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Genetic variation in VEGF does not contribute significantly to the risk of congenital cardiovascular malformation.

Griffin HR, Hall DH, Topf A, Eden J, Stuart AG, Parsons J, Peart I, Deanfield JE, O'Sullivan J, Babu-Narayan SV, Gatzoulis MA, Bu'lock FA, Bhattacharya S, Bentham J, Farrall M, Granados Riveron J, Brook JD, Burn J, Cordell HJ, Goodship JA, Keavney B - PLoS ONE (2009)

Bottom Line: However, results have been discrepant between studies and no study to date has comprehensively characterised variation throughout the gene.There was no significant effect of any VEGF haplotype-tagging SNP on the risk of CVM in our analyses of 771 probands.When the results of this and all previous studies were combined, there was no significant effect of the VEGF promoter SNPs rs699947 (OR 1.05 [95% CI 0.95-1.17]); rs1570360 (OR 1.17 [95% CI 0.99-1.26]); and rs2010963 (OR 1.04 [95% CI 0.93-1.16]) on the risk of CVM in 1341 cases.

View Article: PubMed Central - PubMed

Affiliation: Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, United Kingdom.

ABSTRACT
Several previous studies have investigated the role of common promoter variants in the vascular endothelial growth factor (VEGF) gene in causing congenital cardiovascular malformation (CVM). However, results have been discrepant between studies and no study to date has comprehensively characterised variation throughout the gene. We genotyped 771 CVM cases, of whom 595 had the outflow tract malformation Tetralogy of Fallot (TOF), and carried out TDT and case-control analyses using haplotype-tagging SNPs in VEGF. We carried out a meta-analysis of previous case-control or family-based studies that had typed VEGF promoter SNPs, which included an additional 570 CVM cases. To identify rare variants potentially causative of CVM, we carried out mutation screening in all VEGF exons and splice sites in 93 TOF cases. There was no significant effect of any VEGF haplotype-tagging SNP on the risk of CVM in our analyses of 771 probands. When the results of this and all previous studies were combined, there was no significant effect of the VEGF promoter SNPs rs699947 (OR 1.05 [95% CI 0.95-1.17]); rs1570360 (OR 1.17 [95% CI 0.99-1.26]); and rs2010963 (OR 1.04 [95% CI 0.93-1.16]) on the risk of CVM in 1341 cases. Mutation screening of 93 TOF cases revealed no VEGF coding sequence variants and no changes at splice consensus sequences. Genetic variation in VEGF appears to play a small role, if any, in outflow tract CVM susceptibility.

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Related in: MedlinePlus

Schematic diagram of VEGF based on transcript NM_003376.3; exons are represented as boxes (shaded – coding, unshaded - UTR), introns, up- and down-stream regions as dotted lines; SNPs were selected 15 Kb upstream, within and 15 Kb downstream of VEGF; the location of SNPs is indicated by dashed arrows; the three SNPs in the previously reported haplotype are bracketed; the approximate position of PCR products for sequencing are represented as solid lines with forward (F) and reverse (R) primer pairs indicated; the proportions of exons, introns, up- and down-stream regions are not to scale.
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pone-0004978-g001: Schematic diagram of VEGF based on transcript NM_003376.3; exons are represented as boxes (shaded – coding, unshaded - UTR), introns, up- and down-stream regions as dotted lines; SNPs were selected 15 Kb upstream, within and 15 Kb downstream of VEGF; the location of SNPs is indicated by dashed arrows; the three SNPs in the previously reported haplotype are bracketed; the approximate position of PCR products for sequencing are represented as solid lines with forward (F) and reverse (R) primer pairs indicated; the proportions of exons, introns, up- and down-stream regions are not to scale.

Mentions: htSNPs were selected for genotyping from within and 15 KB up- and down-stream of VEGF using the HapMap data for the samples of Northern and Western European ancestry (CEU samples: www.broad.mit.edu/mpg/haploview) and the Tagger utility of Haploview v3.2. Eighteen SNPs with MAF>0.05 were selected that were in linkage disequilibrium at r2>0.8 with all other genetic variation within the region. The SNP rs699947 previously reported to be associated with TOF was among the selected htSNPs. The other two SNPs typed in previous studies, rs1570360 and rs2010963, which were not genotyped in the HapMap, were additionally selected for genotyping. The location of the SNPs is shown in figure 1.


