In this case-control study, allele, genotype and haplotype frequencies of five SNPs in the VEGFA gene between CHD patients and healthy controls were compared and stratification analyses were conducted. The genotype“C/T”of rs3025021 in VEGFA was found to be associated with CHD susceptibility in the codominant model (adjusted, OR = 1.35, 95% CI = 1.02–1.80, p = 0.038) in the overall. The stratification analysis by age showed that rs833068 in VEGFA were observed to be associated with the reduced risk of CHD at age > 61 years and age ≤ 61 years, respectively. And the stratification analysis by gender found that three loci (rs833068, rs3025021 and rs6905288) in VEGFA were related to the CHD risk in males. In addition, we found that rs3025021 was associated with increased risk of CHD in patients with hypertension. Conversely, three loci (rs833068, rs3025030 and rs6905288) in VEGFA were related to the CHD risk in patients without hypertension. Furthermore, rs3025021 was associated with increased risk of CHD in patients with diabetes. The rs833068 was associated with reduced risk of CHD in patients without diabetes. Finally, we found a strong LD between rs833068 and rs833070. To our knowledge, this is the first study that evaluate and show an association of VEGFA genetic variants with risk of developing CHD in Han Chinese population.
Coronary heart disease (CHD) is a common and complicated cardiovascular disease in the worldwide, and caused by narrowing of the coronary arteries and a lack of blood supply (12). However, the etiological factors for CHD are not fully understood. Like lung cancer (19) and glioma (20), it's clear that genetic factors, such as single nucleotide polymorphism (SNPs) may also play a pivotal role in determining susceptibility of CHD (21). VEGF can not only promote the vascular recanalization and establishment of collateral circulation, but also enhance the dependent vasodilatation of endothelial cells which are closely related to coronary heart disease (22). Several studies have shown that appropriate timing and dose of VEGF is essential to avoid cardiovascular defects during heart development (23, 24). VEGFA, as a member of VEGF, has been proved to promote the differentiation, proliferation and migration of microvascular endothelial cells by binding to their receptors, thus improving the formation and development (24). In addition, the study has shown that VEGFA may play an important role in the process of epithelial-mesenchymal transformation (EMT) and regulate the formation of endocardial cushion (22).
Recently, several studies have explored the association between the SNPs in VEGFA and the susceptibility to CHD (12, 25, 26). Han et al (25) showed that rs3025039 in VEGFA gene was remarkably associated with CHD risk in Han Chinese population. On the contrary, Griffin et al (26) conducted a meta-analysis which demonstrated VEGFA polymorphisms may not be associated with CHD. Furthermore, Dong et al (12) found three SNPs (rs699947, rs3025039, and rs1570360) were remarkably correlated with the susceptibility to CHD. To further clarify the relationship between SNPs within VEGFA and CHD,we genotyped five SNPs (rs833068, rs833070, rs3025021, rs3025030, rs6905288) in this study and discovered that all the five SNPs were significantly with the risk of CHD.
Inevitably, several limitations should be addressed with regard to the case-control study. First, our sample was limited to the Han Chinese population, thus the investigation results might not be applicable to other Chinese populations or additional ethnic groups. Larger and more diversity sample is needed to identify the role of VEGFA genetic polymorphisms in CHD risk. Besides, it could not be ignored that the uniqueness of samples might exaggerate the correlation between the selected 5 SNPs and CHD risk, or neglect the role of some other vital polymorphisms in VEGFA in susceptibility to CHD. Therefore, large prospective cohort studies or combined meta-analyses should be designed to address these limitations.