Kuo Chia-Ling, Pilling Luke C, Kuchel George A, Ferrucci Luigi, Melzer David
Department of Community Medicine and Health Care, Connecticut Convergence Institute for Translation in Regenerative Engineering, Institute for Systems Genomics, University of Connecticut Health, Farmington, CT, USA.
Epidemiology and Public Health Group, University of Exeter Medical School, RILD Level 3, Royal Devon & Exeter Hospital, Exeter, UK.
Aging Cell. 2019 Dec;18(6):e13017. doi: 10.1111/acel.13017. Epub 2019 Aug 24.
Inherited genetic variation influencing leukocyte telomere length provides a natural experiment for testing associations with health outcomes, more robust to confounding and reverse causation than observational studies. We tested associations between genetically determined telomere length and aging-related health outcomes in a large European ancestry older cohort. Data were from n = 379,758 UK Biobank participants aged 40-70, followed up for mean of 7.5 years (n = 261,837 participants aged 60 and older by end of follow-up). Thirteen variants strongly associated with longer telomere length in peripheral white blood cells were analyzed using Mendelian randomization methods with Egger plots to assess pleiotropy. Variants in TERC, TERT, NAF1, OBFC1, and RTEL1 were included, and estimates were per 250 base pairs increase in telomere length, approximately equivalent to the average change over a decade in the general white population. We highlighted associations with false discovery rate-adjusted p-values smaller than .05. Genetically determined longer telomere length was associated with lowered risk of coronary heart disease (CHD; OR = 0.95, 95% CI: 0.92-0.98) but raised risk of cancer (OR = 1.11, 95% CI: 1.06-1.16). Little evidence for associations were found with parental lifespan, centenarian status of parents, cognitive function, grip strength, sarcopenia, or falls. The results for those aged 60 and older were similar in younger or all participants. Genetically determined telomere length was associated with increased risk of cancer and reduced risk of CHD but little change in other age-related health outcomes. Telomere lengthening may offer little gain in later-life health status and face increasing cancer risks.
影响白细胞端粒长度的遗传变异为测试与健康结果的关联提供了一项自然实验，相较于观察性研究，它对混杂因素和反向因果关系的影响更具稳健性。我们在一个大型欧洲血统老年队列中测试了基因决定的端粒长度与衰老相关健康结果之间的关联。数据来自379,758名年龄在40至70岁之间的英国生物银行参与者，平均随访7.5年（随访结束时，261,837名参与者年龄在60岁及以上）。使用孟德尔随机化方法和Egger图分析了与外周血白细胞中端粒长度较长密切相关的13种变异，以评估基因多效性。纳入了TERC、TERT、NAF1、OBFC1和RTEL1中的变异，估计值为端粒长度每增加250个碱基对，这大约相当于一般白人人群十年间的平均变化。我们重点关注了错误发现率调整后p值小于0.05的关联。基因决定的较长端粒长度与冠心病（CHD）风险降低相关（OR = 0.95，95% CI：0.92 - 0.98），但与癌症风险升高相关（OR = 1.11，95% CI：1.06 - 1.16）。未发现与父母寿命、父母的百岁老人身份、认知功能、握力、肌肉减少症或跌倒之间存在关联的证据。60岁及以上人群的结果在年轻参与者或所有参与者中相似。基因决定的端粒长度与癌症风险增加和冠心病风险降低相关，但在其他与年龄相关的健康结果方面变化不大。端粒延长可能对晚年健康状况益处不大，且面临癌症风险增加的问题。
