Department of Public Health Sciences.
Department of Human Genetics, University of Chicago, Illinois.
J Gerontol A Biol Sci Med Sci. 2021 Jan 1;76(1):15-22. doi: 10.1093/gerona/glz240.
Telomere length (TL) shortens over time in most human cell types and is a potential biomarker of aging. However, the causal association of TL on physical and cognitive traits that decline with age has not been extensively examined in middle-aged adults. Using a Mendelian randomization (MR) approach, we utilized genetically increased TL (GI-TL) to estimate the impact of TL on aging-related traits among U.K. Biobank (UKB) participants (age 40-69 years). We manually curated 53 aging-related traits from the UKB and restricted to unrelated participants of British ancestry (n = 337,522). We estimated GI-TL as a linear combination of nine TL-associated single nucleotide polymorphisms (SNPs), each weighted by its previously-reported association with leukocyte TL. Regression models were used to assess the associations between GI-TL and each trait. We obtained MR estimates using the two-sample inverse variance weighted (IVW) approach. We identified six age-related traits associated with GI-TL (Bonferroni-corrected threshold p < .001): pulse pressure (PP) (p = 5.2 × 10-14), systolic blood pressure (SBP) (p = 2.9 × 10-15), diastolic blood pressure (DBP) (p = 5.5 × 10-6), hypertension (p = 5.5 × 10-11), forced expiratory volume (FEV1) (p = .0001), and forced vital capacity (FVC) (p = 3.8 × 10-6). Under MR assumptions, one standard deviation increase in TL (~1,200 base pairs) increased PP, SBP, and DBP by 1.5, 2.3, and 0.8 mmHg, respectively, while FEV1 and FVC increased by 34.7 and 52.2 mL, respectively. The observed associations appear unlikely to be due to selection bias based on analyses including inverse probability weights and analyses of simulated data. These findings suggest that longer TL increases pulmonary function and blood pressure traits among middle-aged UKB participants.
端粒长度（TL）在大多数人类细胞类型中随时间逐渐缩短，是衰老的潜在生物标志物。然而，TL 与随年龄增长而下降的身体和认知特征之间的因果关系，在中年人群中尚未得到广泛研究。本研究采用孟德尔随机化（MR）方法，利用遗传上增加的 TL（GI-TL），来估计 TL 对英国生物库（UKB）参与者（年龄 40-69 岁）与衰老相关特征的影响。我们从 UKB 中手动整理了 53 种与衰老相关的特征，并将其限制在无亲缘关系的英国血统参与者（n = 337,522）中。我们将 GI-TL 估计为 9 个与 TL 相关的单核苷酸多态性（SNP）的线性组合，每个 SNP 均按其与白细胞 TL 的先前报道的关联进行加权。回归模型用于评估 GI-TL 与每个特征之间的关联。我们使用两样本逆方差加权（IVW）方法获得 MR 估计值。我们确定了与 GI-TL 相关的六个与年龄相关的特征（Bonferroni 校正的阈值 p <.001）：脉搏压（PP）（p = 5.2 × 10-14）、收缩压（SBP）（p = 2.9 × 10-15）、舒张压（DBP）（p = 5.5 × 10-6）、高血压（p = 5.5 × 10-11）、用力呼气量（FEV1）（p =.0001）和用力肺活量（FVC）（p = 3.8 × 10-6）。根据 MR 假设，TL 增加一个标准差（约 1,200 个碱基对），PP、SBP 和 DBP 分别增加 1.5、2.3 和 0.8 mmHg，而 FEV1 和 FVC 分别增加 34.7 和 52.2 mL。基于包括逆概率权重和模拟数据分析的分析，这些观察到的关联不太可能是由于选择偏倚引起的。这些发现表明，在英国生物库的中年参与者中，TL 较长会增加肺功能和血压特征。
