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

Chang SW, McDonough CW, Gong Y, Johnson TA, Tsunoda T, Gamazon ER, Perera MA, Takahashi A, Tanaka T, Kubo M, Pepine CJ, Johnson JA, Cooper-DeHoff RM
Pharmacogenomics J. 2018 18 (1): 106-112

PMID: 27670767 · PMCID: PMC5368017 · DOI:10.1038/tpj.2016.67

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). 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), 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). eQTL annotation of the 2p21 locus provides functional support for regulating gene expression.

MeSH Terms (19)

Adrenergic beta-Antagonists African Americans Aged Alleles Antihypertensive Agents Calcium Channel Blockers Diabetes Mellitus Female Follow-Up Studies Genome-Wide Association Study Humans Hypertension Male Meta-Analysis as Topic Middle Aged Odds Ratio Pharmacogenetics Polymorphism, Single Nucleotide Quantitative Trait Loci

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