title: Variants in angiogenesis-related genes and the risk of clear cell renal cell carcinoma.
abstract: Angiogenesis is fundamentally important to the pathogenesis of clear cell renal cell carcinoma (ccRCC). We investigated the association between variations of genes related to angiogenesis and the risk of ccRCC. In a case-control study of 859 ccRCC patients and 1004 cancer-free subjects, we genotyped 24 potentially functional single nucleotide polymorphisms (SNPs) in seven angiogenesis-related genes (HIF1A, EPAS1, VEGFA, VEGFR1, VEGFR2, VEGFR3 and PDGFRB) using the TaqMan or Snapshot method. Unconditional logistic regression, adjusted for potential confounding factors, was used to assess the risk associations. The functionality of selected SNPs was assessed by real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) and luciferase reporter gene assays. We found two SNPs (VEGFA rs2010963 and VEGFR3 rs448012) that were significantly associated with increased risk of ccRCC, after adjusting for multiple comparisons [rs2010963 CC/GC cf. GG: false discovery rate (FDR) = 0.048, odds ratio (OR) = 1.36, 95% confidence interval (95% CI) = 1.12-1.66; rs448012 CC/GC cf. GG: FDR = 0.048, OR = 1.38, 95% CI =1.13-1.69]. Real-time quantitative PCR revealed that the variant genotypes of rs2010963, but not rs448012, were associated with increased gene expression in normal tissues of ccRCC patients (CC/GC cf. GG: P = 0.036). The luciferase reporter assay showed that the rs2010963 C allele significantly increased luciferase activity over that of the rs2010963 G allele. Our results indicate that VEGFA rs2010963 and VEGFR3 rs448012 are associated with risk of ccRCC. Furthermore, rs2010963 is a functional SNP that may affect ccRCC susceptibility by modulating endogenous VEGFA expression.
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, China and Cancer Center of Nanjing Medical University, Department of Molecular and Genetic Toxicology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Qin
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, China and Cancer Center of Nanjing Medical University, Department of Molecular and Genetic Toxicology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China.
authors.forename: Jianchun
authors.initials: J
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, China and Cancer Center of Nanjing Medical University, Department of Molecular and Genetic Toxicology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, China and Cancer Center of Nanjing Medical University, Department of Molecular and Genetic Toxicology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Ju
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, China and Cancer Center of Nanjing Medical University, Department of Molecular and Genetic Toxicology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China.
authors.forename: Shaobo
authors.initials: S
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, China and Cancer Center of Nanjing Medical University, Department of Molecular and Genetic Toxicology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, China and Cancer Center of Nanjing Medical University, Department of Molecular and Genetic Toxicology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Han
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, China and Cancer Center of Nanjing Medical University, Department of Molecular and Genetic Toxicology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China.
authors.forename: Pu
authors.initials: P
authors.lastname: Li
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, China and Cancer Center of Nanjing Medical University, Department of Molecular and Genetic Toxicology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China.
authors.forename: Peifei
authors.initials: P
authors.lastname: Shao
authors.affiliation: Cancer Center of Nanjing Medical University, Department of Molecular and Genetic Toxicology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China.
authors.forename: Meilin
authors.initials: M
authors.lastname: Wang
authors.affiliation: Cancer Center of Nanjing Medical University, Department of Molecular and Genetic Toxicology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China.
authors.forename: Zhengdong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, China and Cancer Center of Nanjing Medical University, Department of Molecular and Genetic Toxicology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China.
authors.forename: Min
authors.initials: M
authors.lastname: Gu
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, China and Cancer Center of Nanjing Medical University, Department of Molecular and Genetic Toxicology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, China and Cancer Center of Nanjing Medical University, Department of Molecular and Genetic Toxicology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China drcjyin@gmail.com.
authors.forename: Changjun
authors.initials: C
authors.lastname: Yin
mesh_terms: D002292:Carcinoma, Renal Cell / Q000098:blood supply* / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007680:Kidney Neoplasms / Q000098:blood supply* / Q000235:genetics* / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000235:genetics*; D010957:Plasmids / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics
chemical_list: D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D008156:Luciferases; C581309:FLT4 protein, human; D040321:Vascular Endothelial Growth Factor Receptor-3