Isoprostane, an "intermediate phenotype" for oxidative stress: Heritability, risk trait associations, and the influence of chromogranin b polymorphism

Abstract

Objectives The purpose of this study is to understand whether isoprostane, a biomarker of oxidative stress, is subject to heritable control; whether it shares heritability with other cardiometabolic risk traits; and finally whether genetic variation at a specific candidate locus contributes to isoprostane variability. Background Isoprostane marks oxidative stress, and elevated isoprostane excretion might be involved in cardiovascular target organ damage. Here we used the classical twin pair method to probe the role of heredity in generating the isoprostane trait. Methods Trait heritability (h2) and shared genetic determination among traits (pleiotropy, genetic covariance, ρG) were estimated by variance components in twin pairs. Because the isoprostane and Chromogranin B (CHGB) traits shared ρG, we examined the CHGB locus for effects on the traits. Results Urinary isoprostane excretion was substantially heritable (h2 = 65.8 ± 4.3%), and the isoprostane trait aggregated with multiple traits (CHGB, catecholamines, autonomic/baroreceptor, and renal function), including several features of the metabolic syndrome (body mass index, insulin resistance, dyslipidemia). Isoprostane excretion also aggregated with systemic hypertension. Twin studies demonstrated genetic covariance (pleiotropy) for the isoprostane and CHGB traits (ρG = 0.27), and therefore we investigated the CHGB locus for trait effects. A common variant in the 3′-UTR of CHGB (C+84A) associated with plasma CHGB as well as isoprostane excretion. The C+84A disrupted an A/U-rich messenger ribonucleic acid stability element, and in transfected luciferase/3′-UTR plasmids, the C+84 and +84A alleles differed markedly in reporter expression in chromaffin and neuroblastoma cells, whereas site-directed mutagenesis confirmed the importance of this variant within the context of the A/U-rich motif. Conclusions Isoprostane excretion is substantially heritable and shares joint genetic determination with CHGB as well as multiple features of the metabolic syndrome. A common polymorphism in the 3′-UTR (C+84A) of CHGB, which disrupts an A/U-rich messenger ribonucleic acid stability element, associates with not only CHGB secretion but also excretion of isoprostane. We propose a chain of events whereby CHGB genetic variation results in oxidative stress, with isoprostane formation. The results suggest novel links among the catecholaminergic system, oxidative pathways, and systemic hypertension. © 2010 American College of Cardiology Foundation.