Functional variants of the angiotensinogen gene determine antihypertensive responses to angiotensin-converting enzyme inhibitors in subjects of African origin

Woodiwiss, Angela J.; Nkeh, Benedicta; Samani, Nilesh J.; Badenhorst, Danelle; Maseko, Muzi J.; Tiago, Armindo; Candy, Geoffrey P.; Libhaber, Elena; Sareli, Pinhas; Brooksbank, Richard; Norton, Gavin R.

doi:10.1097/01.hjh.0000226195.59428.57

Cited by 21 publications

(16 citation statements)

References 26 publications

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“…Studies of the effects of ACE inhibitors on blood pressure in relation to the ACE I/D or AGT M235T polymorphisms have likewise resulted in conflicting data [23,[27][28][29][30][31][32][33][34]. Collectively, there are no conclusive and well replicated data on the relation between various RAS gene variants and response to prolonged ACE inhibitor or AGTR1 antagonist treatment.…”

Section: Discussionmentioning

confidence: 96%

Common genetic variations of the renin–angiotensin–aldosterone system and response to acute angiotensin I-converting enzyme inhibition in essential hypertension

Hannila‐Handelberg

Kontula²,

Paukku³

et al. 2010

Journal of Hypertension

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Objective In order to get insight into possible genetic determinants of antihypertensive drug action, we analysed the relations between polymorphisms of the genes of the renin-angiotensin-aldosterone system and acute effects of ACE inhibition on blood pressure as well as circulating renin and aldosterone levels in hypertensive patients.Methods A total of 315 hypertensive patients referred for problems in drug treatment were given a single 50 mg dose of captopril. Plasma renin and aldosterone were measured before and 60 min after the drug administration. Four DNA variants, including angiotensin type I receptor (AGTR1) 1166 A/C, angiotensin-converting enzyme (ACE) I/D, angiotensinogen (AGT) M235T and AGT -217 G/A, were genotyped in the patients and normotensive men (n U 175). A replication study on the relation between AGTR1 1166 A/C and plasma renin and aldosterone levels was carried out in the 244 hypertensive men of the pharmacogenetic GENRES Study.Results Referred hypertensive patients with the AGTR1 CC genotype had higher aldosterone at baseline (P U 0.02) and after 60 min of captopril administration (P U 0.01) compared with the AA genotype. Replicate analysis in the GENRES patients showed a similar trend. When the two studies were combined (315 and 244 patients, respectively), plasma aldosterone level (P U 0.007) as well as aldosterone/renin ratio (P U 0.04) were significantly higher in the CC genotype (n U 13) than in the AA genotype (n U 370). Transfection studies in cultured HEK293 cells indicated that the 1166C allele was associated with higher mRNA levels than the 1166A allele.Conclusion The AGTR1 1166C allele when present in homozygous form may be associated with a form of essential hypertension characterized by high plasma aldosterone and low plasma renin levels, possibly due to increased AGTR1 mRNA levels and augmented angiotensin II action.

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Section: Discussionmentioning

confidence: 96%

Common genetic variations of the renin–angiotensin–aldosterone system and response to acute angiotensin I-converting enzyme inhibition in essential hypertension

Hannila‐Handelberg

Kontula²,

Paukku³

et al. 2010

Journal of Hypertension

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“…In other situations, such as non-communicable diseases, the eYcacy may be more tied to the actual etiological risk. For example, it has been shown in Black South Africans that AGT genotype can aVect response to ACE inhibitor therapy for hypertension (Woodiwiss et al 2006). Pharmacogenetics aims at understanding this genetic diversity underlying the pharmacokinetic and pharmacodynamic variability in drug response among patients, enabling personalized treatment, optimal dosing and minimal adverse eVects.…”

Section: Pharmacogeneticsmentioning

confidence: 99%

Genetic studies of African populations: an overview on disease susceptibility and response to vaccines and therapeutics

et al. 2008

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Africa is the ultimate source of modern humans and as such harbors more genetic variation than any other continent. For this reason, studies of the patterns of genetic variation in African populations are crucial to understanding how genes affect phenotypic variation, including disease predisposition. In addition, the patterns of extant genetic variation in Africa are important for understanding how genetic variation affects infectious diseases that are a major problem in Africa, such as malaria, tuberculosis, schistosomiasis, and HIV/AIDS. Therefore, elucidating the role that genetic susceptibility to infectious diseases plays is critical to improving the health of people in Africa. It is also of note that recent and ongoing social and cultural changes in sub-Saharan Africa have increased the prevalence of non-communicable diseases that will also require genetic analyses to improve disease prevention and treatment. In this review we give special attention to many of the past and ongoing studies, emphasizing those in Sub-Saharan Africans that address the role of genetic variation in human disease.

