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

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 [OR=0.38 (0.24-0.60), p=4.0×10(−5)], while 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.