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Discovery and Functional Assessment of Gene Variants in the Vascular Endothelial Growth Factor Pathway

2013; Wiley; Volume: 35; Issue: 2 Linguagem: Inglês

10.1002/humu.22475

1098-1004

Laia Paré, Dylan M. Glubb, Patrick Evans, Antonio Berenguer, Amy S. Etheridge, Andrew D. Skol, Anna Di Rienzo, Shiwei Duan, Eric R. Gamazon, Federico Innocenti,

Angiogenesis and VEGF in Cancer

Human MutationVolume 35, Issue 2 p. 227-235 Research Article Discovery and Functional Assessment of Gene Variants in the Vascular Endothelial Growth Factor Pathway Laia Paré-Brunet, Laia Paré-Brunet Department of Genetics, Hospital de la Santa Creu i Sant Pau, Barcelona, SpainSearch for more papers by this authorDylan Glubb, Dylan Glubb Eshelman School of Pharmacy, Institute for Pharmacogenomics and Individualized Therapy, Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, North CarolinaSearch for more papers by this authorPatrick Evans, Patrick Evans Department of Medicine, University of Chicago, Chicago, IllinoisSearch for more papers by this authorAntoni Berenguer-Llergo, Antoni Berenguer-Llergo Biomarkers and Susceptibility Unit, Catalan Institute of Oncology (ICO-IDIBELL), L'Hospitalet de Llobregat, CIBER de Epidemiologia y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Barcelona, SpainSearch for more papers by this authorAmy S. Etheridge, Amy S. Etheridge Eshelman School of Pharmacy, Institute for Pharmacogenomics and Individualized Therapy, Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, North CarolinaSearch for more papers by this authorAndrew D. Skol, Andrew D. Skol Department of Medicine, University of Chicago, Chicago, IllinoisSearch for more papers by this authorAnna Di Rienzo, Anna Di Rienzo Department of Genetics, University of Chicago, Chicago, IllinoisSearch for more papers by this authorShiwei Duan, Shiwei Duan School of Medicine, Ningbo University, Zhejiang, 315211 ChinaSearch for more papers by this authorEric R. Gamazon, Eric R. Gamazon Department of Medicine, University of Chicago, Chicago, IllinoisSearch for more papers by this authorFederico Innocenti, Corresponding Author Federico Innocenti Eshelman School of Pharmacy, Institute for Pharmacogenomics and Individualized Therapy, Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, North CarolinaCorrespondence to: Federico Innocenti, University of North Carolina at Chapel Hill, 1014 Genetic Medicine Bldg, CB 7361, 120 Mason Farm Road, Chapel Hill, NC 27599-7361. E-mail: innocent@unc.eduSearch for more papers by this author Laia Paré-Brunet, Laia Paré-Brunet Department of Genetics, Hospital de la Santa Creu i Sant Pau, Barcelona, SpainSearch for more papers by this authorDylan Glubb, Dylan Glubb Eshelman School of Pharmacy, Institute for Pharmacogenomics and Individualized Therapy, Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, North CarolinaSearch for more papers by this authorPatrick Evans, Patrick Evans Department of Medicine, University of Chicago, Chicago, IllinoisSearch for more papers by this authorAntoni Berenguer-Llergo, Antoni Berenguer-Llergo Biomarkers and Susceptibility Unit, Catalan Institute of Oncology (ICO-IDIBELL), L'Hospitalet de Llobregat, CIBER de Epidemiologia y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Barcelona, SpainSearch for more papers by this authorAmy S. Etheridge, Amy S. Etheridge Eshelman School of Pharmacy, Institute for Pharmacogenomics and Individualized Therapy, Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, North CarolinaSearch for more papers by this authorAndrew D. Skol, Andrew D. Skol Department of Medicine, University of Chicago, Chicago, IllinoisSearch for more papers by this authorAnna Di Rienzo, Anna Di Rienzo Department of Genetics, University of Chicago, Chicago, IllinoisSearch for more papers by this authorShiwei Duan, Shiwei Duan School of Medicine, Ningbo University, Zhejiang, 315211 ChinaSearch for more papers by this authorEric R. Gamazon, Eric R. Gamazon Department of Medicine, University of Chicago, Chicago, IllinoisSearch for more papers by this authorFederico Innocenti, Corresponding Author Federico Innocenti Eshelman School of Pharmacy, Institute for Pharmacogenomics