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Identification of c...
Identification of cis- and trans-Acting Genetic Variants Explaining Up to Half the Variation in Circulating Vascular Endothelial Growth Factor Levels
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Debette, Stephanie (author)
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Visvikis-Siest, Sophie (author)
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Chen, Ming-Huen (author)
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Ndiaye, Ndeye-Coumba (author)
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- Song, Ci (author)
- Karolinska Institutet
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Destefano, Anita (author)
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Safa, Radwan (author)
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Nezhad, Mohsen Azimi (author)
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Sawyer, Douglas (author)
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Marteau, Jean-Brice (author)
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Xanthakis, Vanessa (author)
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Siest, Gerard (author)
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Sullivan, Lisa (author)
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Pfister, Michele (author)
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Smith, Holly (author)
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Choi, Seung-Hoan (author)
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Lamont, John (author)
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- Lind, Lars (author)
- Uppsala universitet,Institutionen för medicinska vetenskaper
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Yang, Qiong (author)
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Fitzgerald, Peter (author)
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- Ingelsson, Erik (author)
- Karolinska Institutet
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Vasan, Ramachandran S. (author)
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Seshadri, Sudha (author)
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(creator_code:org_t)
- 2011
- 2011
- English.
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In: Circulation Research. - 0009-7330 .- 1524-4571. ; 109:5, s. 554-563
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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- 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<5x10(-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=6.11x10(-506) and P=1.47x10(-12)), rs6993770 (8q23.1, P=2.50x10(-16)), and rs10738760 (9p24.2, P=1.96x10(-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.
Keyword
- growth factors
- genome-wide association study
- gene expression
- pathway analysis
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Debette, Stephan ...
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Visvikis-Siest, ...
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Chen, Ming-Huen
-
Ndiaye, Ndeye-Co ...
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Song, Ci
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Destefano, Anita
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show more...
-
Safa, Radwan
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Nezhad, Mohsen A ...
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Sawyer, Douglas
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Marteau, Jean-Br ...
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Xanthakis, Vanes ...
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Siest, Gerard
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Sullivan, Lisa
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Pfister, Michele
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Smith, Holly
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Choi, Seung-Hoan
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Lamont, John
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Lind, Lars
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Yang, Qiong
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Fitzgerald, Pete ...
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Ingelsson, Erik
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Vasan, Ramachand ...
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Seshadri, Sudha
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show less...
- Articles in the publication
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Circulation Rese ...
- By the university
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Uppsala University
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Karolinska Institutet