A multilocus approach to the antihypertensive pharmacogenetics of hydrochlorothiazide

Anke Hilse Maitland-Van Der Zee, Stephen T Turner, Gary Lee Schwartz, Arlene B. Chapman, Olaf H. Klungel, Eric Boerwinkle

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Objectives: To assess the influence of variations in multiple candidate genes on inter-individual variation in diastolic blood pressure (DBP) response to hydrochlorothiazide. Methods: A community-based sample of 585 adults with essential hypertension underwent monotherapy with hydrochlorothiazide for 4 weeks. In a nested case-control design, 195 individuals in the highest tertile of DBP response (responders) and 195 individuals in the lowest tertile of DBP response (non-responders) were genotyped for 45 polymorphisms in 19 candidate genes. For those polymorphisms where the set association approach found to be significantly associated with DBP response, logistic regression was performed to estimate the odds ratio (OR) for response associated variation in the identified genotype/haplotype. Results: Two polymorphisms in the sodium channel γ-subunit promotor gene, and a polymorphism in the endothelial nitric oxide synthase gene, were significantly associated with blood pressure response to hydrochlorothiazide. In the final experiment for the set association model P=0.038. In the logistic regression analyses, compared to subjects with the CT/CT haplotype of the SCNN1G gene, those with the GA/GA haplotype had OR 5.21 of being a DBP responder [95% CI 1.65-16.47]. Compared to subjects with the GT genotype of the ENOSA_rs1799983 polymorphism, those with the GG genotype had an OR 2.19 of being a DBP responder [95% CI 1.27-3.77]. Conclusions: Two polymorphisms in the sodium channel γ-subunit promotor gene, and a polymorphism in the endothelial nitric oxide synthase gene, were associated with significant differences in odds of DBP response to hydrochlorothiazide. Follow-up studies are needed to define the functional genetic variations and their mechanisms of pharmacogenetic effects.

Original languageEnglish (US)
Pages (from-to)287-293
Number of pages7
JournalPharmacogenetics and Genomics
Volume15
Issue number5
StatePublished - May 2005

Fingerprint

Hydrochlorothiazide
Pharmacogenetics
Antihypertensive Agents
Blood Pressure
Genes
Haplotypes
Sodium Channels
Nitric Oxide Synthase Type III
Odds Ratio
Genotype
Logistic Models

Keywords

  • Aldosterone synthase
  • Diastolic blood pressure
  • Endothelial nitric oxide synthase
  • Hydrochlorothiazide
  • Pharmacogenetics
  • Sodium channel gamma subunit promoter

ASJC Scopus subject areas

  • Genetics
  • Pharmacology

Cite this

Maitland-Van Der Zee, A. H., Turner, S. T., Schwartz, G. L., Chapman, A. B., Klungel, O. H., & Boerwinkle, E. (2005). A multilocus approach to the antihypertensive pharmacogenetics of hydrochlorothiazide. Pharmacogenetics and Genomics, 15(5), 287-293.

A multilocus approach to the antihypertensive pharmacogenetics of hydrochlorothiazide. / Maitland-Van Der Zee, Anke Hilse; Turner, Stephen T; Schwartz, Gary Lee; Chapman, Arlene B.; Klungel, Olaf H.; Boerwinkle, Eric.

In: Pharmacogenetics and Genomics, Vol. 15, No. 5, 05.2005, p. 287-293.

