Identification of cis- and trans-Acting Genetic Variants Explaining Up to Half the Variation in Circulating Vascular Endothelial Growth Factor Levels
Rationale: Vascular endothelial growth factor (VEGF) affects angiogenesis, atherosclerosis, and cancer. Although the heritability of circulating VEGF levels is high, little is known about its genetic underpinnings.
Objective: Our aim was to identify genetic variants associated with circulating VEGF levels, using an unbiased genome-wide approach, and to explore their functional significance with gene expression and pathway analysis.
Methods and Results: We undertook a genome-wide association study of serum VEGF levels in 3527 participants of the Framingham Heart Study, with preplanned replication in 1727 participants from 2 independent samples, the STANISLAS Family Study and the Prospective Investigation of the Vasculature in Uppsala Seniors study. One hundred forty single nucleotide polymorphism (SNPs) reached genome-wide significance (P<5×10−8). We found evidence of replication for the most significant associations in both replication datasets. In a conditional genome-wide association study, 4 SNPs mapping to 3 chromosomal regions were independently associated with circulating VEGF levels: rs6921438 and rs4416670 (6p21.1, P=6.11×10−506 and P=1.47×10−12), rs6993770 (8q23.1, P=2.50×10−16), and rs10738760 (9p24.2, P=1.96×10−34). A genetic score including these 4 SNPs explained 48% of the heritability of serum VEGF levels. Six of the SNPs that reached genome-wide significance in the genome-wide association study were significantly associated with VEGF messenger RNA levels in peripheral blood mononuclear cells. Ingenuity pathway analyses showed found plausible biological links between VEGF and 2 novel genes in these loci (ZFPM2 and VLDLR).
Conclusions: Genetic variants explaining up to half the heritability of serum VEGF levels were identified. These new insights provide important clues to the pathways regulating circulating VEGF levels.
- Received March 2, 2011.
- Revision received June 28, 2011.
- Accepted June 30, 2011.
- © 2011 American Heart Association, Inc.