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“…ACE inhibitors are less effective as monotherapy in black adults because of low renin levels and a high degree of salt sensitivity (14). This differential response of the renin angiotensin system in blacks may be due to genetic polymorphisms in the angiotensinogen gene (15,16). In black adults, the intrarenal reninangiotensin system is not suppressed as effectively as in whites in response to high salt intake but shows the same level of activation with low salt intake.…”

Section: Discussionmentioning

confidence: 97%

Racial Differences in Blood Pressure Response to Angiotensin-Converting Enzyme Inhibitors in Children: A Meta-Analysis

Smith

et al. 2008

Clin Pharmacol Ther

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Angiotensin-converting enzyme (ACE) inhibitors are frequently used to treat hypertension in children (1). ACE inhibitors alter the balance between the vasoconstrictive, salt-retentive, and cardiac hypertrophic properties of angiotensin II and the vasodilatory and natriuretic properties of bradykinin; they also alter the metabolism of other vasoactive substances (2). Through these mechanisms, ACE inhibitors decrease systemic vascular resistance and promote natriuresis without increasing heart rate. They have proven efficacy in the treatment of hypertension, congestive heart failure, and left ventricular dysfunction and also delay the progression of diabetic nephropathy (2). In adults, ACE inhibitors are less potent in blacks than in whites (3,4). Although racial differences in response to ACE inhibitors are established in adults, data in children are limited by small sample sizes of individual trials (5,6). We evaluated results of 6 trials of ACE inhibitors submitted to the US Food and Drug Administration (FDA) for pediatric exclusivity using meta-analytic techniques to estimate the effect of race on blood pressure response. METHODS The cohortBetween January 1, 1998, and December 31, 2005, efficacy data from 12 antihypertensive products were submitted to the FDA's Division of Cardiovascular and Renal Products. We used the randomized, blinded efficacy trials for this analysis (7). One efficacy trial and at least 1 pharmacokinetic-pharmacodynamic (PK-PD) trial were completed for each agent. Summaries of medical and clinical pharmacology reviews of several of the studies are publicly available (8). Except for demonstrating differences in clearance and half-life for benazepril, the PK trials did not indicate differential dosing from adult data and did not suggest differences in absorption, bioavailability, clearance, or differential response by age or development. PK-PD samples were not obtained in the efficacy trials; therefore, we did not include PK-PD results in this analysis. The PK trials were performed in children ages 1 month to 16 years with the exception of the quinapril trial which was performed in children ages 2.5 months to 6 years and the ramipril trial which was performed in children ages 2 years to 6 years (8-11). In our Of the 12 efficacy trials, 6 were conducted with ACE inhibitors. Inclusion and exclusion criteria among trials were similar. The studies enrolled children 6-16 years of age. The trials excluded children with severe hypertension (because of a placebo phase), low glomerular filtration rates (< 30 mL/min/1.73 m 2 ), electrolyte abnormalities, renal disease, and other substantive medical problems including clinically significant cardiac disease (5). The trial design (12) and dosing strata of each study are shown in Table 1. Data managementThe data, protocols, and case report forms from these 6 trials were submitted electronically to the FDA. Source data were available in SAS datasets, which we converted to STATA datasets via STAT Transfer. We combined patient-level data to obtain 1...

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Functional variants of the angiotensinogen gene determine antihypertensive responses to angiotensin-converting enzyme inhibitors in subjects of African origin

Abstract: 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.

Cited by 21 publications

References 26 publications

Common genetic variations of the renin–angiotensin–aldosterone system and response to acute angiotensin I-converting enzyme inhibition in essential hypertension

Common genetic variations of the renin–angiotensin–aldosterone system and response to acute angiotensin I-converting enzyme inhibition in essential hypertension

Genetic studies of African populations: an overview on disease susceptibility and response to vaccines and therapeutics

Racial Differences in Blood Pressure Response to Angiotensin-Converting Enzyme Inhibitors in Children: A Meta-Analysis

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