on August 18, 2003
Published online before print August 18, 2003, doi: 10.1161/01.HYP.0000088853.27673.D0
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Submitted on March 24, 2003
From the Centre for Cardiovascular Genetics, Royal Free and University College Medical School, London, UK, and Medical Research Council Cardiovascular Research Group (G.J.M.), Wolfson Institute of Preventative Medicine, London, UK. * To whom correspondence should be addressed. E-mail: h.montgomery{at}ucl.ac.uk.
Abstract--Renin-angiotensin systems may mediate cardiovascular disease pathogenesis through a balance of actions of angiotensin II on (potentially proatherogenic) constitutive type 1 (AT1R) and (potentially antiatherogenic) inducible type 2 (AT2R) 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 AT1R1166A>C and the X chromosome located AT2R1675A>G and 3123C>A polymorphisms. Baseline characteristics, including blood pressure, were independent of genotype. The AT1R1166CC 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 AT2R1675A allele carriers (P<0.00001), with G allele carriers protected from the risk associated with blood pressure (P=0.18). Hypertensive carriers with the AT2R1675A/3123A haplotype were at most risk, with 37.5% having an event. This is the first study to demonstrate an association of AT2R genotype with coronary risk, an effect that was confined to hypertensive subjects and supports the concept that the inducible AT2R is protective. Conversely, the AT1R1166CC 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.
Revised on May 1, 2003
Genetic Variants of Angiotensin II Receptors and Cardiovascular Risk in Hypertension
Alun Jones;
Key words: receptors, angiotensin II • genetics • polymorphism • cardiovascular diseases • hypertension, genetic
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