Variation in bradykinin receptor genes increases the cardiovascular risk associated with hypertension

Aims The contribution of kinins to the beneficial effects of angiotensin I converting enzyme (ACE) inhibition in cardiovascular risk reduction remains unclear. The genes for the kinin inducible B1 receptor (B1R) and constitutive B2 receptor (B2R) contain functional variants: the B1R−699C (rather than G) and the B2R(−9) (rather than +9) alleles are associated with greater mRNA expression and the B2R(−9) allele with reduced left ventricular hypertrophic responses. We tested whether these gene variants influenced hypertensive coronary risk in a large prospective study. Methods and results Two thousand, seven hundred and six previously healthy UK men (mean age at recruitment 56 years; median follow-up 10.8 years) were genotyped for the kinin receptor variants. The coronary risk attributable to systolic hypertension (SBP≥160mmHg) was significantly higher only in B1R−699GG homozygotes (HR 2.14 [1.42–3.22]; P <0.0001) and B2R(+9,+9) individuals (HR 3.51 [1.69–7.28]; P =0.001) but not in B1R−699C allele carriers (HR 0.82 [0.28–2.42]; P =0.76) or in B2R(−9,−9) homozygotes (HR 1.25 [0.51-3.04]; P =0.63). Conclusions Common variation in the genes for the kinin B1and B2receptors influences prospective hypertensive coronary risk. These are the first reported human data to suggest a role for the B1R in human coronary vascular disease, and the first prospective study to demonstrate a similar role for the B2R.