High-order interactions among genetic polymorphisms in nucleotide excision repair pathway genes and smoking in modulating bladder cancer risk
High-order interactions among genetic polymorphisms in nucleotide excision repair pathway genes and smoking in modulating bladder cancer risk
复制标题
DOI：
10.1093/carcin/bgm167
复制
发表时间：
2007-10-01
期刊：
影响因子：
4.7
通讯作者：
Gu, Jian
中科院分区：
文献类型：
--
作者：
Chen, Meng;Kamat, Ashish M.;Gu, Jian
核苷酸切除修复（NER）基因的多态性可能导致DNA修复能力的变化，并通过复杂的基因-基因和基因-吸烟相互作用增加膀胱癌的易感性。我们应用两种数据挖掘方法，探讨了696例膀胱癌患者和629例对照组9个主要NER基因的13个多态性之间的高阶基因-基因和基因-环境相互作用。单独来看，只有XPD D312 N变异基因型表现出膀胱癌风险略有增加。在分类和回归树分析中，我们观察到在曾经吸烟者中CCNH V270 A、ERCC 6 M1097 V和RAD 23 B A249 V之间的基因-基因相互作用：在这三个位点具有变异等位基因的吸烟者患膀胱癌的风险增加近30倍[比值比（OR）：29.6，95%置信区间（CI）：9.3-93.7]。当评估上述四种单核苷酸多态性的联合作用时，我们发现随着不利基因型数量的增加，膀胱癌风险增加的基因剂量效应显著。与携带2种以下不利基因型的个体相比，携带2种及2种以上不利基因型的个体患膀胱癌的风险增加，OR值分别为1.14（95% CI：0.87-1.51）和2.15（95% CI：1.56-2.97）（P < 0.001）。曾吸烟者的风险更明显，OR值分别为1.43（95%CI：1.02-2.01）和3.40（95%CI：2.24-5.15）（P < 0.001）。在多因素降维分析中，吸烟、CCNH V270 A、ERCC 6 M1097 V、RAD 23 B A249 V和XPD D312 N五因素模型预测膀胱癌风险能力最强。这些多态性的贡献可能通过基因-基因和基因-吸烟相互作用共同影响膀胱癌风险。和
Polymorphisms in nucleotide excision repair (NER) genes may cause variations in DNA repair capacity and increase susceptibility to bladder cancer through complex gene - gene and gene - smoking interactions. We applied two data mining approaches to explore high-order gene - gene and gene-environment interactions among 13 polymorphisms in nine major NER genes in 696 bladder cancer patients and 629 controls. Individually, only the XPD D312N variant genotypes exhibited a slightly increased risk for bladder cancer. In classification and regression tree analysis, we observed gene - gene interactions among CCNH V270A, ERCC6 M1097V and RAD23B A249V in ever smokers: smokers with the variant alleles at these three loci had an almost 30-fold increased risk of bladder cancer [odds ratio (OR): 29.6, 95% confidence interval (CI): 9.3-93.7]. When evaluating combined effect of above four single nucleotide polymorphisms, we found a significant gene dosage effect for increased bladder cancer risk with increasing numbers of unfavorable genotypes. Compared with individuals with less than 2 unfavorable genotypes, those with 2 unfavorable genotypes and more than 2 unfavorable genotypes exhibited increased bladder cancer risk with ORs of 1.14 (95% CI: 0.87-1.51) and 2.15 (95% CI: 1.56-2.97), respectively (P < 0.001). The risks were more evident in ever smokers with ORs of 1.43 ( 95% CI: 1.02-2.01) and 3.40 (95% CI: 2.24-5.15), respectively ( P < 0.001). In multifactor dimensionality reduction (MDR) analysis, the five-factor model including smoking, CCNH V270A, ERCC6 M1097V, RAD23B A249V and XPD D312N had the best ability to predict bladder cancer risk. The contributions of these polymorphisms may jointly affect bladder cancer risk through gene - gene and gene - smoking interactions. and