Research output: Contribution to journalArticle

Maitland-Van Der Zee, AH, Turner, ST, Schwartz, GL, Chapman, AB, Klungel, OH & Boerwinkle, E 2005, 'A multilocus approach to the antihypertensive pharmacogenetics of hydrochlorothiazide', Pharmacogenetics and Genomics, vol. 15, no. 5, pp. 287-293.
Maitland-Van Der Zee, Anke Hilse ; Turner, Stephen T ; Schwartz, Gary Lee ; Chapman, Arlene B. ; Klungel, Olaf H. ; Boerwinkle, Eric. / A multilocus approach to the antihypertensive pharmacogenetics of hydrochlorothiazide. In: Pharmacogenetics and Genomics. 2005 ; Vol. 15, No. 5. pp. 287-293.
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abstract = "Objectives: To assess the influence of variations in multiple candidate genes on inter-individual variation in diastolic blood pressure (DBP) response to hydrochlorothiazide. Methods: A community-based sample of 585 adults with essential hypertension underwent monotherapy with hydrochlorothiazide for 4 weeks. In a nested case-control design, 195 individuals in the highest tertile of DBP response (responders) and 195 individuals in the lowest tertile of DBP response (non-responders) were genotyped for 45 polymorphisms in 19 candidate genes. For those polymorphisms where the set association approach found to be significantly associated with DBP response, logistic regression was performed to estimate the odds ratio (OR) for response associated variation in the identified genotype/haplotype. Results: Two polymorphisms in the sodium channel γ-subunit promotor gene, and a polymorphism in the endothelial nitric oxide synthase gene, were significantly associated with blood pressure response to hydrochlorothiazide. In the final experiment for the set association model P=0.038. In the logistic regression analyses, compared to subjects with the CT/CT haplotype of the SCNN1G gene, those with the GA/GA haplotype had OR 5.21 of being a DBP responder [95{\%} CI 1.65-16.47]. Compared to subjects with the GT genotype of the ENOSA_rs1799983 polymorphism, those with the GG genotype had an OR 2.19 of being a DBP responder [95{\%} CI 1.27-3.77]. Conclusions: Two polymorphisms in the sodium channel γ-subunit promotor gene, and a polymorphism in the endothelial nitric oxide synthase gene, were associated with significant differences in odds of DBP response to hydrochlorothiazide. Follow-up studies are needed to define the functional genetic variations and their mechanisms of pharmacogenetic effects.",
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AU - Klungel, Olaf H.

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N2 - Objectives: To assess the influence of variations in multiple candidate genes on inter-individual variation in diastolic blood pressure (DBP) response to hydrochlorothiazide. Methods: A community-based sample of 585 adults with essential hypertension underwent monotherapy with hydrochlorothiazide for 4 weeks. In a nested case-control design, 195 individuals in the highest tertile of DBP response (responders) and 195 individuals in the lowest tertile of DBP response (non-responders) were genotyped for 45 polymorphisms in 19 candidate genes. For those polymorphisms where the set association approach found to be significantly associated with DBP response, logistic regression was performed to estimate the odds ratio (OR) for response associated variation in the identified genotype/haplotype. Results: Two polymorphisms in the sodium channel γ-subunit promotor gene, and a polymorphism in the endothelial nitric oxide synthase gene, were significantly associated with blood pressure response to hydrochlorothiazide. In the final experiment for the set association model P=0.038. In the logistic regression analyses, compared to subjects with the CT/CT haplotype of the SCNN1G gene, those with the GA/GA haplotype had OR 5.21 of being a DBP responder [95% CI 1.65-16.47]. Compared to subjects with the GT genotype of the ENOSA_rs1799983 polymorphism, those with the GG genotype had an OR 2.19 of being a DBP responder [95% CI 1.27-3.77]. Conclusions: Two polymorphisms in the sodium channel γ-subunit promotor gene, and a polymorphism in the endothelial nitric oxide synthase gene, were associated with significant differences in odds of DBP response to hydrochlorothiazide. Follow-up studies are needed to define the functional genetic variations and their mechanisms of pharmacogenetic effects.

AB - Objectives: To assess the influence of variations in multiple candidate genes on inter-individual variation in diastolic blood pressure (DBP) response to hydrochlorothiazide. Methods: A community-based sample of 585 adults with essential hypertension underwent monotherapy with hydrochlorothiazide for 4 weeks. In a nested case-control design, 195 individuals in the highest tertile of DBP response (responders) and 195 individuals in the lowest tertile of DBP response (non-responders) were genotyped for 45 polymorphisms in 19 candidate genes. For those polymorphisms where the set association approach found to be significantly associated with DBP response, logistic regression was performed to estimate the odds ratio (OR) for response associated variation in the identified genotype/haplotype. Results: Two polymorphisms in the sodium channel γ-subunit promotor gene, and a polymorphism in the endothelial nitric oxide synthase gene, were significantly associated with blood pressure response to hydrochlorothiazide. In the final experiment for the set association model P=0.038. In the logistic regression analyses, compared to subjects with the CT/CT haplotype of the SCNN1G gene, those with the GA/GA haplotype had OR 5.21 of being a DBP responder [95% CI 1.65-16.47]. Compared to subjects with the GT genotype of the ENOSA_rs1799983 polymorphism, those with the GG genotype had an OR 2.19 of being a DBP responder [95% CI 1.27-3.77]. Conclusions: Two polymorphisms in the sodium channel γ-subunit promotor gene, and a polymorphism in the endothelial nitric oxide synthase gene, were associated with significant differences in odds of DBP response to hydrochlorothiazide. Follow-up studies are needed to define the functional genetic variations and their mechanisms of pharmacogenetic effects.

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