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Introduction: 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, remains controversial. One of the hypotheses concerns the genetic contribution of the sex chromosomes. However, while genomewide association studies identified many lung cancer susceptibility loci, these analyses have excluded X-linked loci. Methods: To account for non-genetic factors, we first presented an association test based on an additive-multiplicative hazard model accounting for random/non-random 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 non-random 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. Conclusion: 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.

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