1166 A/C polymorphism of the angiotensin II type 1 receptor gene and the response to short-term infusion of angiotensin II.

Department of Medicine/Nephrology, University of Erlangen-Nürnberg, Germany.
Circulation (Impact Factor: 14.95). 10/1999; 100(13):1394-9. DOI: 10.1161/01.CIR.100.13.1394
Source: PubMed

ABSTRACT Previous studies reported an association of the 1166 A/C polymorphism of the angiotensin II (Ang II) type 1 receptor gene with high blood pressure and cardiovascular disease. We tested the hypothesis that this polymorphism affects the blood-pressure, renal hemodynamic, and aldosterone response to infused Ang II.
Young, male, white volunteers (n = 116) with normal (n = 65) or mildly elevated (n = 51) blood pressure on a high salt intake were genotyped for the 1166 A/C polymorphism. Two doses of Ang II (0.5 and 3 ng x kg(-1) x min(-1) over 30 minutes each) increased blood pressure, plasma aldosterone, glomerular filtration rate, and filtration fraction and decreased renal blood flow. The blood-pressure, renal hemodynamic, and aldosterone responses were not significantly different between subjects homozygous for the A allele (n = 56) and heterozygous subjects (n = 47) or subjects homozygous for the C allele (n = 13). Comparison of A allele homozygotes with all C allele carriers pooled (n = 60) or restriction of the analysis to normotensive volunteers also revealed no significant differences between genotypes.
The 1166 C variant of the Ang II type 1 receptor does not lead to a greater blood-pressure, aldosterone, or renal vascular response to infused Ang II in young, male, white subjects. We conclude that the 1166 A/C polymorphism does not have a major effect on these actions of Ang II.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Whether the 1166 (A/C) polymorphism of the Angiotensin II (AII) type 1 receptor (AT1R) gene does correlate with increased vascular reactivity to AII is unclear. Accordingly we measured the blood pressure response to exogenous AII and determined the 1166A/C AT1R gene polymorphism in patients with Chronic Heart Failure (CHF). 40 patients with CHF and functional capacity compatible with NYHA class II-III were studied. All patients were genotyped for the 1166 A/C polymorphism. The frequency of the C allele was 0.2. Radial Artery Systolic Pressure (RASP) was non- invasively monitored using a Colins Pilot Monitor 9200. Ascending doses of AII were administered intravenously to increase RASP by 20 mmHg (AII Pd 20). Patients with CHF exhibited a 10-fold variability in their response to AII with Pd 20 ranging from 2.5 to 25 ng/kg. Patients with AA or AC/CC genotype, had similar AII Pd 20: 11.35 ± 1.18 vs. 13.21 ± 2.2 respectively (p = 0.42). Similarly, among the patients with decreased vascular reactivity who required ≥ 10 ng/kg of AII to achieve Pd 20 (n = 29), RASP response to 10 ng/kg of AII was comparable among patients with AA and AC/CC genotype 22.5 ± 2.8 vs. 21.9 ± 3.3 mmHg respectively (p = 0.9). In patients with CHF, the doses of AII required to increase BP by 20 mmHg demonstrate a 10-fold variability. The 1166A/C polymorphism of the AT1R gene does not account for the wide range of AII Pd 20. Factors other than 1166A/C polymorphism of the AT1R gene are likely to determine BP response to exogenous AII in CHF patients. J Clin Basic Cardiol 2001; 4: 75-77.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Molecular variants of individual components of the renin-angiotensin system have been thought to contribute to inherited predisposition toward essential hypertension. Angiotensin II type 1 receptor (AT-1) mediates the major pressor and trophic actions of angiotensin II (Ang II). Moreover, polymorphisms in genes of angiotensinogen and angiotensin-converting enzyme (ACE) have been associated with arterial hypertension and cardiovascular diseases, and some of them have been related to differential responses to antihypertensive drugs. So far, at least 25 different polymorphisms have been described in AT-1 gene (AT 1 R gene), both at the 3′ untranslated region and in its promoter region. Best evaluated with respect to the association with cardiovascular phenotypes is the +1166 A/C polymorphism. In particular, the C allele has been associated with the severe form of