Rho kinase polymorphism influences blood pressure and systemic vascular resistance in human twins - Role of heredity

The Rho/ Rho kinase ( ROCK) pathway is implicated in experimental hypertension. We, therefore, explored the role of ROCK2 genetic variation in human blood pressure ( BP) regulation, exploiting the advantages of a human twin sample to probe heritability. The focus of this work is the common nonsynonymous variant at ROCK2: Thr431Asn. Cardiovascular and autonomic traits displayed substantial heritability ( from approximate to 33% to 71%; P < 0.05). The Asn/ Asn genotype ( compared with Asn/ Thr or Thr/ Thr) was associated with greater resting systolic ( P < 0.001), diastolic ( P < 0.0001), and mean BP ( P < 0.0001); allelic variation at ROCK2 accounted for up to approximate to 5% of BP variation ( P < 0.0001). Systemic vascular resistance was higher in Asn/ Asn individuals ( P = 0.049), whereas cardiac output, large artery compliance, and vasoactive hormone secretion were not different. Coupling of the renin- angiotensin system to systemic resistance and BP was diminished in Asn/ Asn homozygotes, suggesting genetic pleiotropy of Thr431Asn, confirmed by bivariate genetic analyses. The Asn/ Asn genotype also predicted higher BP after environmental ( cold) stress. The rise in heart rate after cold was less pronounced in Asn/ Asn individuals, consistent with intact baroreceptor function, and baroreceptor slope was not influenced by genotype. Common genetic variation ( Thr431Asn) at ROCK2 predicts increased BP, systemic vascular resistance ( although not large artery compliance), and resistance in response to the endogenous renin- angiotensin system, indicating a resistance vessel- based effect on elevated BP. The results suggest that common variation in ROCK2 exerts systemic resistance- mediated changes in BP, documenting a novel mechanism for human circulatory control, and suggesting new possibilities for diagnostic profiling and treatment of subjects at risk of developing hypertension.