Data_Sheet_8_Telomere length and the risk of cardiovascular diseases: A Mendelian randomization study.PDF

BackgroundThe causal direction and magnitude of the associations between telomere length (TL) and cardiovascular diseases (CVDs) remain uncertain due to susceptibility of reverse causation and confounding. This study aimed to investigate the associations between TL and CVDs using Mendelian randomization (MR).
Materials and methodsIn this two-sample MR study, we identified 154 independent TL-associated genetic variants from a genome-wide association study (GWAS) consisting of 472,174 individuals (aged 40–69) in the UK Biobank. Summary level data of CVDs were obtained from different GWASs datasets. Methods of inverse variance weighted (IVW), Mendelian Randomization-Egger (MR-Egger), Mendelian Randomization robust adjusted profile score (MR-RAPS), maximum likelihood estimation, weighted mode, penalized weighted mode methods, and Mendelian randomization pleiotropy residual sum and outlier test (MR-PRESSO) were conducted to investigate the associations between TL and CVDs.
ResultsOur findings indicated that longer TL was significantly associated with decreased risk of coronary atherosclerosis [odds ratio (OR), 0.85; 95% confidence interval (CI), 0.75–0.95; P = 4.36E-03], myocardial infarction (OR, 0.72; 95% CI, 0.63–0.83; P = 2.31E-06), ischemic heart disease (OR, 0.87; 95% CI, 0.78–0.97; P = 1.01E-02), stroke (OR, 0.87; 95% CI, 0.79–0.95; P = 1.60E-03), but an increased risk of hypertension (OR, 1.12; 95% CI, 1.02–1.23; P = 2.00E-02). However, there was no significant association between TL and heart failure (OR, 0.94; 95% CI, 0.87–1.01; P = 1.10E-01), atrial fibrillation (OR, 1.01; 95% CI, 0.93–1.11; P = 7.50E-01), or cardiac death (OR, 0.95; 95% CI, 0.82–1.10; P = 4.80E-01). Both raw and outlier corrected estimates from MR-PRESSO were consistent with those of IVW results. The sensitivity analyses showed no evidence of pleiotropy (MR-Egger intercept, P > 0.05), while Cochran’s Q test and MR-Egger suggested different degrees of heterogeneity.
ConclusionOur MR study suggested that longer telomeres were associated with decreased risk of several CVDs, including coronary atherosclerosis, myocardial infarction, ischemic heart disease, and stroke, as well as an increased risk of hypertension. Future studies are still warranted to validate the results and investigate the mechanisms underlying these associations.

背景 由于反向因果关联与混杂因素的影响，端粒长度（telomere length, TL）与心血管疾病（cardiovascular diseases, CVDs）之间关联的因果方向和强度仍不明确。本研究旨在通过孟德尔随机化（Mendelian randomization, MR）方法探究端粒长度与心血管疾病之间的关联。
材料与方法 本项两样本孟德尔随机化研究中，我们从英国生物库（UK Biobank）包含472174名40~69岁个体的全基因组关联研究（genome-wide association study, GWAS）中，筛选得到154个独立的端粒长度相关遗传变异。心血管疾病的汇总级数据来自不同的全基因组关联研究数据集。本研究采用逆方差加权（inverse variance weighted, IVW）、孟德尔随机化-埃格检验（Mendelian Randomization-Egger, MR-Egger）、孟德尔随机化稳健调整轮廓得分法（Mendelian Randomization robust adjusted profile score, MR-RAPS）、极大似然估计、加权众数法、惩罚加权众数法，以及孟德尔随机化多效性残差和离群值检验（Mendelian randomization pleiotropy residual sum and outlier test, MR-PRESSO）等方法，探究端粒长度与心血管疾病之间的关联。
结果 本研究结果显示，较长的端粒长度与冠状动脉粥样硬化[比值比（odds ratio, OR）=0.85，95%置信区间（confidence interval, CI）：0.75~0.95，P=4.36×10^-3]、心肌梗死（OR=0.72，95%CI：0.63~0.83，P=2.31×10^-6）、缺血性心脏病（OR=0.87，95%CI：0.78~0.97，P=1.01×10^-2）、脑卒中（OR=0.87，95%CI：0.79~0.95，P=1.60×10^-3）的发病风险降低显著相关，但与高血压发病风险升高相关（OR=1.12，95%CI：1.02~1.23，P=2.00×10^-2）。然而，端粒长度与心力衰竭（OR=0.94，95%CI：0.87~1.01，P=1.10×10^-1）、心房颤动（OR=1.01，95%CI：0.93~1.11，P=7.50×10^-1）或心源性死亡（OR=0.95，95%CI：0.82~1.10，P=4.80×10^-1）均无显著关联。孟德尔随机化多效性残差和离群值检验的原始估计与离群值校正后的估计值均与逆方差加权法结果一致。敏感性分析未发现多效性证据（孟德尔随机化-埃格检验截距项P>0.05），但科克伦Q检验与孟德尔随机化-埃格检验提示存在不同程度的异质性。
结论 本项孟德尔随机化研究表明，较长的端粒长度与多种心血管疾病的发病风险降低相关，包括冠状动脉粥样硬化、心肌梗死、缺血性心脏病及脑卒中，同时与高血压发病风险升高相关。未来仍需开展相关研究验证本研究结果，并探究上述关联背后的潜在机制。