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 (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.
Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
S-W
SW
Chang
Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
C W
CW
McDonough
Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
Y
Y
Gong
Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
T A
TA
Johnson
Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.|Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
T
T
Tsunoda
Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, TN, USA.
E R
ER
Gamazon
Department of Medicine, University of Chicago, Chicago, IL, USA.
M A
MA
Perera
Laboratory for Statistical Analysis, SNP Research Center, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
A
A
Takahashi
Laboratory for Cardiovascular Diseases, SNP Research Center, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
T
0000-0001-6201-9784
T
Tanaka
Laboratory for Genotyping Development, SNP Research Center, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
M
M
Kubo
Division of Cardiovascular Medicine, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
C J
CJ
Pepine
Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL, USA.|Division of Cardiovascular Medicine, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
J A
JA
Johnson
Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL, USA.|Division of Cardiovascular Medicine, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
R M
RM
Cooper-DeHoff
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D001741:Black or African American; D000368:Aged; D000483:Alleles; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D016017:Odds Ratio; D010597:Pharmacogenetics / Q000379:methods; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*
D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers
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