Center for Research in Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Free Radic Biol Med. 2012 May 1;52(9):1577-83. doi: 10.1016/j.freeradbiomed.2012.02.025. Epub 2012 Mar 1.
Not all cigarette smokers develop chronic obstructive pulmonary disease, and discovering susceptibility factors is an important research priority. The oxidative burden of smoking may overwhelm antioxidant defenses, and vulnerabilities may exist as a result of sequence variants in genes encoding antioxidant enzymes. This study explored the association between genetic variation in a network of antioxidant enzymes and lung phenotypes. Linear models evaluated single-locus marker associations in 2387 European American and African American participants in the Health, Aging, and Body Composition Study. After corrections were made for multiple comparisons, 15 statistically significant associations were identified, all of which were for SNP by smoking interactions. The most statistically significant findings were for genes encoding members of the isocitrate dehydrogenase gene family (IDH3A, IDH3B, IDH2). For rs6107100 (IDH3B) the variant genotype was associated with a difference of 6% in the FEV(1)/FVC ratio in African American current smokers, but the SNP had little or no association with FEV(1)/FVC in former and never smokers (nominal p(interaction)=5×10(-6)). A variant of the peroxiredoxin gene (rs9787810, PRDX5) was associated with lower percentage predicted FEV(1) and a lower ratio in European American current smokers, with little or no association in other smoking groups (nominal p(interaction)=0.0001 and 0.0003, respectively). The studied genes have not been reported in previous candidate gene association studies, and thus the findings suggest novel mechanisms and targets for future research and provide evidence for a contribution of sequence variation in genes encoding antioxidant enzymes to susceptibility in smokers.
并非所有吸烟的人都会患上慢性阻塞性肺病，发现易感性因素是一个重要的研究重点。吸烟的氧化负担可能会超过抗氧化防御能力，并且由于编码抗氧化酶的基因序列变异，可能会存在脆弱性。本研究探讨了抗氧化酶网络中的基因遗传变异与肺表型之间的关联。线性模型评估了健康、衰老和身体成分研究中 2387 名欧洲裔美国人和非裔美国参与者的单个基因座标记关联。在对多次比较进行校正后，确定了 15 个具有统计学意义的关联，所有这些关联都是 SNP 与吸烟的相互作用。最具统计学意义的发现是编码异柠檬酸脱氢酶基因家族成员（IDH3A、IDH3B、IDH2）的基因。对于 rs6107100（IDH3B），变体基因型与非裔美国当前吸烟者的 FEV(1)/FVC 比值差异为 6%有关，但该 SNP 与以前和从不吸烟者的 FEV(1)/FVC 几乎没有关联（名义 p(相互作用)=5×10(-6)）。过氧化物酶基因（rs9787810，PRDX5）的变体与欧洲裔美国当前吸烟者的 FEV(1)百分比预测值和比值降低有关，而在其他吸烟组中几乎没有关联（名义 p(相互作用)=0.0001 和 0.0003）。研究的基因在以前的候选基因关联研究中没有报道过，因此这些发现表明了新的机制和靶点，为未来的研究提供了证据，并为编码抗氧化酶的基因序列变异对吸烟者易感性的贡献提供了证据。
