背景:肺癌是全球死亡率中最常见的癌症,发病率排名第二。流行病学研究发现,与男性相比,吸烟女性患肺癌的风险更高,但是这些性别差异,不管吸烟习惯如何,仍然有争议。其中一个假设涉及性染色体的遗传贡献。然而,虽然全基因组关联研究确定了许多肺癌易感位点,这些分析排除了X连锁基因座.
方法:考虑非遗传因素,我们首先提出了一个基于加法-乘法风险模型的关联检验,该模型考虑了随机/非随机X失活过程.与具有随机X失活过程的Cox模型的Wald检验和Xu等人提出的部分似然比检验进行了模拟研究,以研究所提出的检验的性质。考虑非随机X失活过程。然后,我们对基于人群的队列CARTaGENE中的9,261名个体进行了全X染色体关联研究,以确定当前和过去吸烟者中肺癌的易感基因座.我们调整了筛查项目中使用的PLCOm2012肺癌风险评分。
结果:仿真结果表明,与Xu等人相比,所提出的测试在功率和I型错误概率方面表现良好。还有Wald测试.使用建议的检验统计量并对PLCOm2012分数进行调整,X染色体范围的统计分析确定了位于IL1RAPL1(IL-1R辅助蛋白样)基因中的两个低连锁不平衡SNP:rs12558491(p=2.75*10-9)和rs12835699(p=1.26*10-6)。对于这两个SNP,次要等位基因与较低的肺癌风险相关.调整多次测试,使用Wald或Xu等人未检测到信号。似然比测试。
结论:通过考虑吸烟行为和X-灭活过程,对X染色体的研究为X连锁位点与肺癌之间的关联提供了新的思路.我们确定了位于IL1RAPL1基因中与肺癌相关的两个基因座。如果只检查其他测试统计数据的结果,这一发现就会被忽视。
BACKGROUND: Lung cancer is the most common cancer worldwide in mortality and the second in incidence. Epidemiological studies found a higher lung cancer risk for smoking women in comparison to men, but these sex differences, irrespective of smoking habits, remain controversial. One of the hypotheses concerns the genetic contribution of the sex chromosomes. However, while genome-wide association studies identified many lung cancer susceptibility loci, these analyses have excluded X-linked loci.
METHODS: To account for nongenetic factors, we first presented an association test based on an additive-multiplicative hazard model accounting for random/nonrandom X-inactivation process. A simulation study was performed to investigate the properties of the proposed test as compared with the Wald test from a Cox model with random X-inactivation process and the partial likelihood ratio test proposed by Xu et al. accounting for nonrandom X-inactivation process. Then, we performed an X chromosome-wide association study on 9,261 individuals from the population-based cohort CARTaGENE to identify susceptibility loci for lung cancer among current and past smokers. We adjusted for the PLCOm2012 lung cancer risk score used in screening programs.
RESULTS: Simulation results show the good behavior of the proposed test in terms of power and type I error probability as compared to the Xu et al. and the Wald test. Using the proposed test statistic and adjusting for the PLCOm2012 score, the X chromosome-wide statistical analysis identified two SNPs in low-linkage disequilibrium located in the IL1RAPL1 (IL-1 R accessory protein-like) gene: rs12558491 (p = 2.75×10-9) and rs12835699 (p = 1.26×10-6). For both SNPs, the minor allele was associated with lower lung cancer risk. Adjusting for multiple testing, no signal was detected using the Wald or the Xu et al. likelihood ratio tests.
CONCLUSIONS: By taking into account smoking behavior and the X-inactivation process, the investigation of the X chromosome has shed a new light on the association between X-linked loci and lung cancer. We identified two loci associated with lung cancer located in the IL1RAPL1 gene. This finding would have been overlooked by examining only results from other test statistics.