Andrew Angeline S, Karagas Margaret R, Nelson Heather H, Guarrera Simonetta, Polidoro Silvia, Gamberini Sara, Sacerdote Carlotta, Moore Jason H, Kelsey Karl T, Demidenko Eugene, Vineis Paolo, Matullo Giuseppe
Department of Community and Family Medicine, Section of Biostatistics and Epidemiology, Dartmouth Medical School, Lebanon, NH 03756, USA.
Hum Hered. 2008;65(2):105-18. doi: 10.1159/000108942. Epub 2007 Sep 26.
A number of common non-synonymous single nucleotide polymorphisms (SNPs) in DNA repair genes have been reported to modify bladder cancer risk. These include: APE1-Asn148Gln, XRCC1-Arg399Gln and XRCC1-Arg194Trp in the BER pathway, XPD-Gln751Lys in the NER pathway and XRCC3-Thr241Met in the DSB repair pathway.
To examine the independent and interacting effects of these SNPs in a large study group, we analyzed these genotypes in 1,029 cases and 1,281 controls enrolled in two case-control studies of incident bladder cancer, one conducted in New Hampshire, USA and the other in Turin, Italy.
The odds ratio among current smokers with the variant XRCC3-241 (TT) genotype was 1.7 (95% CI 1.0-2.7) compared to wild-type. We evaluated gene-environment and gene-gene interactions using four analytic approaches: logistic regression, Multifactor Dimensionality Reduction (MDR), hierarchical interaction graphs, classification and regression trees (CART), and logic regression analyses. All five methods supported a gene-gene interaction between XRCC1-399/XRCC3-241 (p = 0.001) (adjusted OR for XRCC1-399 GG, XRCC3-241 TT vs. wild-type 2.0 (95% CI 1.4-3.0)). Three methods predicted an interaction between XRCC1-399/XPD-751 (p = 0.008) (adjusted OR for XRCC1-399 GA or AA, XRCC3-241 AA vs. wild-type 1.4 (95% CI 1.1-2.0)).
These results support the hypothesis that common polymorphisms in DNA repair genes modify bladder cancer risk and highlight the value of using multiple complementary analytic approaches to identify multi-factor interactions.
据报道，DNA修复基因中的一些常见非同义单核苷酸多态性（SNP）会改变膀胱癌风险。这些包括：碱基切除修复（BER）途径中的APE1-Asn148Gln、XRCC1-Arg399Gln和XRCC1-Arg194Trp，核苷酸切除修复（NER）途径中的XPD-Gln751Lys，以及双链断裂（DSB）修复途径中的XRCC3-Thr241Met。
为了在一个大型研究组中检验这些SNP的独立和相互作用效应，我们在两项新发性膀胱癌病例对照研究中分析了1029例病例和1281例对照的这些基因型，一项研究在美国新罕布什尔州进行，另一项在意大利都灵进行。
与野生型相比，携带变异型XRCC3-241（TT）基因型的当前吸烟者的优势比为1.7（95%可信区间1.0-2.7）。我们使用四种分析方法评估基因-环境和基因-基因相互作用：逻辑回归、多因素降维法（MDR）、分层相互作用图、分类与回归树（CART）以及逻辑回归分析。所有五种方法均支持XRCC1-399/XRCC3-241之间存在基因-基因相互作用（p = 0.001）（XRCC1-399 GG、XRCC3-241 TT与野生型相比的调整优势比为2.0（95%可信区间1.4-3.0））。三种方法预测XRCC1-399/XPD-751之间存在相互作用（p = 0.008）（XRCC1-399 GA或AA、XRCC3-241 AA与野生型相比的调整优势比为1.4（95%可信区间1.1-2.0））。
这些结果支持DNA修复基因中的常见多态性会改变膀胱癌风险这一假设，并突出了使用多种互补分析方法来识别多因素相互作用的价值。
