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      Large-Scale Evaluation of Candidate Genes Identifies Associations between VEGF Polymorphisms and Bladder Cancer Risk

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          Abstract

          Common genetic variation could alter the risk for developing bladder cancer. We conducted a large-scale evaluation of single nucleotide polymorphisms (SNPs) in candidate genes for cancer to identify common variants that influence bladder cancer risk. An Illumina GoldenGate assay was used to genotype 1,433 SNPs within or near 386 genes in 1,086 cases and 1,033 controls in Spain. The most significant finding was in the 5′ UTR of VEGF (rs25648, p for likelihood ratio test, 2 degrees of freedom = 1 × 10 −5). To further investigate the region, we analyzed 29 additional SNPs in VEGF, selected to saturate the promoter and 5′ UTR and to tag common genetic variation in this gene. Three additional SNPs in the promoter region (rs833052, rs1109324, and rs1547651) were associated with increased risk for bladder cancer: odds ratio (95% confidence interval): 2.52 (1.06–5.97), 2.74 (1.26–5.98), and 3.02 (1.36–6.63), respectively; and a polymorphism in intron 2 (rs3024994) was associated with reduced risk: 0.65 (0.46–0.91). Two of the promoter SNPs and the intron 2 SNP showed linkage disequilibrium with rs25648. Haplotype analyses revealed three blocks of linkage disequilibrium with significant associations for two blocks including the promoter and 5′ UTR (global p = 0.02 and 0.009, respectively). These findings are biologically plausible since VEGF is critical in angiogenesis, which is important for tumor growth, its elevated expression in bladder tumors correlates with tumor progression, and specific 5′ UTR haplotypes have been shown to influence promoter activity. Associations between bladder cancer risk and other genes in this report were not robust based on false discovery rate calculations. In conclusion, this large-scale evaluation of candidate cancer genes has identified common genetic variants in the regulatory regions of VEGF that could be associated with bladder cancer risk.

          Author Summary

          This article reports findings from a large-scale evaluation of common variation in candidate genes for cancer to identify variants that influence bladder cancer risk. We first evaluated 1,433 common variants within or near 386 genes in a large case-control study in Spain. The most significant finding was the gene coding for the vascular endothelial growth factor (VEGF). To further investigate this finding, we identified markers that captured most common variation in the whole gene. Analyses indicated that variants in regulatory regions of VEGF could modify the risk for developing bladder cancer. This association is biologically plausible since VEGF is critical for the growth of new blood vessels, which is important for tumor development, and its elevated expression in bladder tumors correlates with tumor progression. Future studies are required to confirm these findings, as well as to investigate the mechanisms for the observed associations.

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          Most cited references 18

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          MEGA3: Integrated software for Molecular Evolutionary Genetics Analysis and sequence alignment.

           S. KUMAR (2004)
          With its theoretical basis firmly established in molecular evolutionary and population genetics, the comparative DNA and protein sequence analysis plays a central role in reconstructing the evolutionary histories of species and multigene families, estimating rates of molecular evolution, and inferring the nature and extent of selective forces shaping the evolution of genes and genomes. The scope of these investigations has now expanded greatly owing to the development of high-throughput sequencing techniques and novel statistical and computational methods. These methods require easy-to-use computer programs. One such effort has been to produce Molecular Evolutionary Genetics Analysis (MEGA) software, with its focus on facilitating the exploration and analysis of the DNA and protein sequence variation from an evolutionary perspective. Currently in its third major release, MEGA3 contains facilities for automatic and manual sequence alignment, web-based mining of databases, inference of the phylogenetic trees, estimation of evolutionary distances and testing evolutionary hypotheses. This paper provides an overview of the statistical methods, computational tools, and visual exploration modules for data input and the results obtainable in MEGA.
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            Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium.

