测量的白细胞端粒长度（LTL）、基因预测的LTL（gTL）与癌症发生之间的复杂关系在肺癌中得到了很好的证明。我们先前在欧洲人和东亚人群之间报告了LTL及gTL较长的患者与肺癌风险增加之间的关联。然而，我们在性别和组织学上对从未吸烟者之间的关联研究的统计学力量有限。 为了进一步调查这一关联，我们在上海女性和男性健康研究的从未吸烟者中进行了嵌套病例对照分析（SWHS：798例和792例对照；SMHS：161例和162例对照）。我们打破了病例对照匹配，并使用多变量无条件 logistic 回归模型，估计使用定量 PCR 测量的 LTL 和使用多基因分数确定的 gTL 与新发肺癌和腺癌（LUAD）的比值比（OR）和 95% 置信区间（CI）。另外，我们还进行了遗传学随机化（MR）分析。 我们发现在从未吸烟的女性中，LTL 和 gTL 的增长与肺癌风险呈明显的剂量-反应关系（p-trendLTL=4x10-6；p-trendgTL=3x10-4）。同样，在从未吸烟的男性中，相较于端粒长度最短的个体，较长的测得 LTL 与风险增加了三倍以上（OR=3.48，95%CI：1.85，6.57）。总体结果在女性和男性 LUAD 上也是类似的。MR 分析支持了在女性 LUAD 中的因果关联（OR1 SD gTL=1.19，95%CI：1.03，1.37；p=0.03）。 在从未吸烟者中，较长的白细胞端粒长度与肺癌风险增加相关。我们的研究结果坚定支持了白细胞端粒在肺癌发生中的作用。

The complex relationship between measured leukocyte telomere length (LTL), genetically-predicted LTL (gTL), and carcinogenesis is exemplified by lung cancer. We previously reported associations between longer pre-diagnostic LTL, gTL, and increased lung cancer risk among European and East Asian populations. However, we had limited statistical power to examine the associations among never smokers by gender and histology.To investigate further, we conducted nested case-control analyses on an expanded sample of never smokers from the prospective Shanghai Women's and Men's Health Studies (SWHS: 798 cases and 792 controls; SMHS: 161 cases and 162 controls). We broke the case-control matching and used multivariable unconditional logistic regression models to estimate the odds ratios (ORs) and 95% confidence intervals (CI) of incident lung cancer and adenocarcinoma (LUAD), in relation to LTL measured using quantitative PCR and gTL determined using a polygenic score. Additionally, we conducted Mendelian Randomization (MR) using MR-PRESSO.We found striking dose-response relationships between longer LTL and gTL, and increased lung cancer risk among never-smoking women (p-trendLTL=4x10-6; p-trendgTL=3x10-4). Similarly among never-smoking men, longer measured LTL was associated with over triple the risk compared to those with the shortest (OR=3.48, 95%CI: 1.85, 6.57). The overall results were similar for LUAD among women and men. MR analyses supported causal associations with LUAD among women (OR1 SD gTL=1.19 (95%CI: 1.03, 1.37; p=0.03).Longer pre-diagnostic leukocyte telomere length is associated with increased lung cancer risk among never smokers.Our findings firmly support the role of longer telomeres in lung carcinogenesis.