Identification of cis-and trans-acting genetic variants explaining up to half the variation in circulating vascular endothelial growth factor levels

Stephanie Debette, Sophie Visvikis-Siest, Ming Huen Chen, Ndeye Coumba Ndiaye, Ci Song, Anita Destefano, Radwan Safa, Mohsen Azimi Nezhad, Douglas Sawyer, Jean Brice Marteau, Vanessa Xanthakis, Gerard Siest, Lisa Sullivan, Michele Pfister, Holly Smith, Seung Hoan Choi, John Lamont, Lars Lind, Qiong Yang, Peter FitzgeraldErik Ingelsson, Ramachandran S. Vasan, Sudha Seshadri

Research output: Contribution to journalArticlepeer-review

64 Scopus citations


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). 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 and P=1.47×10), rs6993770 (8q23.1, P=2.50×10), and rs10738760 (9p24.2, P=1.96×10). 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.

Original languageEnglish (US)
Pages (from-to)554-563
Number of pages10
JournalCirculation research
Issue number5
StatePublished - Aug 19 2011
Externally publishedYes


  • gene expression
  • genome-wide association study
  • growth factors
  • pathway analysis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology


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