(Hypertension. 2001;38:204.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Interaction of 
1-Na,K-ATPase and Na,K,2Cl-Cotransporter Genes in Human Essential Hypertension
From Clinica Medica, Universita di Sassari (N.G., F.F., C.T., A.S., P.P.P.), Sassari, Italy; and Whitaker Cardiovascular Institute, Evans Department of Medicine (A.T., V.L.M.H., N.R.-O.) and Department of Neurology (R.H.M.), Boston University School of Medicine, Mass.
Correspondence to Nelson Ruiz-Opazo, PhD, Whitaker Cardiovascular Institute, Boston University School of Medicine, 700 Albany St, Boston, MA 02118, E-mail nruizo{at}bu.edu; and Nicola Glorioso, MD, Clinica Medica University of Sassari, Viale S Pietro 8, 07100, Sassari, Italy. E-mail glorioso@ssmain.uniss.it
Abstract—— Essential hypertension is a common disease the genetic determinants of which have been difficult to unravel because of its clinical heterogeneity and complex, multifactorial, polygenic etiology. Based on our observations that 
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, we 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 comparing hypertensive patients (blood pressure [BP] >165/95 mm Hg) with normotensive controls age >60 years with BP <140/85 mm Hg. Genotype analysis with microsatellite markers revealed conformation to Hardy-Weinberg proportions for 6 alleles of both ATP1A1 (D1S453) and NKCC2 (NKCGT7) markers, respectively. Two-by-six 
2 analysis of alleles identified overrepresentation of ATP1A1 No. 4 and NKCC2 No. 4 alleles, respectively, in hypertensives compared with controls. With a qualitative trait framework, single-gene analysis detected association of both the ATP1A1 No. 4 allele (P=0.004, 2=8.094, df=1) and the NKCC2 No. 4 allele (P=0.0002, 2=14.279, df=1) with moderate to severe hypertension. Digenic analysis revealed that ATP1A1 No. 4–NKCC2 No. 4 allele interaction increases susceptibility to hypertension (P<0.0001, 2=22.3, df=1) beyond levels obtained in single-gene 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 systolic (1-way ANOVA, P=0.000076) and diastolic (P=0.00099) BP. Interaction was corroborated by 2x2 factorial ANOVA for interaction (systolic BP interaction term, P<0.05, diastolic BP interaction term, P=0.035). The data are compelling that ATP1A1 and NKCC2 genes are candidate interacting hypertension-susceptibility loci in human essential hypertension and affirm gene interaction as an important genetic mechanism underlying hypertension susceptibility. Although corroboration in other cohorts and identification of functionally significant mutations are imperative next steps, the data provide a genotype-stratification scheme, with 4-fold predictive value (odds ratio, 4.28; 95% confidence interval, 2.29 to 8.0), which could help decipher the complex genetics of essential hypertension.
Key Words: complex polygenic disease • hypertension, essential • genes • epistasis • genetics
This article has been cited by other articles:
 |
|
 |
|
  C. Esteva-Font, E. Ars, E. Guillen-Gomez, J. M. Campistol, L. Sanz, W. Jimenez, M. A. Knepper, F. Torres, R. Torra, J. A. Ballarin, et al. Ciclosporin-induced hypertension is associated with increased sodium transporter of the loop of Henle (NKCC2) Nephrol. Dial. Transplant., October 1, 2007; 22(10): 2810 - 2816. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. K. Arnett, A. E. Baird, R. A. Barkley, C. T. Basson, E. Boerwinkle, S. K. Ganesh, D. M. Herrington, Y. Hong, C. Jaquish, D. A. McDermott, et al. Relevance of Genetics and Genomics for Prevention and Treatment of Cardiovascular Disease: A Scientific Statement From the American Heart Association Council on Epidemiology and Prevention, the Stroke Council, and the Functional Genomics and Translational Biology Interdisciplinary Working Group Circulation, June 5, 2007; 115(22): 2878 - 2901. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Glorioso, V. L.M. Herrera, P. Bagamasbad, F. Filigheddu, C. Troffa, G. Argiolas, E. Bulla, J. L. Decano, and N. Ruiz-Opazo Association of ATP1A1 and Dear Single-Nucleotide Polymorphism Haplotypes With Essential Hypertension: Sex-Specific and Haplotype-Specific Effects Circ. Res., May 25, 2007; 100(10): 1522 - 1529. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. L. M. Herrera, A. Tsikoudakis, L. R. B. Ponce, Y. Matsubara, and N. Ruiz-Opazo Sex-specific QTLs and interacting loci underlie salt-sensitive hypertension and target organ complications in Dahl S/jrHS hypertensive rats Physiol Genomics, September 14, 2006; 26(3): 172 - 179. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Wang, I. Le Roy, E. Nicodeme, R. Li, R. Wagner, C. Petros, G. A. Churchill, S. Harris, A. Darvasi, J. Kirilovsky, et al. Using Advanced Intercross Lines for High-Resolution Mapping of HDL Cholesterol Quantitative Trait Loci Genome Res., July 1, 2003; 13(7): 1654 - 1664. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Gimenez, P. Isenring, and B. Forbush Spatially Distributed Alternative Splice Variants of the Renal Na-K-Cl Cotransporter Exhibit Dramatically Different Affinities for the Transported Ions J. Biol. Chem., March 8, 2002; 277(11): 8767 - 8770. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Glorioso, F. Filigheddu, D. Cusi, C. Troffa, M. Conti, M. Natalizio, G. Argiolas, C. Barlassina, and G. Bianchi {alpha}-Adducin 460Trp Allele Is Associated With Erythrocyte Na Transport Rate in North Sardinian Primary Hypertensives Hypertension, February 1, 2002; 39(2): 357 - 362. [Abstract] [Full Text] [PDF]
|
|