初产年龄与肺癌：一项两样本孟德尔随机化研究。

Age at first birth and lung cancer: a two-sample Mendelian randomization study.

作者信息

Peng Haoxin, Wu Xiangrong, Wen Yaokai, Du Xiaoqin, Li Caichen, Liang Hengrui, Lin Jinsheng, Liu Jun, Ge Fan, Huo Zhenyu, He Jianxing, Liang Wenhua

机构信息

Department of Thoracic Oncology and Surgery, China State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

Nanshan School, Guangzhou Medical University, Guangzhou, China.

出版信息

Transl Lung Cancer Res. 2021 Apr;10(4):1720-1733. doi: 10.21037/tlcr-20-1216.

DOI:10.21037/tlcr-20-1216

PMID:34012788

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8107761/

Abstract

BACKGROUND

Growing evidence suggests that female reproductive factors, like age at first birth (AFB), may play a potential role in the progression of lung cancer (LC). However, previous studies are susceptible to confounding factors, inadequate attention to variation by histology or reverse causality. Few studies have comprehensively evaluated their association and the causal effect remains unclear.

METHODS

We aimed to determine whether AFB is causally correlated with the risk of LC, by means of utilizing aggregated data from the large genome-wide association studies conducted on AFB (251,151 individuals) and data of LC from International Lung and Cancer Consortium (ILCCO, 11,348 cases and 15,861 controls). We used 10 AFB-related single nucleotide polymorphisms as instrument variables and applied several two-sample Mendelian randomization (MR) methods. Secondary results according to different histological subtypes of lung cancer were also implemented.

RESULTS

Conventional inverse-variance weighted method indicated that genetic predisposition towards number unit (1 year) increase of AFB was associated with a 18% lower risk of LC [odds ratio (OR) =0.82, 95% confidence interval (CI): 0.69-0.97; P=0.029]. When results were examined by histotypes, an inverse association was observed between genetically predisposed number unit (1 year) increase of AFB and lung adenocarcinoma (OR =0.75, 95% CI: 0.59-0.97, P=0.017) but not with squamous cell lung cancer (OR =0.77, 95% CI: 0.57-1.05, P=0.103). The results demonstrated no association between number unit decrease of AFB and LC. Pleiotropy was not presented through sensitivity analyses including MR pleiotropy residual sum and outlier test (P=0.412). Genetic predisposition towards older AFB was additionally associated with longer years of schooling (OR =1.12, 95% CI: 1.08-1.16, P<0.001), lower body mass index (OR =0.93, 95% CI: 0.88-0.98, P=0.004) and less alcohol consumption (OR =0.99, 95% CI: 0.99-1.00, P=0.004).

CONCLUSIONS

Our study suggested that older AFB was a causal protective factor in the progression of LC. Further studies elucidating the potential mechanisms are needed.

摘要

背景

越来越多的证据表明，女性生殖因素，如初产年龄（AFB），可能在肺癌（LC）进展中发挥潜在作用。然而，以往研究易受混杂因素影响，对组织学差异关注不足或存在反向因果关系。很少有研究全面评估它们之间的关联，因果效应仍不明确。

方法

我们旨在通过利用针对AFB进行的大型全基因组关联研究（251,151例个体）的汇总数据以及国际肺癌联盟（ILCCO，11,348例病例和15,861例对照）的LC数据，来确定AFB是否与LC风险存在因果关联。我们使用10个与AFB相关的单核苷酸多态性作为工具变量，并应用了几种双样本孟德尔随机化（MR）方法。还根据肺癌的不同组织学亚型进行了次要分析。

结果

传统的逆方差加权法表明，AFB每增加一个单位（1年）的遗传易感性与LC风险降低18%相关[比值比（OR）=0.82，95%置信区间（CI）：0.69 - 0.97；P = 0.029]。按组织学类型检查结果时，观察到AFB每增加一个遗传易感性单位（1年）与肺腺癌呈负相关（OR = 0.75，95% CI：0.59 - 0.97，P = 0.017），但与肺鳞状细胞癌无关（OR = 0.77，95% CI：0.57 - 1.05，P = 0.103）。结果表明AFB每降低一个单位与LC之间无关联。通过包括MR多效性残差和离群值检验在内的敏感性分析未发现多效性（P = 0.412）。AFB较大的遗传易感性还与受教育年限较长（OR = 1.12，95% CI：1.08 - 1.16，P < 0.001）、体重指数较低（OR = 0.93，95% CI：0.88 - 0.98，P = 0.004）和饮酒量较少（OR = 0.99，95% CI：0.99 - 1.00，P = 0.004）相关。