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(Hypertension. 2003;42:500.)
© 2003 American Heart Association, Inc.

Scientific Contributions

Genetic Variants of Angiotensin II Receptors and Cardiovascular Risk in Hypertension

Alun Jones; Sukhbir S. Dhamrait; John R. Payne; Emma Hawe; Ping Li; Iqbal S. Toor; Le Luong; Peter T.E. Wootton; George J. Miller; Steve E. Humphries; Hugh E. Montgomery

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.

Correspondence to Dr Hugh E. Montgomery, Portex Senior Lecturer in Cardiovascular Genetics, British Heart Foundation Laboratories, Royal Free and University College Medical School, Rayne Building, 5 University Street, London WC1E 6JF, UK. E-mail h.montgomery{at}ucl.ac.uk

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.

Key Words: receptors, angiotensin II • genetics • polymorphism • cardiovascular diseases • hypertension, genetic

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