Interactions among genetic variants from contractile pathway of vascular smooth muscle cell in essential hypertension susceptibility of Chinese Han population.
OBJECTIVE
Recent study supports the hypothesis that the abnormalities of vascular smooth muscle cell (VSMC) that alter the intrinsic contractile state of the cell can directly cause abnormal vascular tone and disorders of blood pressure regulation, including hypertension. This study aimed to explore the individual and interactive effects of five genes from the contractile pathway of VSMC (KCNMB1, RGS2, PRKG, ROCK2, and MYLK) on the risk of essential hypertension.


METHODS
Potential functional polymorphisms of the five genes were analyzed in a large, representative Chinese Han sample of 4759 individuals, including 2411 hypertensive patients and 2348 age-matched and sex-matched healthy controls.


RESULTS
Single locus analyses showed significant association of the alleles of RGS2-rs34717272 with hypertension (original P of chi2 test=0.005; P value of permutation=0.019). After the adjustment for covariates, the carriers of minor D allele of RGS2-rs34717272 had an increased hypertension risk (DD+ID vs. II; odds ratio=1.19; 95% confidence interval, 1.04-1.35; P value after the Bonferroni correction=0.009 x 5=0.045). We also found that the carriers of minor T allele of KCNMB1-rs11739136 had a significantly decreased risk for hypertension (TT+CT vs. CC; odds ratio=0.83; 95% confidence interval, 0.72-0.95; P value after the Bonferroni correction=0.008 x 5=0.040). Final interaction models were selected and evaluated by permutation test and/or cross-validation test. Both the multifactor-dimensionality reduction and classification and regression trees methods showed a high-order gene-gene interaction among KCNMB1, RGS2, PRKG, and MYLK genes (P value of permutation in multifactor-dimensionality reduction=0.012).


CONCLUSIONS
The overall results supported that the genetic variants in the contractile pathway of VSMC could contribute to hypertension risk independently or in an interactive manner.
Zhao
Qi
Q
Department of Evidence Based Medicine and Division of Population Genetics, Cardiovascular Institute and Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.
Wang
Laiyuan
L
Yang
Wei
W
Chen
Shufeng
S
Huang
Jianfeng
J
Fan
Zhongjie
Z
Li
Hongfan
H
Lu
Xiangfeng
X
Gu
Dongfeng
D
D000328:Adult; D000483:Alleles; D044466:Asian People / Q000235:genetics*; D002135:Calcium-Binding Proteins / Q000235:genetics; D016022:Case-Control Studies; D002681:China; D017869:Cyclic GMP-Dependent Protein Kinases / Q000235:genetics; D004843:Epistasis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000503:physiopathology*; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D009119:Muscle Contraction / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology*; D009219:Myosin-Light-Chain Kinase / Q000235:genetics; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D020710:RGS Proteins / Q000235:genetics; D014661:Vasoconstriction / Q000235:genetics; D054460:rho-Associated Kinases / Q000235:genetics
D002135:Calcium-Binding Proteins; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits; D020710:RGS Proteins; C087182:RGS2 protein, human; C515852:ROCK2 protein, human; D054460:rho-Associated Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; C499378:MYLK protein, human; D009219:Myosin-Light-Chain Kinase