Tobacco smoking and smoking-related DNA methylation are associated with the development of frailty among older adults

Tobacco smoking is a preventable environmental factor that contributes to a wide spectrum of age-related health outcomes; however, its association with the development of frailty is not yet well established. We examined the associations of self-reported smoking indicators, serum cotinine levels and smoking-related DNA methylation biomarkers with a quantitative frailty index (FI) in 2 independent subsets of older adults (age 50–75) recruited in Saarland, Germany in 2000 – 2002 (discovery set: n = 978, validation set: n = 531). We obtained DNA methylation profiles in whole blood samples by Illumina HumanMethylation450 BeadChip and calculated the FI according to the method of Mitnitski and Rockwood. Mixed linear regression models were implemented to assess the associations between smoking indicators and the FI. After controlling for potential covariates, current smoking, cumulative smoking exposure (pack-years), and time after smoking cessation (years) were significantly associated with the FI (<i>P</i>-value &lt; 0.05). In the discovery panel, 17 out of 151 previously identified smoking-related CpG sites were associated with the FI after correction for multiple testing (FDR &lt; 0.05). Nine of them survived in the validation phase and were designated as frailty-associated loci. A smoking index (SI) based on the 9 loci manifested a monotonic association with the FI. In conclusion, this study suggested that epigenetic alterations could play a role in smoking-associated development of frailty. The identified CpG sites have the potential to be prognostic biomarkers of frailty and frailty-related health outcomes. Our findings and the underlying mechanisms should be followed up in further, preferably longitudinal studies.

吸烟是一种可预防的环境危险因素，可引发广泛的年龄相关性健康结局，但目前其与衰弱（frailty）发生的关联尚未明确。本研究针对2000-2002年于德国萨尔兰州招募的2个独立老年受试者亚组（年龄50~75岁），分析了自我报告的吸烟指标、血清可替宁水平及吸烟相关DNA甲基化生物标志物与定量衰弱指数（FI）的关联：其中发现队列（discovery set）样本量为978，验证队列（validation set）样本量为531。本研究采用Illumina HumanMethylation450 BeadChip对全血样本进行DNA甲基化谱检测，并依据Mitnitski与Rockwood的方法计算衰弱指数（FI）。采用混合线性回归模型评估吸烟指标与衰弱指数（FI）之间的关联。在校正潜在混杂因素后，当前吸烟、累积吸烟暴露量（pack-years，包-年）以及戒烟后时长（年）均与衰弱指数（FI）呈显著关联（P值<0.05）。在发现队列中，151个已报道的吸烟相关CpG位点中有17个在校正多重检验后仍与衰弱指数（FI）显著关联（错误发现率FDR<0.05）。其中9个位点在验证阶段得到重复验证，被鉴定为衰弱相关位点。基于这9个位点构建的吸烟指数（SI）与衰弱指数（FI）呈单调关联。综上，本研究提示表观遗传改变可能在吸烟相关衰弱发生过程中发挥作用。本研究鉴定的CpG位点有望成为衰弱及衰弱相关健康结局的预后生物标志物。本研究结果及潜在机制有待后续（最好为纵向）研究进一步验证与阐明。