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Clinical Trial
. 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

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Free PMC article
Clinical Trial

Genome-wide Association Study Identifies Pharmacogenomic Loci Linked With Specific Antihypertensive Drug Treatment and New-Onset Diabetes

S-W Chang et al. Pharmacogenomics J. .
Free PMC article

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.

Figures

Figure 1
Figure 1. Regional plot at chromosome 2p21 locus for new-onset diabetes (NOD) association in INVEST European Americans
Regional SNP*Treatment interaction analysis results (−log p-value) are plotted for INVEST European Americans. Figure is generated using LocusZoom. The diamond-shaped dot represent the SNP with lowest interaction p-value in the loci. The lower panel demonstrated the RefSeq genes.
Figure 2
Figure 2. Forest plot of the PLEKHH2 rs11124945 pharmacogenomics association with New-onset Diabetes (NOD)
This figure shows PLEKHH2 rs11124945 genotypes specific odds ratio and 95% confidence interval for NOD in each race groups and combined meta-analysis from the INVEST NOD case-control study (n = 1140). Point estimate was reported under a dominant genetic model for each genotype group, which represents higher risk for NOD in the CCB strategy or the β-blocker strategy. Interaction p-values for Hispanics and African Americans are one-sided.

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