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Discovery and Functional Assessment of Gene Variants in the Vascular Endothelial Growth Factor Pathway
Author(s) -
ParéBrunet Laia,
Glubb Dylan,
Evans Patrick,
BerenguerLlergo Antoni,
Etheridge Amy S.,
Skol Andrew D.,
Rienzo Anna,
Duan Shiwei,
Gamazon Eric R.,
Innocenti Federico
Publication year - 2014
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22475
Subject(s) - biology , expression quantitative trait loci , international hapmap project , genetics , genome wide association study , genetic association , angiogenesis , quantitative trait locus , single nucleotide polymorphism , human genetics , genetic variation , gene , genotype
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 (e QTL s), and e QTL function in luciferase assays in CEU and Y oruba people of I badan, N igeria ( YRI ) H ap M ap lymphoblastoid cell lines in 23 resequenced genes. Among 356 cis‐e QTL s, 155 and 174 were unique to CEU and YRI , respectively, and 27 were shared between CEU and YRI . Two cis‐e QTL s provided mechanistic evidence for two genome‐wide association study findings. Five e QTL s were tested for function in luciferase assays and the effect of two KRAS variants was concordant with the e QTL effect. Two e QTL s found in each of PRKCE , PIK 3 C 2 A , and MAP 2 K 6 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.