Relationship Between Genetic Polymorphisms Of Hypoxia-Inducible Factor-1 Alpha And Coronary Artery Disease

BackgroundCoronary artery diseas(eCAD) is a polygenic disease leading to severe hypoxia complications. Hypoxia-inducible factor-1α(HIF-1α) is a key regulator of cellular response to hypoxia and has been suggested as playing an important role in the occurrence and progression of CAD disease through activation of various genes that are linked to regulation of angiogenesis, erythropoiesis, energy metabolism, vasomotor function, and apoptotic/proliferative responses. The HIF-1αC1772T (P582S) and G1790A (A588T) polymorphisms seem to be important in the oxygen regulation of protein stability.ObjectiveBecause of known a positive relationship between the HIF protein expression and severity of CAD, and degree of coronary collaterals, this study is aimed to further investigate the association of HIF-1αC1772T and G1790A single nucleotide polymorphisms (SNPs) with the incidence, clinical type, the severity of the coronary artery lesion and collateral circulation of CADMethodsA total of 560 patients, including stable angina pectoris (SAP), unstable angina pectoris (UAP), and acute myocardial infarction (AMI) who were diagnosed as having CAD by coronary angiography were selected in this study. 127 cases with collaterals , 205 without collaterals. In addition, 398 subjects without evidence of CAD under coronary angiography were selected as controls. Demographic features and traditional risk factors of CAD,including age, sex, blood pressure, glucose,cholesterolemia,and past history (with or without diabetes, hypertension, hyperlipidemia) were collected. The genotypes for two SNPs were determined by high resolution melting. Result1. We did not find variant homozygous genotypes for the HIF-1a C1772T and G1790A in either controls or patients. There was no significant difference between CAD patients and controls in terms of the distribution of alleles, genotypes .The haplotype was not associated with CAD. (P > 0.05).2. In a multivariate logistic regression analysis, including clinical data, neither the HIF-1αC1772T genotype (OR: 0.960; 95% CI :0.186-4.938; P=0.961) nor the G1790A genotype was significantly associated with CAD (OR:3.569; 95% CI: 0.336-37.896; P=0.291), and no gene-gene and gene-environmental interactions on CAD risk was identifified using MDR software.3. In an exploratory analysis, both the HIF-1αC1772T (P<0.01) and G1790A (P<0.05) allele was associated with clinical type. Patients carrying genotype CT(P=0.019, OR=4.905,91, 95%CI:1.355-17.761) and GA(P=0.026, OR=3.052, 95%CI: 1.180-7.892) had significantly higher incidence of SAP.4. The frequency of the CT and GA genotypes were significantly higher among patients without collaterals compared to patients with collaterals (p<0.05). The presence of HIF-1 genotype CT (P=0.016, OR=13.373,95%CI:15.468-32.709 ) and GA GA (P=0.001, OR=19.741, 95%CI: 8.125-47.966) predicted the absence of collateral formation. The severity of coronary artery disease predicted the presence of collaterals (r=0.242,p<0.001). However, the genotype was not related with the severity of coronary artery disease (P>0.05).ConclusionWe concluded that functional polymorphisms in the HIF-1αgene do not modify CAD risk but may be associated with development of coronary artery collaterals and clinical presentation of CAD.