Variants in angiogenesis-related genes and the risk of clear cell renal cell carcinoma
Variants in angiogenesis-related genes and the risk of clear cell renal cell carcinoma
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血管生成相关基因的变异和透明细胞肾细胞癌的风险。
DOI：
10.1093/mutage/geu046
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发表时间：
2014-11-01
期刊：
影响因子：
2.7
通讯作者：
Yin, Changjun
中科院分区：
文献类型：
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作者：
Qin, Chao;Chen, Jianchun;Yin, Changjun
血管生成对透明细胞肾细胞癌（ccRCC）的发病机制至关重要。我们研究了血管生成相关基因变异与ccRCC风险之间的关系。在一项859例ccRCC患者和1004例无癌受试者的病例对照研究中，我们使用TaqMan或Snapshot方法对7个血管生成相关基因（HIF1A、EPAS1、VEGFA、VEGFR1、VEGFR2、VEGFR3和PDGFRB）中的24个潜在功能单核苷酸多态性（snp）进行了基因分型。对潜在的混杂因素进行调整后，采用无条件逻辑回归来评估风险关联。通过实时定量逆转录聚合酶链反应（RT-PCR）和荧光素酶报告基因检测来评估所选snp的功能。在调整多重比较后，我们发现两个snp （VEGFA rs2010963和VEGFR3 rs448012）与ccRCC风险增加显著相关[rs2010963 CC/GC cf. GG：错误发现率(FDR) = 0.048，优势比(OR) = 1.36, 95%置信区间(95% CI) = 1.12-1.66；rs448012 CC/GC cf. GG: FDR = 0.048, OR = 1.38, 95% CI =1.13-1.69]。实时荧光定量PCR结果显示，rs2010963的变异基因型与ccRCC患者正常组织中基因表达增加相关，而rs448012的变异基因型与ccRCC患者正常组织中基因表达增加相关（CC/GC cf. GG: P = 0.036）。荧光素酶报告基因实验显示，rs2010963 C等位基因比rs2010963 G等位基因显著提高了荧光素酶活性。我们的研究结果表明VEGFA rs2010963和VEGFR3 rs448012与ccRCC的风险相关。此外，rs2010963是一个功能性SNP，可能通过调节内源性VEGFA表达影响ccRCC易感性。
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.