any version derived from it by third parties. The definitive publisher-authenticated version will be available in a future issue of Diabetes in print and online at http://diabetes.diabetesjournals.org.
Genome-wide association studies (GWAS) have identified variation at >65 genomic loci associated with susceptibility to type 2 diabetes, but little progress has been made in elucidating the molecular mechanisms behind most of these associations. Using samples heterozygous for transcribed single nucleotide polymorphisms (SNPs), allelic expression profiling is a powerful technique for identifying cis-regulatory variants controlling gene expression. In this study, exonic SNPs, suitable for measuring mature mRNA levels and in high linkage disequilibrium with 65 lead type 2 diabetes GWAS SNPs, were identified and allelic expression determined by real-time PCR using RNA and DNA isolated from islets of 36 white nondiabetic donors. A significant allelic expression imbalance (AEI) was identified for 7/14 (50%) genes tested (ANPEP, CAMK2B, HMG20A, KCNJ11, NOTCH2, SLC30A8, and WFS1), with significant AEI confirmed for five of these genes using other linked exonic SNPs. Lastly, results of a targeted islet expression quantitative trait loci experiment support the AEI findings for ANPEP, further implicating ANPEP as the causative gene at its locus. The results of this study support the hypothesis that changes to cis-regulation of gene expression are involved in a large proportion of SNP associations with type 2 diabetes susceptibility.
Research Support, Non-U.S. Gov't
Copyright © 2015 by the American Diabetes Association.
Vol. 64, No. 4, pp. 1484 - 1491
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