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 approximately 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 approximately 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.
Department of Pharmacology, University of California, San Diego, CA, USA.
Tammy M
TM
Seasholtz
Jennifer
J
Wessel
Fangwen
F
Rao
Brinda K
BK
Rana
Srikrishna
S
Khandrika
Brian P
BP
Kennedy
Elizabeth O
EO
Lillie
Michael G
MG
Ziegler
Douglas W
DW
Smith
Nicholas J
NJ
Schork
Joan Heller
JH
Brown
Daniel T
DT
O'Connor
D000328:Adult; D000450:Aldosterone / Q000097:blood; D001216:Asparagine; D001794:Blood Pressure / Q000235:genetics; D002302:Cardiac Output; D003080:Cold Temperature; D005260:Female; D005838:Genotype; D006720:Homozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D010641:Phenotype; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011311:Pressoreceptors / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012083:Renin / Q000097:blood; D013312:Stress, Physiological / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D013912:Threonine; D014655:Vascular Resistance / Q000235:genetics*; D054460:rho-Associated Kinases
D047908:Intracellular Signaling Peptides and Proteins; D013912:Threonine; D000450:Aldosterone; D001216:Asparagine; D017346:Protein Serine-Threonine Kinases; C515852:ROCK2 protein, human; D054460:rho-Associated Kinases; D012083:Renin