essential hypertension and in some studies an association was found between C allele in AT 1 R gene and D allele in ACE gene; but large discrepancies arise from ethnic variability. The role of AT1R A1166C polymorphism is ambiguous in pathologies related to high Ang II levels, such as deterioration of renal function (for example in diabetes), arterial stiffness, and hypertrophic cardiomyopathy. Recently, polymorphisms have also been described in angiotensin II type 2 receptor (AT-2) gene (AT 2 R gene), AT-2 being the mediator for vasodilatation, natriuresis, and apoptosis of smooth muscle cells. Associations were found between some of these polymorphisms and left ventricular structure, whereas the response to Ang II infusion did not differ across AT1R and AT2R genotypes. On the other hand, a relationship was suggested between AT1R A1166C polymorphism and the humoral and renal hemodynamic responses to losartan, an antihypertensive drug acting as an AT-1 blocker, as well as with enhanced Ang II vascular reactivity or sensitivity even when conflicting results were observed. The variability in the individual response to AT-1 antagonists could also result from variations in the pharmacokinetics of the drugs; in particular, losartan is essentially metabolized to its active form by cytochrome P450 2C9, which biotransforms many cardiovascular drugs but at different rates in function of both ethnic and individual genotypes. The other angiotensin II receptor, AT-2, should also be investigated because the different AT-1 antagonists do not share the same selectivity for both subtypes but all are able to increase Ang II levels, which enhances AT-2 related effects. Arterial hypertension is one of the main risk factors for stroke and coronary artery disease (CAD); however, no clear association was found between AT1R gene polymorphisms and the development of white matter lesions, stroke, CAD, or myocardial infarction, although some studies described relationships between AT1R A1166C polymorphism and hypercholesterolemia, or greater induced arterial vasoconstriction in CAD. Moreover, AT1R C allele, when associated with ACE D allele (of I/D polymorphism), could contribute to susceptibility to CAD and to interindividual differences in severity of cardiovascular disease. Further evaluation in adequately powered studies is necessary for final assessment of allelic markers in RAS component genes, namely AT 1 R and AT 2 R genes, as well as to determine predisposition to hypertension or related diseases, and to choose an antihypertensive drug for an individual and to develop more specifically targeted drugs.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A common molecular variant of the angiotensinogen gene had been reported to predispose some ethnic groups to hypertension. This case–control study was designed to determine the frequency and association of the angiotensinogen M235T allele with hypertension in residents of Calabar and Uyo cities, south–south Nigeria.The study involved 1308 subjects, 612 patients and 696 controls. The M235T variant was investigated using an allele specific polymerase chain reaction and enzymatic digestion to determine allele frequencies. Hypertensinogenic factors such as dietary habits, physical activity, smoking and drinking habits were assessed using questionnaires. Descriptive statistics, chi-square and multiple regression analysis were used to analyze the data obtained.The M235T allele frequency was high (0.94 for hypertensives and 0.96 for controls) though it was not associated with hypertension status. The odds ratio for hypertension was 0.64 (95% confidence interval: 0.39–1.06) there were no significant differences between the genotype frequency of hypertensives and controls. By multiple regression, Hypertension was observed to be associated with age and was a predictor for systolic blood pressure in both patient r2 = 0.359; p < 0.05 and control groups r2 = 0.26.Age and body mass index were predictors for diastolic blood pressure in the control group, r2 = 0.28.Although the frequency of the M235T variant was high, it was not a significant risk factor for hypertension in the study population.
    Egyptian Journal of Medical Human Genetics 01/2013; 14(1):13–19. DOI:10.1016/j.ejmhg.2012.06.007