AUTHOR=Chen Hongyin , Lv Xingyu , Yang Jinzhao , Chen Zhaojun , Qiao Wanning , Zhou Tao , Zhang Yang 

TITLE=Variation in VEGFA and risk of cardiovascular disease in the UK Biobank

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=10

YEAR=2023

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2023.1240288

DOI=10.3389/fcvm.2023.1240288

ISSN=2297-055X

ABSTRACT=<sec><title>Background</title><p>Cardiovascular disease (CVD) is an escalating global health crisis, contributing significantly to worldwide mortality and morbidity. Dyslipidemia stands as a critical risk factor for CVD. Vascular endothelial growth factor A (<italic>VEGFA</italic>) is pivotal in angiogenesis and represents a clinical target for CVD intervention. However, the impact of genetic modulation of <italic>VEGFA</italic> on lipid levels and the subsequent risk of cardiovascular events remains unclear.</p></sec><sec><title>Methods</title><p>We used LDpred2 to calculate genetic scores for lipid levels based on <italic>VEGFA</italic> variation, serving as instrumental variables to simulate the effect of <italic>VEGFA</italic> inhibitors. We then assessed the associations between genetic risk for lipid levels and CVD risk by conducting One-sample Mendelian randomization.</p></sec><sec><title>Results</title><p>Our results indicated that low-density lipoprotein cholesterol [LDL-C; odds ratio (OR) = 1.09, 95% CI: 1.06–1.11], remnant cholesterol (RC; OR = 1.24, 95% CI: 1.13–1.36), and triglycerides (TG; OR = 1.14, 95% CI: 1.07–1.22) were positively associated with the incidence of CVD. In contrast, high-density lipoprotein cholesterol (HDL-C) was inversely associated with the incidence of CVD (OR = 0.80, 95% CI: 0.76–0.86). When considering the genetic score for LDL-C constructed based on <italic>VEGFA</italic>, the group with a high genetic score demonstrated an elevated CVD risk (OR = 1.11, 95% CI: 1.04–1.19) compared to those with a low genetic score. Notably, One-sample Mendelian randomization results provided evidence of a causal relationship between LDL-C and CVD (<italic>p </italic>= 8.4×10<sup>−3</sup>) when using genetic variation in <italic>VEGFA</italic> as an instrumental variable.</p></sec><sec><title>Conclusions</title><p>Genetic variation mimicking the effect of <italic>VEGFA</italic> inhibition, which lowers LDL-C levels, was causally associated with a reduced risk of cardiovascular events. These findings offer insight into the potential therapeutic relevance of modulating <italic>VEGFA</italic>-mediated lipid changes in the prevention and management of CVD.</p></sec>