Interaction of alpha(1)-Na,K-ATPase and Na,K,2Cl-cotransporter genes in human essential hypertension

Essential hypertension is a common disease the genetic determinants of whic h have been difficult to unravel because of its clinical heterogeneity and complex, multifactorial, polygenic etiology. Based on our observations that alpha (1)-Na,K-ATPase (ATP1A1) and renal-specific, bumetanide-sensitive Na ,K,2Cl-cotransporter (NKCC2) genes interactively increase susceptibility to hypertension in the Dahl salt-sensitive hypertensive (Dahl S) rat model, w e investigated whether parallel molecular genetic mechanisms might exist in human essential hypertension in a relatively genetic homogeneous cohort in northern Sardinia. Putative ATP1A1-NKCC2 gene interaction was tested by co mparing hypertensive patients (blood pressure [BP] > 165/95 mm Hg) with nor motensive controls age >60 years with BP < 140/85 mm Hg. Genotype analysis with microsatellite markers revealed conformation to Hardy-Weinberg proport ions for 6 alleles of both ATP1A1 (D1S453) and NKCC2 (NKCGT7) markers, resp ectively. Two-by-six <chi>(2) analysis of alleles identified overrepresenta tion of ATP1A1 No. 4 and NKCC2 No. 4 alleles, respectively, in hypertensive s compared with controls. With a qualitative trait framework, single-gene a nalysis detected association of both the ATP1A1 No. 4 allele (P=0.004, chi (2)=8.094, df=1) and the NKCC2 No. 4 allele (P=0.0002, chi (2)=14.279, df=1 ) with moderate to severe hypertension. Digenic analysis revealed that ATP1 A1 No. 4-NKCC2 No. 4 allele interaction increases susceptibility to hyperte nsion (P<0.0001, <chi>(2) = 22.3, df=1) beyond levels obtained in single-ge ne analysis. Analysis was also performed in a quantitative trait framework with BP as the continuous trait parameter. Digenic analysis of ATP1A1 No. 4 -NKCC2 No. 4 allele interaction revealed significant association with systo lic (1-way ANOVA, P=0.000076) and diastolic (P=0.00099) BP. Interaction was corroborated by 2X2 factorial ANOVA for interaction (systolic BP interacti on term, P<0.05, diastolic BP interaction term, P=0.035). The data are comp elling that ATP1A1 and NKCC2 genes are candidate interacting hypertension-s usceptibility loci in human essential hypertension and affirm gene interact ion as an important genetic mechanism underlying hypertension susceptibilit y. Although corroboration in other cohorts and identification of functional ly significant mutations are imperative next steps, the data provide a geno type-stratification scheme, with 4-fold predictive value (odds ratio, 4.28; 95% confidence interval, 2.29 to 8.0), which could help decipher the compl ex genetics of essential hypertension.