端粒长度与食管癌发生风险的孟德尔随机化研究

Causal relationship between telomere length and esophageal cancer:Mendelian randomization study

目的:采用孟德尔随机化方法,探索端粒长度与食管癌发生风险的关系,为食管癌防治提供理论依据。方法:利用中国人群食管癌的全基因组关联研究(genome-wide association studies,GWAS)中1 877例食管癌病例和2 084例无肿瘤独立对照样本,使用与白细胞端粒长度具有显著相关性的9个单核苷酸多态性(single nucleotide polymorphisms,SNP)位点作为工具变量,通过遗传风险得分法(genetic risk score,GRS)和逆方差加权法(the inverse-variance weighting method,IVW)估计端粒长度与食管癌发生风险之间的关联。此外,根据年龄、性别做分层分析,探讨是否存在分层因素与暴露因素之间的交互作用。结果:孟德尔随机化分析结果显示端粒长度与食管癌发生风险无统计学上的显著关联,无论是基于基因型个体数据(individual-level data)的GRS法还是基于汇总数据(summarized data)的IVW法均得出一致的结果(GRS:OR=1.19,95%CI:0.81~1.77,P=0.380;IVW:OR=1.22,95%CI:0.81~1.84,P=0.380)。分层分析发现性别之间有层间异质性,但进一步分析各性别人群中端粒长度与食管癌的关系都没有得到显著性关联(女性:OR=0.83,95%CI:0.43~1.6,P=0.582;男性:OR=1.49,95%CI:0.91~2.44,P=0.115)。结论:研究尚未发现端粒长度与食管癌发生风险之间有显著性关联。

Objective:This study used mendelian randomization method to explore the relationship between telomere length and esophageal cancer,and to provide a theoretical basis for the prevention and treatment of esophageal cancer. Methods:Our study was based on previous esophageal cancer genome-wide association studies(GWAS)data(1 877 esophageal cancer patients and 2 084 controls),and nine telomere length-related single nucleotide polymorphisms(SNPs)reaching genome-wide association significant level were systematically selected as instrumental variables. Genetic risk score(GRS)and the inverse-variance weighting method(IVW)were applied to estimate the causal effect of telomere length on esophageal cancer risk. In addition,a stratified analysis based on age and gender was conducted to explore whether there was interaction between variables. Results:MR analyses indicated that both GRS and IVW methods suggested that there is no significant risk signal between genetically increased telomere length and esophageal cancer risk(GRS:OR=1.19,95%CI:0.81-1.77,P=0.380;IVW:OR=1.22,95%CI:0.81-1.84,P=0.380). Subgroup analysis revealed significant heterogeneity between different gender. Conclusion:The study has not found a significant association between telomere length and the risk of esophageal cancer.