Discovery and Functional Assessment of Gene Variants in the Vascular Endothelial Growth Factor Pathway |
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| Authors: | Laia Paré‐Brunet Dylan Glubb Patrick Evans Antoni Berenguer‐Llergo Amy S. Etheridge Andrew D. Skol Anna Di Rienzo Shiwei Duan Eric R. Gamazon Federico Innocenti |
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| Affiliation: | 1. Department of Genetics, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain;2. 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 Carolina;3. Department of Medicine, University of Chicago, Chicago, Illinois;4. 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, Spain;5. Department of Genetics, University of Chicago, Chicago, Illinois;6. School of Medicine, Ningbo University, Zhejiang, China |
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| 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. |
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| Keywords: | VEGF angiogenesis pharmacogenetics pathway GWAS QTL expression |
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