Abstract
BackgroundVia sequencing the genes of apelin/angiotensin receptor-like 1 (apelin/APJ) pathway, we have recently identified and validated four common polymorphisms (rs3761581, rs56204867, rs7119375, and rs10501367) implicated in the development of hypertension. Extending these findings, we, in Chinese hypertensive patients, sought to investigate the association of these four polymorphisms and one additional promising candidate (rs9943582) from this pathway with the risk of developing coronary artery disease (CAD).Methodology/Principal FindingsGenotypes were obtained from 994 sporadic CAD patients and 708 age- and sex-matched controls. All participants were hypertensives and angiographically-confirmed. Data were analyzed by Haplo.Stats and multifactor dimensionality reduction (MDR) softwares. Genotype distributions of five examined polymorphisms satisfied Hardy-Weinberg equilibrium in controls of both genders. Single-locus analyses exhibited no significant differences in the genotype/allele frequencies of examined polymorphisms between CAD patients and controls (P>0.05), even after controlling traditional cardiovascular confounders. In haplotype analyses, low-penetrance haplotype G-A (in order of rs56204867 and rs3761581 from apelin gene) was significantly overrepresented in controls (1.73%) relative to in CAD patients (0.4%) in males (P = 0.047). Further interaction analyses suggested an overall best MDR model including rs3761581 in males (P = 0.0408) and including rs7119375 and rs9943582 in females (P<0.0001), which were further substantiated in the classical logistical regression model.ConclusionsOur findings demonstrated a contributive role of low-penetrance haplotype in apelin gene on CAD in males, and more importantly, interactive effects of genetic defects in apelin/APJ pathway might confer a potential risk in Chinese hypertensive patients.
Highlights
Investigations from single locus to genome wide association studies are proliferating in the literature, the challenge to unravel the ultimate genetic underpinnings of cardiovascular diseases obsesses global geneticists [1]
Our findings demonstrated a contributive role of low-penetrance haplotype in apelin gene on coronary artery disease (CAD) in males, and more importantly, interactive effects of genetic defects in apelin/APJ pathway might confer a potential risk in Chinese hypertensive patients
The discovery of susceptibility loci by highthroughput genomic techniques has shed some light on the fundamental mechanisms that influence disease predisposition [9], genetic data on apelin/APJ pathway and the risk of CAD are sparse in the literature
Summary
Investigations from single locus to genome wide association studies are proliferating in the literature, the challenge to unravel the ultimate genetic underpinnings of cardiovascular diseases obsesses global geneticists [1]. We have identified 12 common polymorphisms in apelin/APJ pathway by direct sequencing, and investigated for the first time the association of these polymorphisms with hypertension and its related phenotypes in a familybased association study [10], and we further validated the top four polymorphisms (rs3761581, rs56204867 (T-1860C), rs7119375, and rs10501367) in a large population-based case-control study [11]. Via sequencing the genes of apelin/angiotensin receptor-like 1 (apelin/APJ) pathway, we have recently identified and validated four common polymorphisms (rs3761581, rs56204867, rs7119375, and rs10501367) implicated in the development of hypertension. Extending these findings, we, in Chinese hypertensive patients, sought to investigate the association of these four polymorphisms and one additional promising candidate (rs9943582) from this pathway with the risk of developing coronary artery disease (CAD)
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