Department of Epidemiology and Biostatistics and Ministry of Education (MOE), Key Laboratory for Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
Carcinogenesis. 2014 Mar;35(3):572-7. doi: 10.1093/carcin/bgt400. Epub 2013 Dec 9.
Lung cancer is the leading cause of cancer-related deaths worldwide. By now, genome-wide association studies (GWAS) have identified numerous loci associated with the risk of developing lung cancer. However, these loci account for only a small fraction of the familial lung cancer risk. We hypothesized that epistasis may contribute to the missing heritability. To test this hypothesis, we systematically evaluated the association of epistasis of genetic variants with risk of lung cancer in Han Chinese cohorts. We conducted a pairwise genetic interaction analysis of 591370 variants, using BOolean Operation-based Screening and Testing (BOOST), in an ongoing GWAS of lung cancer that includes 2331 cases and 3077 controls. Pairs of epistatic loci with P BOOST ≤ 1.00×10(-6) were further evaluated by a logistic regression model (LRM) with covariate adjustment. Four promising epistatic pairs identified at the screening stage (P LRM ≤ 2.86×10(-) (13)) were validated in two replication cohorts: the first from Beijing (1534 cases and 1489 controls) and the second from Shenyang and Guangzhou (2512 cases and 2449 controls). Using this combined analysis, we identified an interaction between rs2562796 and rs16832404 at 2p32.2 that was significantly associated with the risk of developing lung cancer (P LRM = 1.03×10(-13) in total 13 392 subjects). This study is the first investigation of epistasis for lung cancer on a genome-wide scale in Han Chinese. It addresses part of the missing heritability in lung cancer risk and provides novel insight into the multifactorial etiology of lung cancer.
肺癌是全球癌症相关死亡的主要原因。到目前为止，全基因组关联研究（GWAS）已经确定了许多与肺癌发病风险相关的基因位点。然而，这些基因位点仅占家族性肺癌风险的一小部分。我们假设，上位性可能导致遗传易感性缺失。为了检验这一假设，我们系统地评估了遗传变异上位性与汉族人群肺癌风险的关联。我们对正在进行的肺癌 GWAS 中包含的 2331 例病例和 3077 例对照的 591370 个变异进行了基于布尔运算的筛选和检验（BOOST）的成对遗传互作分析。对筛选阶段 P BOOST ≤ 1.00×10(-6)的双等位基因互作位点，进一步用协变量调整的逻辑回归模型（LRM）进行评估。在筛选阶段发现的四个有前途的双等位基因互作对（P LRM ≤ 2.86×10(-) (13)），在两个验证队列中进行了验证：第一个来自北京（1534 例病例和 1489 例对照），第二个来自沈阳和广州（2512 例病例和 2449 例对照）。通过这项联合分析，我们在 2p32.2 上确定了 rs2562796 和 rs16832404 之间的相互作用，与肺癌发病风险显著相关（在总共 13392 例个体中，P LRM = 1.03×10(-13)）。这项研究是首次在汉族人群中对肺癌进行全基因组范围内的上位性研究。它解决了肺癌风险遗传易感性缺失的一部分问题，并为肺癌的多因素病因提供了新的见解。
