Friday, November 29, 2013

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

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

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.

Thumbnail image of graphical abstract

Listed genes (highlighted in red) selected for resequencing in the VEGF pathway (www.pharmgkb.org): CRK, FLT1, FRS2, GRB2, NRP1, PGF, RAF1, VEGFA and VEGFB. In some genes one or more genes are involved, RAS refers to KRAS, NRAS. PRKC refers to PRKCA and PRKCE. PIK3 refers to PIK3C2A, PIK3C2B and PIK3R5. MAP2K refers to MAP2K6. MAPK refers to MAPK1, MAPK11, MAPK14, MAPK3. AKT refers to AKT1. Integrin refers to ITGAV and ITGB5

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(Via human mutation.)