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

Hongyin Chen; Xingyu Lv; Jinzhao Yang; Zhaojun Chen; Wanning Qiao; Tao Zhou; Yang Zhang

doi:10.3389/fcvm.2023.1240288

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

Front Cardiovasc Med. 2023 Nov 28:10:1240288. doi: 10.3389/fcvm.2023.1240288. eCollection 2023.

Authors

Hongyin Chen^#¹, Xingyu Lv^#¹, Jinzhao Yang¹, Zhaojun Chen¹, Wanning Qiao¹, Tao Zhou¹, Yang Zhang^{1

2}

Affiliations

¹ School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, China.
² Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

^# Contributed equally.

Abstract

Background: 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 (VEGFA) is pivotal in angiogenesis and represents a clinical target for CVD intervention. However, the impact of genetic modulation of VEGFA on lipid levels and the subsequent risk of cardiovascular events remains unclear.

Methods: We used LDpred2 to calculate genetic scores for lipid levels based on VEGFA variation, serving as instrumental variables to simulate the effect of VEGFA inhibitors. We then assessed the associations between genetic risk for lipid levels and CVD risk by conducting One-sample Mendelian randomization.

Results: 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 VEGFA, 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 (p = 8.4×10^-3) when using genetic variation in VEGFA as an instrumental variable.

Conclusions: Genetic variation mimicking the effect of VEGFA 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 VEGFA-mediated lipid changes in the prevention and management of CVD.

Keywords: Mendelian randomization; VEGFA variation; cardiovascular disease; genetic risk score; lipid metabolism.

Grants and funding

This work was supported by the National Natural Science Foundation of China (82000462 and 82170883) (YZ).