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

Abstract：

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.

journal_name

Circ Res

journal_title

Circulation research

authors

Debette S,Visvikis-Siest S,Chen MH,Ndiaye NC,Song C,Destefano A,Safa R,Azimi Nezhad M,Sawyer D,Marteau JB,Xanthakis V,Siest G,Sullivan L,Pfister M,Smith H,Choi SH,Lamont J,Lind L,Yang Q,Fitzgerald P,Ingelsson E,

doi

10.1161/CIRCRESAHA.111.243790

subject

Has Abstract

pub_date

2011-08-19 00:00:00

pages

554-63

issue

eissn

0009-7330

issn

1524-4571

pii

CIRCRESAHA.111.243790

journal_volume

109

pub_type

杂志文章

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