Genomic Association Analysis Reveals Variants Associated With Blood Pressure Response to Beta-Blockers in European Americans

Sonal Singh, Nihal El Rouby, Caitrin W. McDonough, Yan Gong, Kent R. Bailey, Eric Boerwinkle, Arlene B. Chapman, John G. Gums, Stephen T. Turner, Rhonda M. Cooper-DeHoff, Julie A. Johnson

Research output: Contribution to journalArticle

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Abstract

European Americans (EA) have a better antihypertensive response to β-blockers when compared with African Americans, albeit with some variability. We undertook a genomewide association study to elucidate the underlying genetic determinants in EA contributing to this variability in blood pressure (BP) response. A discovery genomewide association study of change in BP post-metoprolol treatment was performed in EA participants (n = 201) from the Pharmacogenomic Evaluation of Antihypertensive Responses-2 (PEAR-2) study and tested for replication in the atenolol-treated EA from the PEAR study (n = 233). Rs294610 in the FGD5, which encodes for FYVE, RhoGEF and PH Domain Containing 5, (expression quantitative trait loci for FGD5 in the small intestine) was significantly associated with increased diastolic BP response to β-blockers in the PEAR-2 study (P = 3.41 × 10-6 , β = -2.70) and replicated (P = 0.01, β = -1.17) in the PEAR study. Post-meta-analysis of these studies, an additional single nucleotide polymorphism rs45545233 in the SLC4A1, encoding for Solute Carrier Family 4 Member 1, (expression quantitative trait loci for dual specificity phosphatase 3 in the artery tibial) was identified that was significantly associated with a poor response to β-blockers (P = 3.43 × 10-6 , β = 4.57) and was replicated in the atenolol add-on cohort (P = 0.007, β = 4.97). We identified variants in FGD5 and SLC4A1, which have been previously cited as candidate genes for hypertension, to be associated with a β-blocker BP response in EA. Further elucidation is warranted of the underlying mechanisms of these variants and genes by which they influence the BP response to β-blockers.

Original languageEnglish (US)
Pages (from-to)497-504
Number of pages8
JournalClinical and translational science
Volume12
Issue number5
DOIs
StatePublished - Sep 1 2019

Fingerprint

Blood pressure
Blood Pressure
Antihypertensive Agents
Atenolol
Dual Specificity Phosphatase 3
Quantitative Trait Loci
Pharmacogenetics
Genes
Rho Guanine Nucleotide Exchange Factors
Erythrocyte Anion Exchange Protein 1
Metoprolol
Tibial Arteries
Polymorphism
African Americans
Nucleotides
Small Intestine
Single Nucleotide Polymorphism
Meta-Analysis
Hypertension

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Genomic Association Analysis Reveals Variants Associated With Blood Pressure Response to Beta-Blockers in European Americans. / Singh, Sonal; El Rouby, Nihal; McDonough, Caitrin W.; Gong, Yan; Bailey, Kent R.; Boerwinkle, Eric; Chapman, Arlene B.; Gums, John G.; Turner, Stephen T.; Cooper-DeHoff, Rhonda M.; Johnson, Julie A.

In: Clinical and translational science, Vol. 12, No. 5, 01.09.2019, p. 497-504.

Research output: Contribution to journalArticle

Singh, S, El Rouby, N, McDonough, CW, Gong, Y, Bailey, KR, Boerwinkle, E, Chapman, AB, Gums, JG, Turner, ST, Cooper-DeHoff, RM & Johnson, JA 2019, 'Genomic Association Analysis Reveals Variants Associated With Blood Pressure Response to Beta-Blockers in European Americans', Clinical and translational science, vol. 12, no. 5, pp. 497-504. https://doi.org/10.1111/cts.12643
Singh, Sonal ; El Rouby, Nihal ; McDonough, Caitrin W. ; Gong, Yan ; Bailey, Kent R. ; Boerwinkle, Eric ; Chapman, Arlene B. ; Gums, John G. ; Turner, Stephen T. ; Cooper-DeHoff, Rhonda M. ; Johnson, Julie A. / Genomic Association Analysis Reveals Variants Associated With Blood Pressure Response to Beta-Blockers in European Americans. In: Clinical and translational science. 2019 ; Vol. 12, No. 5. pp. 497-504.
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abstract = "European Americans (EA) have a better antihypertensive response to β-blockers when compared with African Americans, albeit with some variability. We undertook a genomewide association study to elucidate the underlying genetic determinants in EA contributing to this variability in blood pressure (BP) response. A discovery genomewide association study of change in BP post-metoprolol treatment was performed in EA participants (n = 201) from the Pharmacogenomic Evaluation of Antihypertensive Responses-2 (PEAR-2) study and tested for replication in the atenolol-treated EA from the PEAR study (n = 233). Rs294610 in the FGD5, which encodes for FYVE, RhoGEF and PH Domain Containing 5, (expression quantitative trait loci for FGD5 in the small intestine) was significantly associated with increased diastolic BP response to β-blockers in the PEAR-2 study (P = 3.41 × 10-6 , β = -2.70) and replicated (P = 0.01, β = -1.17) in the PEAR study. Post-meta-analysis of these studies, an additional single nucleotide polymorphism rs45545233 in the SLC4A1, encoding for Solute Carrier Family 4 Member 1, (expression quantitative trait loci for dual specificity phosphatase 3 in the artery tibial) was identified that was significantly associated with a poor response to β-blockers (P = 3.43 × 10-6 , β = 4.57) and was replicated in the atenolol add-on cohort (P = 0.007, β = 4.97). We identified variants in FGD5 and SLC4A1, which have been previously cited as candidate genes for hypertension, to be associated with a β-blocker BP response in EA. Further elucidation is warranted of the underlying mechanisms of these variants and genes by which they influence the BP response to β-blockers.",
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