Genetic variants of angiotensin II receptors and cardiovascular risk in hypertension

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, 56.1 +/- 3.5 years; median follow-up, 10.1 years) genotyped for the AT(1)R1166A > C and the X chromosome located AT(2)R1675A > G and 3123C > A 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]; P = 0.03) independent of blood pressure. Systolic blood pressure was associated with risk (P = 0.0005), but this association was restricted to AT(2)R1675A allele carriers (P < 0.00001), with G allele carriers protected from the risk associated with blood pressure (P = 0.18). 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.