and Individualized Therapy, Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, North CarolinaCorrespondence to: Federico Innocenti, University of North Carolina at Chapel Hill, 1014 Genetic Medicine Bldg, CB 7361, 120 Mason Farm Road, Chapel Hill, NC 27599-7361. E-mail: innocent@unc.eduSearch for more papers by this author First published: 04 November 2013 https://doi.org/10.1002/humu.22475Citations: 11 Contract grant sponsors: National Institutes of Health (NIH/NCI K07CA140390-01 and NIH/NIGMS U01 GM61393); National Heart, Lung, and Blood Institute (NHLBI) Resequencing and Genotyping (RS&G) Service. Communicated by George P. Patrinos Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat ABSTRACT Angiogenesis is a host-mediated mechanism in disease pathophysiology. The vascular endothelial growth factor (VEGF) pathway is a major determinant of angiogenesis, and a comprehensive annotation of the functional variation in this pathway is essential to understand the genetic basis of angiogenesis-related diseases. We assessed the allelic heterogeneity of gene expression, population specificity of cis expression quantitative trait loci (eQTLs), and eQTL function in luciferase assays in CEU and Yoruba people of Ibadan, Nigeria (YRI) HapMap lymphoblastoid cell lines in 23 resequenced genes. Among 356 cis-eQTLs, 155 and 174 were unique to CEU and YRI, respectively, and 27 were shared between CEU and YRI. Two cis-eQTLs provided mechanistic evidence for two genome-wide association study findings. Five eQTLs were tested for function in luciferase assays and the effect of two KRAS variants was concordant with the eQTL effect. Two eQTLs found in each of PRKCE, PIK3C2A, and MAP2K6 could predict 44%, 37%, and 45% of the variance in gene expression, respectively. This is the first analysis focusing on the pattern of functional genetic variation of the VEGF pathway genes in CEU and YRI populations and providing mechanistic evidence for genetic association studies of diseases for which angiogenesis plays a pathophysiologic role. Citing Literature Supporting Information Disclaimer: Supplementary materials have been peer-reviewed but not copyedited. Filename Description humu22475-sup-0001-SuppMat.zip9.9 MB Figure S1. Gene expression in CEU and YRI samples. The Mann Whitney test was used to identify genes differing in their expression level between CEU and YRI samples. Horizontal lines show the lower quartile (25%), median and upper quartile (75%). Figure S2. LD and haplotype in CEU and YRI. Display andanalysis of the LD pattern and haplotype for each gene in the CEU and YRI populations using Haploview 4.2. In the LD visual display, the r2 value is shown on a gray scale, where white represents r2=0, shades of gray represent 0<r2<1, and black represents r2=1. The independent cis-eQTLs in CEU and in YRI are highlighted. Figure S3. Concordance Correlation Coefficient (CCC). The concordance correlation coefficient is used to measure the agreement between two variables. Concordance between HapMap data and 1000 Genomes Project data in (A) CEU population (B) in YRI population. Concordance between resequencing data and 1000 Genomes Project data in (C) CEU population (D) in YRI population. Figure S4. Venn diagram of the eQTLs. SNPs significantly associated with the expression in CEU and YRI population and their overlap. Variants with MAF < 0.05 are between parentheses. Table S1. HapMap DNA samples from 23 healthy unrelated individuals of the CEPH families (CEU) and 24 healthy unrelated individuals of the Yoruba people of Ibadan, Nigeria (YRI) Table S2. Primers used to generate DNA fragments for cloning into luciferase reporter gene constructs Table S3. Tagging SNPs (tSNPs) by ethnicity using Haploview 4.2 Table S4. eQTLs located in 5′-regulatory regions from both populations Table S5. Population divergence of cross-population eQTLs Table S6. Predictive analysis of the functionality of the non-synonymous SNPs Table S7. Bioinformatic analyses of eQTL SNPs Table S8. Multivariate eQTL analysis to identify cis-eQTLs that are independently associated with mRNA level variance Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume35, Issue2February 2014Pages 227-235 RelatedInformation