            Common genetic polymorphisms may explain a portion of the heritable risk for common diseases. Within candidate genes, the number of common polymorphisms is finite, but direct assay of all existing common polymorphism is inefficient, because genotypes at many of these sites are strongly correlated. Thus, it is not necessary to assay all common variants if the patterns of allelic association between common variants can be described. We have developed an algorithm to select the maximally informative set of common single-nucleotide polymorphisms (tagSNPs) to assay in candidate-gene association studies, such that all known common polymorphisms either are directly assayed or exceed a threshold level of association with a tagSNP. The algorithm is based on the r(2) linkage disequilibrium (LD) statistic, because r(2) is directly related to statistical power to detect disease associations with unassayed sites. We show that, at a relatively stringent r(2) threshold (r2>0.8), the LD-selected tagSNPs resolve >80% of all haplotypes across a set of 100 candidate genes, regardless of recombination, and tag specific haplotypes and clades of related haplotypes in nonrecombinant regions. Thus, if the patterns of common variation are described for a candidate gene, analysis of the tagSNP set can comprehensively interrogate for main effects from common functional variation. We demonstrate that, although common variation tends to be shared between populations, tagSNPs should be selected separately for populations with different ancestries.
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              Identification of polymorphisms within the vascular endothelial growth factor (VEGF) gene: correlation with variation in VEGF protein production.

              Dysregulated vascular endothelial growth factor (VEGF) expression has been implicated as a major contributor to the development of a number of common disease pathologies. The aim of this study was to establish the extent of genetic variability within the VEGF gene and to determine whether this genetic variation influenced levels of VEGF protein expression. The promoter region and exon 1 of the VEGF gene were screened for polymorphisms using single-stranded conformation (SSCP) polymorphism analysis and direct PCR-sequencing. We identified 15 novel sequence polymorphisms most of which were rare. Eleven of these polymorphisms were single base substitutions, three were single base insertions and one was a two base deletion. Thirteen of the polymorphisms were located within the promoter and two in the 5' untranslated region (5'UTR) of the gene. We established PCR-RFLP typing systems for ten of the polymorphisms. For the two common polymorphisms at -460 and +405, we developed a combined sequence specific priming (SSP) PCR typing system to determine the cis/trans orientation of each allele and hence, ascertain haplotypes. A significant correlation was observed between lipopolysaccharide (LPS) stimulated peripheral blood mononuclear cell (PBMC) VEGF protein production and genotype for the +405 polymorphism. Copyright 2000 Academic Press.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                pgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                February 2007
                23 February 2007
                4 January 2007
                : 3
                : 2
                Affiliations
                [1 ] Division of Cancer Epidemiology and Genetics, National Cancer Institute, Department of Health and Human Services, Bethesda, Maryland, United States of America
                [2 ] Center for Research in Environmental Epidemiology, Municipal Institute of Medical Research (IMIM), Barcelona Spain
                [3 ] Cellular and Molecular Biology Research Unit, Municipal Institute of Medical Research (IMIM), Barcelona, Spain
                [4 ] Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
                [5 ] Core Genotype Facility at the Advanced Technology Center of the National Cancer Institute, Department of Health and Human Services, Bethesda, Maryland, United States of America
                [6 ] Department of Social Medicine, Medical School, University of Crete, Heraklion, Greece
                [7 ] Department of Preventive Medicine and Public Health, Universidad de Oviedo, Oviedo, Spain
                [8 ] Unit of Research in Occupational Health, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain; Corporació Parc Taulí, Sabadell, Spain
                [9 ] Department of Medical Oncology, Hospital General de Elche, Elche, Spain
                [10 ] Department of Preventive Medicine, Hospital Universitario de Canarias, La Laguna, Spain
                University of Michigan, United States of America
                Author notes
                * To whom correspondence should be addressed. E-mail: montse@ 123456nih.gov
                Article
                06-PLGE-RA-0385R2 plge-03-02-13
                10.1371/journal.pgen.0030029
                1802828
                17319747
                Copyright: © 2007 García-Closas et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 7
                Categories
                Research Article
                Genetics and Genomics
                Genetics and Genomics
                Public Health and Epidemiology
                Homo (Human)
                Custom metadata
                García-Closas M, Malats N, Real FX, Yeager M, Welch R, et al. (2007) Large-scale evaluation of candidate genes for cancer identifies associations between VEGF polymorphisms and bladder cancer risk. PLoS Genet 3(2): e29. doi: 10.1371/journal.pgen.0030029

                Genetics

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