Genetic Variants of Angiotensin II Receptors and Cardiovascular Risk in Hypertension

Abstract

Abstract-Renin-angiotensin systems may mediate cardiovascular disease pathogenesis through a balance of actions of angiotensin II on (potentially proatherogenic) constitutive type 1 (AT 1 R) and (potentially antiatherogenic) inducible type 2 (AT 2 R) receptors. We explored such potential roles in a prospective candidate gene association study. Cardiovascular end points (fatal, nonfatal, and silent myocardial infarction and coronary artery bypass surgery/angioplasty) were documented among 2579 healthy UK men (mean age, 56.1Ϯ3.5 years; median follow-up, 10.1 years) genotyped for the AT 1 R1166AϾC and the X chromosome located AT 2 R1675AϾG and 3123CϾA polymorphisms. Baseline characteristics, including blood pressure, were independent of genotype. The AT 1 R1166CC genotype was associated with relative cardiovascular risk (hazard ratio, 1.65 [1.05 to 2.59]; Pϭ0.03) independent of blood pressure. Systolic blood pressure was associated with risk (Pϭ0.0005), but this association was restricted to AT 2 R1675A allele carriers (PϽ0.00001), with G allele carriers protected from the risk associated with blood pressure (Pϭ0.18). Hypertensive carriers with the AT 2 R1675A/3123A haplotype were at most risk, with 37.5% having an event. This is the first study to demonstrate an association of AT 2 R genotype with coronary risk, an effect that was confined to hypertensive subjects and supports the concept that the inducible AT 2 R is protective. Conversely, the AT 1 R1166CC genotype was associated with cardiovascular risk irrespective of blood pressure. These data are important to our understanding of the divergent role of angiotensin II acting at its receptor subtypes and coronary disease pathogenesis and for the development of future cardiovascular therapies. Coronary vascular ACE drives Ang II synthesis, whose action on local AT 1 and inducible AT 2 receptors (AT 2 R) 2,3 may contribute to coronary heart disease (CHD) pathogenesis: AT 1 R activation causes vascular smooth muscle cell hypertrophy, extracellular matrix production, and local inflammation, driving atherogenesis and plaque rupture, 4 whereas AT 2 R agonism inhibits vascular cell proliferation 5 and may be antiatherogenic. 6 The balance between AT 1 R and AT 2 R activation may therefore influence CHD risk. However, this remains difficult to explore, and supportive data are sparse. Studies involving selective AT 1 R antagonism are perhaps less informative than they might at first appear: although lowering CHD risk more than equihypotensive ␤-blockade, 7 this may be partly mediated through AT 2 R agonism-loss of negative feedback raising Ang II levels and hence binding to the vacant AT 2 R. 8Could there be a role for both the AT 1 R and AT 2 R in the development of CHD? Genetic studies may provide insight. A polymorphism of the AT 1 R gene exists at position 1166, where the C (rather than A) allele is associated with increased Ang II responsiveness. 9 Meanwhile, the A (rather than G) allele at position 1675 of the X-chromosomal AT 2 R gene is associated with a greater ...

The two single nucleotide polymorphisms in the H37/RBM5 tumour suppressor gene at 3p21.3 correlated with different subtypes of non-small cell lung cancers

“…For example, a link has been found between the silent SNP 102C/T of the 5-HT2A receptor gene in the temporal cortex and the pathogenesis of schizophrenia [31]. Jones and colleagues have shown that silent polymorphisms of the angiotensin-2 receptor increase cardiovascular risk in hypertension [32], while Arriba-Mendez and colleagues have found that when the C allele is present in the silent SNP 927T/C, male children may be predisposed to asthma and atopic dermatitis [33]. Similarly, a silent SNP, 988C→T of the Fas gene has been shown to have significant implications in the development of papillary thyroid carcinoma [33].…”

Association between plasma activities of semicarbazide-sensitive amine oxidase and angiotensin-converting enzyme in patients with type 1 diabetes mellitus

“…Serum ACE activity, HbA 1 c and ACE I/D, AT1R (AT1R 1166A>C) and AT2R (AT2R 1675A>G) genotypes were determined as previously reported [15,22,23]. Renin concentrations were measured by radioimmunoassay of generated angiotensin I, as was angiotensinogen in the presence of added excess of renin [24].…”

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“…24,25) A number of initial studies attempted to address the possibility that polymorphisms at various candidate genes might be associated with the pathogenesis of CAD and some concluded there was a significant association between them. For example, polymorphisms in renin-angiotensin system gene polymorphisms (angiotensin-type receptor genes, angiotensin II converting enzyme genes) are well known to be associated with hypertension, 26) CAD [27][28][29][30][31] and MI, [32][33][34] though dissenting opinions still exist.…”