The Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
Perelman School of Medicine, Department of Microbiology, University of Pennsylvania, Philadelphia.
JAMA Intern Med. 2022 Mar 1;182(3):291-300. doi: 10.1001/jamainternmed.2021.7804.
IMPORTANCE: Telomeres protect DNA from damage. Because they shorten with each mitotic cycle, leukocyte telomere length (LTL) serves as a mitotic clock. Reduced LTL has been associated with multiple human disorders. OBJECTIVE: To determine the association between LTL and overall as well as disease-specific mortality and morbidity. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, community-based cohort study conducted from March 2006 to December 2010 included longitudinal follow-up (mean [SD], 12 [2] years) for 472 432 English participants from the United Kingdom Biobank (UK Biobank) and analyzed morbidity and mortality. The data were analyzed in 2021. MAIN OUTCOMES AND MEASURES: Hazard ratios (HRs) and odds ratios for mortality and morbidity associated with a standard deviation change in LTL, adjusted for age, sex, body mass index (calculated as weight in kilograms divided by height in meters squared), and ethnicity. RESULTS: This study included a total of 472 432 English participants, of whom 54% were women (mean age, 57 years). Reduced LTL was associated with increased overall (HR, 1.08; 95% CI, 1.07-1.09), cardiovascular (HR, 1.09; 95% CI, 1.06-1.12), respiratory (HR, 1.40; 95% CI, 1.34-1.45), digestive (HR, 1.26; 95% CI, 1.19-1.33), musculoskeletal (HR, 1.51; 95% CI, 1.35-1.92), and COVID-19 (HR, 1.15; 95% CI, 1.07-1.23) mortality, but not cancer-related mortality. A total of 214 disorders were significantly overrepresented and 37 underrepresented in participants with shorter LTL. Respiratory (11%), digestive/liver-related (14%), circulatory (18%), and musculoskeletal conditions (6%), together with infections (5%), accounted for most positive associations, whereas (benign) neoplasms and endocrinologic/metabolic disorders were the most underrepresented entities. Malignant tumors, esophageal cancer, and lymphoid and myeloid leukemia were significantly more common in participants with shorter LTL, whereas brain cancer and melanoma were less prevalent. While smoking and alcohol consumption were associated with shorter LTL, additional adjustment for both factors, as well as cognitive function/major comorbid conditions, did not significantly alter the results. CONCLUSIONS AND RELEVANCE: This cohort study found that shorter LTL was associated with a small risk increase of overall mortality, but a higher risk of mortality was associated with specific organs and diseases.
重要性：端粒可保护 DNA 免受损伤。由于端粒在每次有丝分裂周期中都会缩短，因此白细胞端粒长度（LTL）可作为有丝分裂钟。端粒缩短与多种人类疾病有关。 目的：确定 LTL 与全因死亡率、特定疾病死亡率和发病率之间的关联。 设计、地点和参与者：这是一项多中心、基于社区的队列研究，于 2006 年 3 月至 2010 年 12 月进行，纳入了来自英国生物库（UK Biobank）的 472432 名英国参与者的纵向随访（平均[标准差]，12[2]年），并对发病率和死亡率进行了分析。数据分析于 2021 年进行。 主要结局和测量指标：与 LTL 标准偏差变化相关的死亡率和发病率的风险比（HR）和优势比，调整了年龄、性别、体重指数（计算为体重除以身高的平方）和种族。 结果：本研究共纳入 472432 名英国参与者，其中 54%为女性（平均年龄 57 岁）。端粒缩短与全因（HR，1.08；95%CI，1.07-1.09）、心血管（HR，1.09；95%CI，1.06-1.12）、呼吸（HR，1.40；95%CI，1.34-1.45）、消化/肝脏相关（HR，1.26；95%CI，1.19-1.33）、肌肉骨骼（HR，1.51；95%CI，1.35-1.92）和 COVID-19（HR，1.15；95%CI，1.07-1.23）死亡率增加相关，但与癌症相关死亡率无关。共有 214 种疾病在端粒较短的参与者中显著过表达，37 种疾病表达不足。呼吸（11%）、消化/肝脏相关（14%）、循环（18%）和肌肉骨骼疾病（6%）以及感染（5%）占大多数阳性关联，而（良性）肿瘤和内分泌/代谢疾病是表达不足的主要实体。端粒较短的参与者中恶性肿瘤、食管癌、淋巴和髓系白血病更为常见，而脑癌和黑色素瘤则较少见。尽管吸烟和饮酒与端粒缩短有关，但进一步调整这两个因素以及认知功能/主要合并症并不会显著改变结果。 结论和相关性：这项队列研究发现，端粒较短与全因死亡率的小风险增加相关，但特定器官和疾病的死亡率风险更高。
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