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

• Published in: The pharmacogenomics journal Vol. 18; no. 1; pp. 106 - 112
• Main Authors: Chang, S-W, McDonough, C W, Gong, Y, Johnson, T A, Tsunoda, T, Gamazon, E R, Perera, M A, Takahashi, A, Tanaka, T, Kubo, M, Pepine, C J, Johnson, J A, Cooper-DeHoff, R M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2018; Nature Publishing Group
• Subjects: 45; 45/43; 45/47; 631/208/212; 692/53/2423; Adrenergic beta-Antagonists - therapeutic use; African Americans; Aged; Alleles; Antihypertensive Agents - therapeutic use; Antihypertensives; Biomedical and Life Sciences; Biomedicine; Calcium; Calcium Channel Blockers - therapeutic use; Chromosome 2; Diabetes; Diabetes mellitus; Diabetes Mellitus - drug therapy; Diabetes Mellitus - genetics; Exposure; Female; Follow-Up Studies; Gene Expression; Genome-wide association studies; Genome-Wide Association Study - methods; Genomes; Genotype & phenotype; Homozygotes; Human Genetics; Humans; Hypertension - drug therapy; Hypertension - genetics; Male; Meta-Analysis as Topic; Middle Aged; Minority & ethnic groups; Odds Ratio; Oncology; original-article; Pharmacogenetics - methods; Pharmacogenomics; Pharmacotherapy; Polymorphism, Single Nucleotide - genetics; Psychopharmacology; Quantitative trait loci; Quantitative Trait Loci - genetics; Single-nucleotide polymorphism; Strategy; Verapamil
• ISSN: 1470-269X; 1473-1150
• 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 − 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.