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

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Abstract
β 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 β 2 -adrenergic receptor gene (Arg16Gly and Gln27Glu) and neuropeptide Y (Leu7Pro). Of 3 common haplotypes of β 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 β-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 β 2 -adrenergic receptor gene haplotype and provided evidence for epistatic interaction between β 2 -adrenergic receptor gene and neuropeptide Y gene in determination of LDL-cholesterol in patients with essential hypertension.