Telomere length and aging-related outcomes in humans: A Mendelian randomization study in 261,000 older participants
Telomere length and aging-related outcomes in humans: A Mendelian randomization study in 261,000 older participants
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DOI：
10.1111/acel.13017
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发表时间：
2019-08-24
期刊：
影响因子：
7.8
通讯作者：
Melzer, David
中科院分区：
文献类型：
--
作者：
Kuo, Chia-Ling;Pilling, Luke C.;Melzer, David
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个自然的实验，比观察性研究更容易混淆和逆转因果关系。我们在一个大型的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的健康结果之间的关联。数据来自n = 379，758名40-70岁的英国生物银行参与者，平均随访7.5年（n = 261，837名60岁及以上的参与者随访结束）。使用孟德尔随机化方法和Egger图分析了与外周白色血细胞中较长端粒长度强相关的13种变体，以评估多效性。TERC、TERT、NAF 1、OBFC 1和RTEL 1的变异体被包括在内，估计值为端粒长度每增加250个碱基对，大约相当于一般白色人群十年的平均变化。我们强调了错误发现率调整后p值小于0.05的相关性。基因决定的较长端粒长度与冠心病风险降低（CHD; OR = 0.95，95%CI：0.92-0.98）相关，但与癌症风险升高（OR = 1.11，95%CI：1.06-1.16）相关。几乎没有证据表明与父母的寿命、父母的百岁状态、认知功能、握力、肌肉减少症或福尔斯有关。60岁及以上的参与者的结果在年轻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CHD风险降低相关，但其他与年龄相关的健康结果变化不大。端粒延长可能对晚年的健康状况没有什么好处，并面临着越来越多的癌症风险。
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.