title: A common variant highly associated with plasma VEGFA levels also contributes to the variation of both LDL-C and HDL-C.
abstract: Vascular endothelial growth factor A (VEGFA) is among the most-significant stimulators of angiogenesis. Its effect on cardiovascular diseases and on the variation of related risk factors such as lipid parameters is considered important, although as yet unclear. Recently, we identified four common variants (rs6921438, rs4416670, rs6993770, and rs10738760) that explain up to 50% of the heritability of plasma VEGFA levels. In the present study, we aimed at assessing the contribution of these variants to the variation of blood lipid levels (including apoE, triglycerides, total cholesterol, low- and high-density lipoprotein cholesterol levels (LDL-C and HDL-C)] in healthy subjects. The effect of these single-nucleotide polymorphisms (SNPs) on lipid levels was assessed using linear regression in discovery and replication samples (n = 1,006 and n = 1,145; respectively), followed by a meta-analysis. Their gene×gene and gene×environment interactions were also assessed. SNP rs6921438 was associated with HDL-C (β = -0.08 mmol/l, P(overall) = 1.2 × 10(-7)) and LDL-C (β = 0.13 mmol/l, P(overall) = 1.5 × 10(-4)). We also identified a significant association between the interaction rs4416670×hypertension and apoE variation (P(overall) = 1.7 × 10(-5)). Therefore, our present study shows a common genetic regulation between VEGFA and cholesterol homeostasis molecules. The SNP rs6921438 is in linkage disequilibrium with variants located in an enhancer- and promoter-associated histone mark region and could have a regulatory effect in the expression of surrounding genes, including VEGFA.
authors.affiliation: Université de Lorraine, Génétique Cardio-vasculaire, EA-4373, Nancy, F-54000, France.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Stathopoulou
authors.forename: Amélie
authors.initials: A
authors.lastname: Bonnefond
authors.forename: Ndeye Coumba
authors.initials: NC
authors.lastname: Ndiaye
authors.forename: Mohsen
authors.initials: M
authors.lastname: Azimi-Nezhad
authors.forename: Said
authors.initials: S
authors.lastname: El Shamieh
authors.forename: Abdelsalam
authors.initials: A
authors.lastname: Saleh
authors.forename: Marc
authors.initials: M
authors.lastname: Rancier
authors.forename: Gerard
authors.initials: G
authors.lastname: Siest
authors.forename: John
authors.initials: J
authors.lastname: Lamont
authors.forename: Peter
authors.initials: P
authors.lastname: Fitzgerald
authors.forename: Sophie
authors.initials: S
authors.lastname: Visvikis-Siest
mesh_terms: D000328:Adult; D008076:Cholesterol, HDL / Q000097:blood*; D008078:Cholesterol, LDL / Q000097:blood*; D004843:Epistasis, Genetic / Q000235:genetics; D005260:Female; D059647:Gene-Environment Interaction; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results; D042461:Vascular Endothelial Growth Factor A / Q000097:blood* / Q000235:genetics*
chemical_list: D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A