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(Hypertension. 2006;47:937.)
© 2006 American Heart Association, Inc.

Original Articles

Rho Kinase Polymorphism Influences Blood Pressure and Systemic Vascular Resistance in Human Twins

Role of Heredity

Tammy M. Seasholtz; Jennifer Wessel; Fangwen Rao; Brinda K. Rana; Srikrishna Khandrika; Brian P. Kennedy; Elizabeth O. Lillie; Michael G. Ziegler; Douglas W. Smith; Nicholas J. Schork; Joan Heller Brown; Daniel T. O’Connor

From the Departments of Biology (D.W.S.), Medicine (F.R., S.K., B.P.K., E.O.L., M.G.Z., D.T.O.), Pharmacology (T.M.S., J.H.B., D.T.O.), and Psychiatry (J.W., B.K.R., N.J.S., J.H.B.), Polymorphism Research Laboratory (N.J.S.), Center for Molecular Genetics (D.T.O.), San Diego, Ca; and Center for Human Genetics and Genomics (N.J.S., D.T.O.), University of California at San Diego, San Diego, Ca; and VA San Diego Healthcare System (D.T.O.), San Diego, Ca.

Correspondence to Daniel T. O’Connor or Joan Heller Brown, Departments of Medicine and Pharmacology, University of California at San Diego School of Medicine and VA San Diego Healthcare System, 9500 Gilman Dr, La Jolla, CA 92093-0838. E-mail doconnor{at}ucsd.edu or jhbrown@ucsd.edu

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 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 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.

Key Words: vascular resistance • blood pressure • hypertension, renal • renin

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