The epistasis between vascular homeostasis genes is apparent in essential hypertension

Atherosclerosis. 2012 Feb;220(2):418-24. doi: 10.1016/j.atherosclerosis.2011.10.036. Epub 2011 Nov 2.


Objective: The epistasis influence of vascular homeostasis genes is vital to multigenetic diseases. This study was designed to perceive the possible role of epistasis in the etiology of essential hypertension.

Methods: We investigated seven polymorphisms of ACE, CYP11B2 and NOS3 epistatically, and SBP, DBP, MAP, ACE activity, plasma aldosterone concentration (PAC) and NOx level in 860 age- and ethnicity-matched unrelated north-Indian subjects.

Results: The hypertension risk in individuals with interacted-genotypes (IwIw+IwIc)+(4aa), (IcIc)+(4bb+4ba) and IcIc+4aa of the CYP11B2 and NOS3 was significantly higher with odds ratio 5.5 (95% CI=2.9-10.6, P<0.0001), 2.4 (95% CI=1.4-4.1, P<0.0008) and 7.5 (95% CI=1.6-34.8, P=0.010), respectively. The odds ratio for hypertension with interacted-haplotypes (-344T/Ic)+(-922A/-786T/4a/894G) and (-344T/Ic)+(-922G/-786C/4a/894G) of CYP11B2 and NOS3 was 5.3 (95% CI=2.0-14.2, P=0.005) and 3.9 (95% CI=1.4-10.4, P=0.04), respectively; whereas for the protective interacted-haplotypes (-344T/Iw)+(-922A/-786T/4b/894G), the odds ratio was 0.7 (95% CI=0.5-0.9, P=0.03). While the interacted-genotypes, IcIc+4aa correlated with higher SBP and MAP (P=0.006; P=0.04), the interacted-haplotypes, (-344T/Ic)+(-922A/-786T/4a/894G) and (-344T/Ic)+(-922G/-786C/4a/894G) correlated with higher MAP and lower NOx level (P=0.02 and P=0.03, respectively), and the protective interacted-haplotypes (-344T/Iw)+(-922A/-786T/4b/894G) correlated with lower PAC and MAP (P=0.024 and P=0.018, respectively).

Conclusions: The epistasis between CYP11B2 and NOS3 and its correlation with varied clinical and biochemical parameters signify its possible contribution in the complex etiology of hypertension.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aldosterone / blood
  • Analysis of Variance
  • Blood Pressure / genetics*
  • Case-Control Studies
  • Chi-Square Distribution
  • Cytochrome P-450 CYP11B2 / genetics*
  • Epistasis, Genetic*
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Haplotypes
  • Humans
  • Hypertension / blood
  • Hypertension / genetics*
  • Hypertension / physiopathology
  • India
  • Linkage Disequilibrium
  • Male
  • Middle Aged
  • Nitrates / blood
  • Nitric Oxide / blood
  • Nitric Oxide Synthase Type III / genetics*
  • Nitric Oxide Synthase Type III / metabolism
  • Nitrites / blood
  • Odds Ratio
  • Peptidyl-Dipeptidase A / genetics
  • Peptidyl-Dipeptidase A / metabolism
  • Phenotype
  • Polymorphism, Genetic*
  • Risk Assessment
  • Risk Factors


  • Nitrates
  • Nitrites
  • Nitric Oxide
  • Aldosterone
  • NOS3 protein, human
  • Nitric Oxide Synthase Type III
  • Cytochrome P-450 CYP11B2
  • Peptidyl-Dipeptidase A