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Pharmacogenomics J. 2018 Jan;18(1):106-112. doi: 10.1038/tpj.2016.67. Epub 2016 Sep 27.

Genome-wide association study identifies pharmacogenomic loci linked with specific antihypertensive drug treatment and new-onset diabetes.

Author information

1
Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
2
Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
3
Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
4
Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, TN, USA.
5
Department of Medicine, University of Chicago, Chicago, IL, USA.
6
Laboratory for Statistical Analysis, SNP Research Center, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
7
Laboratory for Cardiovascular Diseases, SNP Research Center, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
8
Laboratory for Genotyping Development, SNP Research Center, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
9
Division of Cardiovascular Medicine, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.

Abstract

We conducted a discovery genome-wide association study with expression quantitative trait loci (eQTL) annotation of new-onset diabetes (NOD) among European Americans, who were exposed to a calcium channel blocker-based strategy (CCB strategy) or a β-blocker-based strategy (β-blocker strategy) in the INternational VErapamil SR Trandolapril STudy. Replication of the top signal from the SNP*treatment interaction analysis was attempted in Hispanic and African Americans, and a joint meta-analysis was performed (total 334 NOD cases and 806 matched controls). PLEKHH2 rs11124945 at 2p21 interacted with antihypertensive exposure for NOD (meta-analysis P=5.3 × 10-8). rs11124945 G allele carriers had lower odds for NOD when exposed to the β-blocker strategy compared with the CCB strategy (Odds ratio OR=0.38(0.24-0.60), P=4.0 × 10-5), whereas A/A homozygotes exposed to the β-blocker strategy had increased odds for NOD compared with the CCB strategy (OR=2.02(1.39-2.92), P=2.0 × 10-4). eQTL annotation of the 2p21 locus provides functional support for regulating gene expression.

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