Renin–Angiotensin–Aldosterone System Gene Polymorphisms and Coronary Artery Disease: Detection of Gene-Gene and Gene-Environment Interactions

Abstract

Objective: The objective of this study was to explore the association between coronary artery disease and genetic polymorphisms of the renin–angiotensin–aldosterone system (RAAS) pathway. In addition, we examined the interactions between demographic and lifestyle risk factors (environmental factors including age, sex, smoking status, alcohol intake) and RAAS polymorphisms on disease risk. Methods: A total of 1089 subjects who underwent coronary angiography were enrolled in this study. Eight RAAS polymorphisms were genotyped in this population: the G2350A (rs4343) polymorphism in exon 17 of the angiotensin converting enzyme (ACE) gene, 1166A→C (rs5186) and 573C/T (rs5182) in the angiotensin II type 1 receptor (AGTR1) gene, the -344C→T transversion (rs1799998) in the aldosterone synthase (CYP11B2) gene, and the G-217A (rs5049), G-6A (rs5051), M235T (rs699; T4072C), and T174M (rs4762; C3889T) polymorphisms in the angiotensinogen (AGT) gene. Subjects with coronary heart disease were defined as those with at least 50% stenosis in at least one major coronary artery, and, the severity of coronary atherosclerosis was defined by the Gensini scoring system. Results: Compared to the subjects with AA genotype, the subjects with AG + GG genotype of rs1799998 had significant lower gensini score (p=0.029). After adjusting for age, gender, cigarette smoking, and alcohol intake status, the AG genotype (OR 0.717 95%CI 0.541–0.950, p=0.021) and the AG + GG genotype (OR 0.730 95%CI 0.559–0.954, p=0.021) distributions of rs1799998 were significantly different between the cases and controls compare to the AA genotype. Subjects with three at-risk loci had increased risk of coronary artery disease compared to subjects carrying 0 or 1 risk-associated polymorphism (OR [95% CI]:1.579 [1.077–2.316], p=0. 019), and the significance of the association was not reduced after adjusting for age, sex, cigarette smoking, or alcohol intake (adjusted OR [95% CI]: 1.673 [1.116–2.507], p=0.013). The results of multifactor-dimensionality reduction analysis revealed an interaction effect of CYP11B2 -344C→T, age, and smoking status on the risk of coronary heart disease (training OR [95% CI]: 3.7685 [2.8463–4.9895], p<0.0001; testing OR [95% CI]: 2.7583 [1.2038–6.3203], p=0.015). Conclusions: Subjects who carried the G allele of the rs1799998 polymorphism significantly associated with coronary heart disease and severity of coronary atherosclerosis estimated by the Gensini score in the whole population of the study. And, multiple RAAS gene polymorphisms are associated with coronary artery disease. The interaction of the CYP11B2 -344C→T polymorphism (rs1799998), age, and smoking status is also associated with enhanced risk of coronary artery disease.

Association between the CYP11B2 gene ˗344T>C polymorphism and coronary artery disease: a meta-analysis

“…The characteristics of the selected studies are summarized in Figure 1. Among the five case-control studies, there were three studies in Caucasians (Hautanen et al, 1999;Patel et al, 2000;Franco et al, 2007) and two studies in Asians (Jia et al, 2012;Mishra et al, 2012). The distribution of genotypes in the controls was consistent with HWE in all studies except for one (Franco et al, 2007).…”

“…Aldosterone secretion is regulated by the aldosterone synthase enzyme, which is encoded by the CYP11B2 gene. Recently, a variety of studies have focused on the association between the CYP11B2 gene ˗344T>C polymorphism and CAD (Jia et al, 2012;Mishra et al, 2012). However, the results from these studies are inconsistent.…”

“…It is also possible that potential functional effects of the ˗344T>C polymorphism might be influenced through gene-environment interaction. For example, evidence has suggested that the ˗344T>C polymorphism and smoking status synergistically increased CAD risk (Jia et al, 2012). However, as the only study that examined smoking status could not be included in our subgroup meta-analysis, studies of gene-environment interaction should be taken into consideration in future analyses.…”

“…Based on our preliminary search criteria, 28 were excluded because they did not satisfy the inclusion criteria. In total, 2122 cases and 1565 controls were included in the meta-analysis (Hautanen et al, 1999;Patel et al, 2000;Franco et al, 2007;Jia et al, 2012;Mishra et al, 2012). The characteristics of the selected studies are summarized in Figure 1.…”

“…To date, several studies have shown that the CYP11B2 gene ˗344T>C polymorphism is associated with CAD (Jia et al, 2012;Mishra et al, 2012). However, the specific association remains controversial.…”