Document Detail


Functional variants of the angiotensinogen gene determine antihypertensive responses to angiotensin-converting enzyme inhibitors in subjects of African origin.
MedLine Citation:
PMID:  16685205     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: To determine whether the response to angiotensin-converting enzyme inhibitor (ACEI) monotherapy in subjects of African origin is determined by genetic variants within the angiotensinogen (AGT) gene. METHODS: A total of 194 hypertensive patients of African ancestry were recruited from district clinics in Johannesburg, South Africa. Eighty patients received open-label ACEI (enalapril or lisinopril) monotherapy, and 114 open-label calcium antagonist (nifedipine) as a drug class comparator. Twenty-four hour ambulatory blood pressure (ABP) monitoring was performed at baseline (off medication) and after 2 months of therapy. DNA was analysed for functional variants (-217G-->A and -20A-->C) of the AGT gene. The impact of genotype on ABP responses to ACEI monotherapy or calcium antagonists; and on plasma aldosterone and renin levels after ACEI monotherapy was assessed. RESULTS: Adjusting for baseline ABP and type of ACEI in the ACEI-treated group, the -217G-->A variant predicted ABP responses to ACEI (n = 77; P < 0.01), but not to nifedipine (n = 108). ACEI in patients with the AA genotype of the -217G-->A variant failed to elicit an antihypertensive response [change in ABP, mmHg: systolic blood pressure (SBP) +0.84 +/- 2.89, P = 0.78; diastolic blood pressure (DBP) -0.47 +/- 1.74, P = 0.79]. In contrast, those patients with at least one copy of the -217G allele developed a 7.23 +/- 1.55 and 5.38 +/- 1.12 mmHg decrease (P < 0.0001) in SBP and DBP, respectively, after ACEI administration. Similarly, the -20A-->C variant predicted ABP responses to ACEI monotherapy (P < 0.01) but not to nifedipine. Moreover, patients who were AA genotype for both variants failed to develop an antihypertensive response to ACEI (change in ABP, mmHg: SBP +1.06 +/- 3.05, P = 0.73; DBP -0.39 +/- 1.83, P = 0.83); whereas patients with at least one copy of both the -217G and the -20C allele developed substantial decreases in ABP (change in ABP, mmHg: SBP -14.08 +/- 3.72, P < 0.0001; DBP -9.62 +/- 2.74, P < 0.0001). Patients with at least one copy of the -217G allele demonstrated a significant reduction in the aldosterone-to-renin ratio (-0.098 +/- 0.035, P < 0.01), whereas in those patients who were -217AA genotype the ratio was unchanged (-0.03 +/- 0.16, P = 0.85). CONCLUSION: Functional variants of the AGT gene contribute to the variability of antihypertensive responses to ACEI monotherapy in individuals of African ancestry, with genotype determining whether or not responses occur.
Authors:
Angela J Woodiwiss; Benedicta Nkeh; Nilesh J Samani; Danelle Badenhorst; Muzi Maseko; Armindo D Tiago; Geoffrey P Candy; Elena Libhaber; Pinhas Sareli; Richard Brooksbank; Gavin R Norton
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of hypertension     Volume:  24     ISSN:  0263-6352     ISO Abbreviation:  J. Hypertens.     Publication Date:  2006 Jun 
Date Detail:
Created Date:  2006-05-10     Completed Date:  2006-08-10     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  8306882     Medline TA:  J Hypertens     Country:  England    
Other Details:
Languages:  eng     Pagination:  1057-64     Citation Subset:  IM    
Affiliation:
Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, University of the Witwatersrand, Johannesburg, South Africa. woodiwissaj@physiology.wits.ac.za
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MeSH Terms
Descriptor/Qualifier:
African Continental Ancestry Group / genetics*
Aldosterone / blood
Angiotensin-Converting Enzyme Inhibitors / pharmacology*
Angiotensinogen / genetics*
Blood Pressure / drug effects*
Body Mass Index
Calcium Channel Blockers / pharmacology
Female
Genotype
Humans
Male
Middle Aged
Renin / blood
South Africa
Chemical
Reg. No./Substance:
0/Angiotensin-Converting Enzyme Inhibitors; 0/Calcium Channel Blockers; 11002-13-4/Angiotensinogen; 52-39-1/Aldosterone; EC 3.4.23.15/Renin

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