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

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.

Impact of renin-angiotensin-aldosterone system gene variants on the severity of hypertension in patients with newly diagnosed hypertension.

BACKGROUND: The severity of hypertension has prognostic significance. Previous studies have assessed the relationship between renin-angiotensin-aldosterone system (RAAS) genotype and the severity of hypertension in either treated patients or those who have only recently discontinued treatment. METHODS: We assessed the impact of RAAS genotype on ambulatory and office blood pressure (BP) in 231 newly diagnosed hypertensive patients of African ancestry who had never received therapy. Subjects were genotyped for variants of the angiotensin-converting enzyme (insertion/deletion), angiotensinogen (M235T, -20A-->C), and aldosterone synthase (CYP11B2)(-344C-->T) genes. RESULTS: The CYP11B2 gene polymorphism was associated with systolic BP (SBP). In comparison to subjects with at least one copy of the -344C allele (n = 75), patients who were homozygous for the -344T allele (n = 156) had both higher ambulatory SBP (150 +/- 1 v 144 +/- 1 mm Hg, P =.002 before and P =.01 after adjusting for multiple genotyping) and office SBP (163 +/- 2 v 156 +/- 2 mm Hg, P =.01 before and P =.05 after adjusting for multiple genotyping). Neither the angiotensin-converting enzyme insertion/deletion nor the angiotensinogen gene polymorphisms were associated with ambulatory or office SBP or diastolic BP (DBP). The CYP11B2 gene variant also did not affect DBP. CONCLUSION: A variant within the CYP11B2 locus has a clinically important impact on the severity of SBP changes in individuals with newly diagnosed hypertension who are of African ethnicity.

T594M variant of the epithelial sodium channel beta-subunit gene and hypertension in individuals of African ancestry in South Africa.

BACKGROUND: The T594M variant of the beta-subunit of the sodium epithelial channel (ENaC) gene may contribute to hypertension in individuals of African origin. METHODS: A case-control study was performed to assess the role of the ENaC gene variant as an independent risk factor for hypertension in subjects of African ancestry. The effects of the ENaC gene variant on ambulatory blood pressure (BP) in hypertensive individuals and on office BP in hypertensive individuals and control subjects were also assessed. A total of 519 hypertensive patients with 24-h ambulatory BP (ABP) values determined while off medication, and 514 normotensive South African individuals of African ancestry were genotyped for the T594M polymorphism of the ENaC gene. RESULTS: A total of 22 (4.2%) hypertensive participants compared with 23 (4.5%) normotensive participants possessed the T594M variant (odds ratio = 1.06, confidence interval = 0.58 to 1.92, not significant). A similar genotype frequency distribution was noted in subjects representing the two predominant chiefdoms (Nguni and Sotho) in both case and control groups. No differences in frequency distribution of the T594M variant were noted with respect to either body mass index or gender. There were no differences in clinic or ambulatory mean, day, or night BP between hypertensive patients with or without the variant. Similarly, no differences were noted in clinic BP between control subjects with or without the variant. Other phenotypic parameters (including age and hypertension duration and severity) were also similar among hypertensive patients with or without the variant. CONCLUSION: These results do not support an important role for the T594M variant of the ENaC gene contributing to either the development or severity of hypertension in subjects of African ancestry.

Association between an atrial natriuretic peptide gene polymorphism and normal blood pressure in subjects of African ancestry.

AIM: The roles of the atrial natriuretic peptide (ANP) gene and the clearance receptor of the ANP (NPRC) gene in hypertensive groups of African ancestry are unclear. The aim of the present study was to assess the relationship between both ANP and NPRC gene polymorphisms and hypertension in Black South Africans. METHODS: 298 patients, diagnosed as having essential hypertension according to 24-hour ambulatory blood pressure (BP) measurements (mean daytime diastolic BP> 90 mm Hg) whilst off medication, and 278 normotensive control subjects of a similar African ancestry, were genotyped for polymorphic markers in intron 2 (which is in complete linkage disequilibrium with a potentially functional exon 1 variant) and exon 3 (which leads to the extension of ANP by two additional arginines) of the ANP gene. Moreover, 64 hypertensives and 63 control from the same groups were genotyped for the cis-acting promoter/enhancer element of the NPRC gene. RESULTS: No relationship between the exon 3 variant and either the presence (odds ratio = 1.075) or the severity (24-hour BP) of hypertension was noted. The intron 2 polymorphism occurred at a low frequency in the control group (frequency of subjects heterozygous for the variant = 6.1%), but was almost absent in the hypertensive group (frequency of heterozygotes = 1.7%). Consequently, a relationship between a normal BP and the intron 2 variant was noted (odds ratio = 0.28, confidence interval = 0.10-0.76, p < 0.01, <1% chance of false positive results). The NPRC gene variant occurred with an equally low frequency in both the hypertensive (4.7%) and the control (4.8%) groups. CONCLUSIONS: The results of the present study suggest that the ANP, but not the NPRC locus contributes to BP in subjects of African ancestry.