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Sökning: onr:"swepub:oai:DiVA.org:uu-294596" > Six Novel Loci Asso...

Six Novel Loci Associated with Circulating VEGF Levels Identified by a Meta-analysis of Genome-Wide Association Studies

Choi, Seung Hoan (författare)
Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.;Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA.;Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA.
Ruggiero, Daniela (författare)
CNR, Inst Genet & Biophys, Naples, Italy.
Sorice, Rossella (författare)
CNR, Inst Genet & Biophys, Naples, Italy.
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Song, Ci (författare)
Uppsala universitet,Molekylär epidemiologi,Science for Life Laboratory, SciLifeLab,Natl Heart Lung & Blood Inst Framingham Heart Stu, Populat Sci Branch, Framingham, MA USA.;Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
Nutile, Teresa (författare)
CNR, Inst Genet & Biophys, Naples, Italy.
Smith, Albert Vernon (författare)
Iceland Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Reykjavik, Iceland.
Concas, Maria Pina (författare)
CNR, Inst Populat Genet, Sassari, Italy.
Traglia, Michela (författare)
Ist Sci San Raffaele, Div Genet & Cell Biol, I-20132 Milan, Italy.
Barbieri, Caterina (författare)
Ist Sci San Raffaele, Div Genet & Cell Biol, I-20132 Milan, Italy.
Ndiaye, Ndeye Coumba (författare)
Univ Lorraine, Fac Pharm, UMR INSERM U1122, IGE PCV Interact Gene Environm Physiopathol Cardi, Nancy, France.
Stathopoulou, Maria G. (författare)
Univ Lorraine, Fac Pharm, UMR INSERM U1122, IGE PCV Interact Gene Environm Physiopathol Cardi, Nancy, France.
Lagou, Vasiliki (författare)
Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.
Maestrale, Giovanni Battista (författare)
CNR, Inst Populat Genet, Sassari, Italy.
Sala, Cinzia (författare)
Ist Sci San Raffaele, Div Genet & Cell Biol, I-20132 Milan, Italy.
Debette, Stephanie (författare)
Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.;Bordeaux Univ Hosp, Dept Neurol, Bordeaux, France.;INSERM, U897, Bordeaux, France.
Kovacs, Peter (författare)
Univ Leipzig, IFB Adipos Dis, D-04109 Leipzig, Germany.
Lind, Lars (författare)
Uppsala universitet,Kardiovaskulär epidemiologi
Lamont, John (författare)
Randox Labs, Crumlin, Ireland.
Fitzgerald, Peter (författare)
Randox Labs, Crumlin, Ireland.
Toenjes, Anke (författare)
Univ Leipzig, Dept Med, D-04109 Leipzig, Germany.
Gudnason, Vilmundur (författare)
Iceland Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Reykjavik, Iceland.
Toniolo, Daniela (författare)
Ist Sci San Raffaele, Div Genet & Cell Biol, I-20132 Milan, Italy.
Pirastu, Mario (författare)
CNR, Inst Populat Genet, Sassari, Italy.
Bellenguez, Celine (författare)
Inst Pasteur, F-59019 Lille, France.;INSEM, U744, Lille, France.;Univ Lille Nord France, Lille, France.
Vasan, Ramachandran S. (författare)
Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA.;Boston Univ, Sch Med, Dept Med, Sect Prevent Med & Epidemiol, Boston, MA 02215 USA.;Boston Univ, Sch Publ Hlth, Boston, MA 02215 USA.
Ingelsson, Erik (författare)
Uppsala universitet,Molekylär epidemiologi,Science for Life Laboratory, SciLifeLab
Leutenegger, Anne-Louise (författare)
INSERM, U946, Paris, France.;Univ Paris Diderot, Sorbonne Paris Cite, IUH, UMR S 946, Paris, France.
Johnson, Andrew D. (författare)
Natl Heart Lung & Blood Inst Framingham Heart Stu, Populat Sci Branch, Framingham, MA USA.
DeStefano, Anita L. (författare)
Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.;Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA.;Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA.
Visvikis-Siest, Sophie (författare)
Univ Lorraine, Fac Pharm, UMR INSERM U1122, IGE PCV Interact Gene Environm Physiopathol Cardi, Nancy, France.
Seshadri, Sudha (författare)
Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.;Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA.
Ciullo, Marina (författare)
CNR, Inst Genet & Biophys, Naples, Italy.
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Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA;Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA.;Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. CNR, Inst Genet & Biophys, Naples, Italy. (creator_code:org_t)
2016-02-24
2016
Engelska.
Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 12:2
Relaterad länk:
https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
https://journals.plo...
https://urn.kb.se/re...
https://doi.org/10.1...
http://kipublication...
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  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
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  • Vascular endothelial growth factor (VEGF) is an angiogenic and neurotrophic factor, secreted by endothelial cells, known to impact various physiological and disease processes from cancer to cardiovascular disease and to be pharmacologically modifiable. We sought to identify novel loci associated with circulating VEGF levels through a genome-wide association meta-analysis combining data from European-ancestry individuals and using a dense variant map from 1000 genomes imputation panel. Six discovery cohorts including 13,312 samples were analyzed, followed by in-silico and de-novo replication studies including an additional 2,800 individuals. A total of 10 genome-wide significant variants were identified at 7 loci. Four were novel loci (5q14.3, 10q21.3, 16q24.2 and 18q22.3) and the leading variants at these loci were rs114694170 (MEF2C, P = 6.79x10(-13)), rs74506613 (JMJD1C, P = 1.17x10(-19)), rs4782371 (ZFPM1, P = 1.59x10(-9)) and rs2639990 (ZADH2, P = 1.72x10(-8)), respectively. We also identified two new independent variants (rs34528081, VEGFA, P = 1.52x10(-18); rs7043199, VLDLR-AS1, P = 5.12x10(-14)) at the 3 previously identified loci and strengthened the evidence for the four previously identified SNPs (rs6921438, LOC100132354, P = 7.39x10(-1467); rs1740073, C6orf223, P = 2.34x10(-17); rs6993770, ZFPM2, P = 2.44x10(-60); rs2375981, KCNV2, P = 1.48x10(-100)). These variants collectively explained up to 52% of the VEGF phenotypic variance. We explored biological links between genes in the associated loci using Ingenuity Pathway Analysis that emphasized their roles in embryonic development and function. Gene set enrichment analysis identified the ERK5 pathway as enriched in genes containing VEGF associated variants. eQTL analysis showed, in three of the identified regions, variants acting as both cis and trans eQTLs for multiple genes. Most of these genes, as well as some of those in the associated loci, were involved in platelet biogenesis and functionality, suggesting the importance of this process in regulation of VEGF levels. This work also provided new insights into the involvement of genes implicated in various angiogenesis related pathologies in determining circulating VEGF levels. The understanding of the molecular mechanisms by which the identified genes affect circulating VEGF levels could be important in the development of novel VEGF-related therapies for such diseases.

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