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

S. W. Chang; C. W. McDonough; Y. Gong; T. A. Johnson; T. Tsunoda; E. R. Gamazon; M. A. Perera; A. Takahashi; T. Tanaka; M. Kubo; C. J. Pepine; J. A. Johnson; R. M. Cooper-Dehoff

doi:10.1038/tpj.2016.67

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

S. W. Chang, C. W. McDonough, Y. Gong, T. A. Johnson, T. Tsunoda, E. R. Gamazon, M. A. Perera, A. Takahashi, T. Tanaka, M. Kubo, C. J. Pepine, J. A. Johnson, R. M. Cooper-Dehoff

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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.

Original language	English
Pages (from-to)	106-112
Number of pages	7
Journal	Pharmacogenomics Journal
Volume	18
Issue number	1
DOIs	https://doi.org/10.1038/tpj.2016.67
Publication status	Published - 01-01-2018

All Science Journal Classification (ASJC) codes

Molecular Medicine
Genetics
Pharmacology

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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. (2018). Genome-wide association study identifies pharmacogenomic loci linked with specific antihypertensive drug treatment and new-onset diabetes. Pharmacogenomics Journal, 18(1), 106-112. https://doi.org/10.1038/tpj.2016.67

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. / Genome-wide association study identifies pharmacogenomic loci linked with specific antihypertensive drug treatment and new-onset diabetes. In: Pharmacogenomics Journal. 2018 ; Vol. 18, No. 1. pp. 106-112.

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

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.",

author = "Chang, {S. W.} and McDonough, {C. W.} and Y. Gong and Johnson, {T. A.} and T. Tsunoda and Gamazon, {E. R.} and Perera, {M. A.} and A. Takahashi and T. Tanaka and M. Kubo and Pepine, {C. J.} and Johnson, {J. A.} and Cooper-Dehoff, {R. M.}",

note = "Funding Information: This project was supported by the National Institute of Health Pharmacogenetics Research Network Grant U01-GM074492, NIH R01 HL074730, UF Opportunity Fund and Abbott Laboratories. The genotyping and imputation were performed by the RIKEN Center for Integrative Medical Sciences. INVEST was supported by the University of Florida and Grants from BASF Pharma and Abbott Laboratories.",

year = "2018",

month = jan,

day = "1",

doi = "10.1038/tpj.2016.67",

language = "English",

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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 2018, 'Genome-wide association study identifies pharmacogenomic loci linked with specific antihypertensive drug treatment and new-onset diabetes', Pharmacogenomics Journal, vol. 18, no. 1, pp. 106-112. https://doi.org/10.1038/tpj.2016.67

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

In: Pharmacogenomics Journal, Vol. 18, No. 1, 01.01.2018, p. 106-112.

Research output: Contribution to journal › Article › peer-review

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T1 - Genome-wide association study identifies pharmacogenomic loci linked with specific antihypertensive drug treatment and new-onset diabetes

AU - Chang, S. W.

AU - McDonough, C. W.

AU - Gong, Y.

AU - Johnson, T. A.

AU - Tsunoda, T.

AU - Gamazon, E. R.

AU - Perera, M. A.

AU - Takahashi, A.

AU - Tanaka, T.

AU - Kubo, M.

AU - Pepine, C. J.

AU - Johnson, J. A.

AU - Cooper-Dehoff, R. M.

N1 - Funding Information: This project was supported by the National Institute of Health Pharmacogenetics Research Network Grant U01-GM074492, NIH R01 HL074730, UF Opportunity Fund and Abbott Laboratories. The genotyping and imputation were performed by the RIKEN Center for Integrative Medical Sciences. INVEST was supported by the University of Florida and Grants from BASF Pharma and Abbott Laboratories.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

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

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