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(Circulation Research. 2007;100:1522.)
© 2007 American Heart Association, Inc.

Clinical Research

Association of ATP1A1 and Dear Single-Nucleotide Polymorphism Haplotypes With Essential Hypertension

Sex-Specific and Haplotype-Specific Effects

Nicola Glorioso, Victoria L.M. Herrera, Pia Bagamasbad, Fabiana Filigheddu, Chiara Troffa, Giuseppe Argiolas, Emanuela Bulla, Julius L. Decano, Nelson Ruiz-Opazo

From the Hypertension and Cardiovascular Prevention Center (N.G., F.F., C.T., G.A., E.B.), ASL n. 1-Universita’ di Sassari, Sassari, Sardinia, Italy; and Section of Molecular Medicine (V.L.M.H., P.B., J.L.D., N.R.-O.), Department of Medicine, Boston University School of Medicine, Mass.

Correspondence to Nelson Ruiz-Opazo, PhD, Whitaker Cardiovascular Institute, W609, Boston University School of Medicine, 700 Albany St, Boston, MA 02118. E-mail nruizo{at}bu.edu

Essential hypertension remains a major risk factor for cardiovascular and cerebrovascular diseases. As a complex multifactorial disease, elucidation of susceptibility loci remains elusive. ATP1A1 and Dear are candidate genes for 2 closely linked rat chromosome-2 blood pressure quantitative trait loci. Because corresponding human syntenic regions are on different chromosomes, investigation of ATP1A1 (chromosome [chr]-1p21) and Dear (chr-4q31.3) facilitates genetic analyses of each blood pressure quantitative trait locus in human hypertension. Here we report the association of human ATP1A1 (P<0.000005) and Dear (P<0.03) with hypertension in a relatively isolated, case/control hypertension cohort from northern Sardinia by single-nucleotide polymorphism haplotype analysis. Sex-specific haplotype analyses detected stronger association of both loci with hypertension in males than in females. Haplotype trend-regression analyses support ATP1A1 and Dear as independent susceptibility loci and reveal haplotype-specific association with hypertension and normotension, thus delineating haplotype-specific subsets of hypertension. Although investigation in other cohorts needs to be performed to determine genetic effects in other populations, haplotype subtyping already allows systematic stratification of susceptibility and, hence, clinical heterogeneity, a prerequisite for unraveling the polygenic etiology and polygene–environment interactions in essential hypertension. As hypertension susceptibility genes, coexpression of ATP1A1 and Dear in both renal tubular cells and vascular endothelium suggest a cellular pathogenic scaffold for polygenic mechanisms of hypertension, as well as the hypothesis that ATP1A1 and/or Dear could contribute to the known renal and vascular endothelial dysfunction associated with essential (polygenic) hypertension.

Key Words: ₁Na,K-ATPase • Dear • hypertension • genetics • risk factor

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