长寿相关的FOXO3基因型减轻戒烟后肺癌风险：一项前瞻性队列研究
Longevity-associated FOXO3 genotype mitigates the risk of lung cancer after smoking cessation: a prospective cohort study.
作者
作者单位
- Kuakini Japan-Hawaii Cancer Study, Kuakini Honolulu Heart Program, Center of Biomedical Research Excellence (COBRE) for Clinical and Translational Research on Aging, Department of Research, Kuakini Medical Center, Honolulu, HI, USA.
- Department of Internal Medicine, University of Hawaii, Honolulu, HI, USA.
摘要
中文
戒烟可降低肺癌（LC）风险，但风险降低的幅度因人而异。FOXO3是细胞应激反应和长寿通路的关键调节因子，可能影响戒烟后对LC的易感性。本研究旨在探讨FOXO3基因型是否改变戒烟与事件性LC之间的关联。我们考察了来自Kuakini日本-夏威夷癌症研究（1971-1975年；平均年龄60岁）中4339名基线无LC的日裔美国男性吸烟者。对参与者进行了FOXO3 rs2802292基因分型，并分为FOXO3-G（TG/GG；长寿相关G等位基因携带者）或FOXO3-TT（TT，常见等位基因纯合子）。评估了吸烟状况（既往或当前）、累积暴露量（包年）和戒烟持续时间（年；当前吸烟者赋值为0）。确定了截至1999年的事件性LC病例。使用调整了潜在混杂因素的Cox比例风险模型估计风险比（HRs）和95%置信区间（CIs），并检验交互作用。在28年的随访中，发生了180例LC病例，其中117例非小细胞肺癌（NSCLC）病例。观察到吸烟状况与FOXO3基因型对LC（P=0.02）和NSCLC（P=0.003）的显著交互作用。在既往吸烟者中，FOXO3-G携带者的风险低于FOXO3-TT携带者（LC：HR，0.42；95%CI，0.23-0.79；NSCLC：HR，0.23；95%CI，0.09-0.60）。相反，在当前吸烟者中未观察到基因型相关差异。在FOXO3-G携带者中，戒烟每增加一年与LC风险降低相关（HR，0.87；95%CI，0.81-0.94）和NSCLC（HR，0.72；95%CI，0.58-0.89），而在FOXO3-TT携带者中仅观察到较弱的关联（LC：HR，0.97；95%CI，0.94-1.00；NSCLC：HR，0.98；95%CI，0.94-1.01）。FOXO3基因型可能修饰与戒烟相关的LC风险。与携带长寿相关FOXO3 G等位基因的个体相比，FOXO3-TT基因型个体在戒烟后LC风险显著升高；这种关联在当前吸烟者中未观察到。这些发现支持基因型指导的精准预防的潜力，有待在更大、更多样化的队列中重复验证。
English
Smoking cessation lowers lung cancer (LC) risk, but the magnitude of risk reduction varies across individuals. FOXO3, a key regulator of cellular stress-response and longevity pathways, may influence susceptibility to LC after smoking cessation. The aim of the present study was to investigate whether FOXO3 genotype modifies the association between smoking cessation and incident LC. We examined 4,339 ever-smoking American men of Japanese ancestry who were free of LC at baseline in the Kuakini Japan-Hawaii Cancer Study (1971-1975; mean age, 60 years). Participants were genotyped for FOXO3 rs2802292 and classified as FOXO3-G (TG/GG; longevity-associated G-allele carriers) or FOXO3-TT (TT, common allele homozygotes). Smoking status (former or current), cumulative exposure (pack-years), and duration of smoking cessation (years; current smokers assigned 0) were assessed. Incident LC cases through 1999 were identified. Cox proportional hazards models adjusted for potential confounders were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), and test interactions. During 28 years of follow-up, 180 LC cases occurred, including 117 non-small cell lung cancer (NSCLC) cases. Significant interactions were observed between smoking status and FOXO3 genotype for LC (P=0.02) and NSCLC (P=0.003). Among former smokers, FOXO3-G carriers had a lower risk than FOXO3-TT carriers (LC: HR, 0.42; 95% CI, 0.23-0.79; NSCLC: HR, 0.23; 95% CI, 0.09-0.60). In contrast, no genotype-related differences were observed among current smokers. Among FOXO3-G carriers, each additional year of smoking cessation was associated with a reduced risk of LC (HR, 0.87; 95% CI, 0.81-0.94) and NSCLC (HR, 0.72; 95% CI, 0.58-0.89), whereas only weaker associations were observed among FOXO3-TT carriers (LC: HR, 0.97; 95% CI, 0.94-1.00; NSCLC: HR, 0.98; 95% CI, 0.94-1.01). FOXO3 genotype may modify LC risk associated with smoking cessation. Compared with carriers of the longevity-associated FOXO3 G allele, individuals with the FOXO3-TT genotype had a substantially elevated risk of LC after smoking cessation; this association was not observed among current smokers. These findings support the potential for genotype-informed precision prevention, pending replication in larger and more diverse cohorts.
分类与指标
- 研究类型
- 临床研究
- 病种
- 肺癌
- JCR 分区
- Q2
- 影响因子
- 3.4
- 新锐分区
- 3区