Published Online
on September 13, 2004

A more recent version of this article appeared on November 1, 2004

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Submitted on June 9, 2004
Revised on July 2, 2004

Epistatic Interaction Between ₂-Adrenergic Receptor and Neuropeptide Y Genes Influences LDL-Cholesterol in Hypertension

Maciej Tomaszewski^*; Fadi J. Charchar; Beata Lacka; Ullamari Pesonen; William Y.S. Wang; Ewa Zukowska-Szczechowska; Wladyslaw Grzeszczak; and Anna F. Dominiczak

From the British Heart Foundation Glasgow Cardiovascular Research Centre (M.T., F.J.C., A.F.D.), Division of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom; Department of Internal Medicine (M.T., B.L., E.Z-S., W.G.), Diabetology and Nephrology, Medical University of Silesia, Zabrze, Poland; Department of Pharmacology and Clinical Pharmacology (U.P.), University of Turku, Finland; and Department of Medical Genetics (W.Y.S.W.), University of Cambridge, United Kingdom.

^* To whom correspondence should be addressed. E-mail: mt65h{at}clinmed.gla.ac.uk.

Abstract--₂-Adrenergic receptor gene and neuropeptide Y gene may potentially influence lipid metabolism and overall energy balance. Therefore, we examined associations of these genes with lipid fractions and obesity-related phenotypes in hypertensive subjects. A total of 638 white individuals from 212 Polish families with clustering of essential hypertension were phenotyped for cardiovascular risk determinants. Each subject was genotyped for functional polymorphisms of ₂-adrenergic receptor gene (Arg16Gly and Gln27Glu) and neuropeptide Y (Leu7Pro). Of 3 common haplotypes of ₂-adrenergic receptor gene, Arg16Gln27 was overtransmitted to offspring with elevated levels of total cholesterol (Z=2.2; P=0.026) and LDL-cholesterol (Z=3.2; P=0.002). Individually, Leu7Pro was not associated with any of the metabolic phenotypes in family-based tests or case-control analyses. However, in the presence of Arg allele of Arg16Gly and Gln allele of Gln27Glu, homozygosity for Leu variant of the Leu7Pro polymorphism was associated with 2.1-increased odds ratio (confidence interval, 1.10 to 3.81; P=0.024) of elevated LDL in hypertensive subjects, independent of age, gender, body mass index, adjusted blood pressures, antihypertensive therapy, and use of nonselective -blockers and diuretics. Consistently, there was a significant multilocus association among variants of Arg16Gly, Gln27Glu, and Leu7Pro in hypertensive probands with elevated LDL (cases; P=0.028) but not in hypertensive subjects with normal LDL (controls). This study revealed an association of LDL-cholesterol with ₂-adrenergic receptor gene haplotype and provided evidence for epistatic interaction between ₂-adrenergic receptor gene and neuropeptide Y gene in determination of LDL-cholesterol in patients with essential hypertension.

Key words: receptors, adrenergic • neuropeptide Y • genes • cholesterol

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