title: Identification of cis- and trans-acting genetic variants explaining up to half the variation in circulating vascular endothelial growth factor levels.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Department of Neurology, Boston University School of Medicine, B602, 72 East Concord St, Boston, MA 02118, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Debette
authors.forename: Sophie
authors.initials: S
authors.lastname: Visvikis-Siest
authors.forename: Ming-Huen
authors.initials: MH
authors.lastname: Chen
authors.forename: Ndeye-Coumba
authors.initials: NC
authors.lastname: Ndiaye
authors.forename: Ci
authors.initials: C
authors.lastname: Song
authors.forename: Anita
authors.initials: A
authors.lastname: Destefano
authors.forename: Radwan
authors.initials: R
authors.lastname: Safa
authors.forename: Mohsen
authors.initials: M
authors.lastname: Azimi Nezhad
authors.forename: Douglas
authors.initials: D
authors.lastname: Sawyer
authors.forename: Jean-Brice
authors.initials: JB
authors.lastname: Marteau
authors.forename: Vanessa
authors.initials: V
authors.lastname: Xanthakis
authors.forename: Gerard
authors.initials: G
authors.lastname: Siest
authors.forename: Lisa
authors.initials: L
authors.lastname: Sullivan
authors.forename: Michele
authors.initials: M
authors.lastname: Pfister
authors.forename: Holly
authors.initials: H
authors.lastname: Smith
authors.forename: Seung-Hoan
authors.initials: SH
authors.lastname: Choi
authors.forename: John
authors.initials: J
authors.lastname: Lamont
authors.forename: Lars
authors.initials: L
authors.lastname: Lind
authors.forename: Qiong
authors.initials: Q
authors.lastname: Yang
authors.forename: Peter
authors.initials: P
authors.lastname: Fitzgerald
authors.forename: Erik
authors.initials: E
authors.lastname: Ingelsson
authors.forename: Ramachandran S
authors.initials: RS
authors.lastname: Vasan
authors.forename: Sudha
authors.initials: S
authors.lastname: Seshadri
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015331:Cohort Studies; D005260:Female; D053263:Gene Regulatory Networks / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011446:Prospective Studies; D012333:RNA, Messenger / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000097:blood* / Q000235:genetics*; D055815:Young Adult
chemical_list: D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A