Genetic variation in VEGF does not contribute significantly to the risk of congenital cardiovascular malformation.

Griffin HR, Hall DH, Topf A, Eden J, Stuart AG, Parsons J, Peart I, Deanfield JE, O'Sullivan J, Babu-Narayan SV, Gatzoulis MA, Bu'lock FA, Bhattacharya S, Bentham J, Farrall M, Granados Riveron J, Brook JD, Burn J, Cordell HJ, Goodship JA, Keavney B - PLoS ONE (2009)

Schematic diagram of VEGF based on transcript NM_003376.3; exons are represented as boxes (shaded – coding, unshaded - UTR), introns, up- and down-stream regions as dotted lines; SNPs were selected 15 Kb upstream, within and 15 Kb downstream of VEGF; the location of SNPs is indicated by dashed arrows; the three SNPs in the previously reported haplotype are bracketed; the approximate position of PCR products for sequencing are represented as solid lines with forward (F) and reverse (R) primer pairs indicated; the proportions of exons, introns, up- and down-stream regions are not to scale.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2654913&req=5

pone-0004978-g001: Schematic diagram of VEGF based on transcript NM_003376.3; exons are represented as boxes (shaded – coding, unshaded - UTR), introns, up- and down-stream regions as dotted lines; SNPs were selected 15 Kb upstream, within and 15 Kb downstream of VEGF; the location of SNPs is indicated by dashed arrows; the three SNPs in the previously reported haplotype are bracketed; the approximate position of PCR products for sequencing are represented as solid lines with forward (F) and reverse (R) primer pairs indicated; the proportions of exons, introns, up- and down-stream regions are not to scale.
Mentions: htSNPs were selected for genotyping from within and 15 KB up- and down-stream of VEGF using the HapMap data for the samples of Northern and Western European ancestry (CEU samples: www.broad.mit.edu/mpg/haploview) and the Tagger utility of Haploview v3.2. Eighteen SNPs with MAF>0.05 were selected that were in linkage disequilibrium at r2>0.8 with all other genetic variation within the region. The SNP rs699947 previously reported to be associated with TOF was among the selected htSNPs. The other two SNPs typed in previous studies, rs1570360 and rs2010963, which were not genotyped in the HapMap, were additionally selected for genotyping. The location of the SNPs is shown in figure 1.

Bottom Line: However, results have been discrepant between studies and no study to date has comprehensively characterised variation throughout the gene.There was no significant effect of any VEGF haplotype-tagging SNP on the risk of CVM in our analyses of 771 probands.When the results of this and all previous studies were combined, there was no significant effect of the VEGF promoter SNPs rs699947 (OR 1.05 [95% CI 0.95-1.17]); rs1570360 (OR 1.17 [95% CI 0.99-1.26]); and rs2010963 (OR 1.04 [95% CI 0.93-1.16]) on the risk of CVM in 1341 cases.

View Article: PubMed Central - PubMed

Affiliation: Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, United Kingdom.

ABSTRACT
Several previous studies have investigated the role of common promoter variants in the vascular endothelial growth factor (VEGF) gene in causing congenital cardiovascular malformation (CVM). However, results have been discrepant between studies and no study to date has comprehensively characterised variation throughout the gene. We genotyped 771 CVM cases, of whom 595 had the outflow tract malformation Tetralogy of Fallot (TOF), and carried out TDT and case-control analyses using haplotype-tagging SNPs in VEGF. We carried out a meta-analysis of previous case-control or family-based studies that had typed VEGF promoter SNPs, which included an additional 570 CVM cases. To identify rare variants potentially causative of CVM, we carried out mutation screening in all VEGF exons and splice sites in 93 TOF cases. There was no significant effect of any VEGF haplotype-tagging SNP on the risk of CVM in our analyses of 771 probands. When the results of this and all previous studies were combined, there was no significant effect of the VEGF promoter SNPs rs699947 (OR 1.05 [95% CI 0.95-1.17]); rs1570360 (OR 1.17 [95% CI 0.99-1.26]); and rs2010963 (OR 1.04 [95% CI 0.93-1.16]) on the risk of CVM in 1341 cases. Mutation screening of 93 TOF cases revealed no VEGF coding sequence variants and no changes at splice consensus sequences. Genetic variation in VEGF appears to play a small role, if any, in outflow tract CVM susceptibility.

Show MeSH
Related in: MedlinePlus