Interactive Association of Five Candidate Polymorphisms in Apelin/APJ Pathway with Coronary Artery Disease among Chinese Hypertensive Patients

BACKGROUND: 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). METHODOLOGY/PRINCIPAL FINDINGS: Genotypes 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. CONCLUSIONS: Our 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.