Data_Sheet_6_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：由于反向因果关系与混杂因素的干扰，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及强度仍未明确。本研究旨在利用孟德尔随机化（Mendelian randomization, MR）方法探究TL与心血管疾病的关联。
材料与方法：本研究为两样本孟德尔随机化研究，从英国生物银行（UK Biobank）一项纳入472174名40~69岁个体的全基因组关联研究（genome-wide association study, GWAS）中，筛选出154个与TL独立相关的遗传变异。心血管疾病的汇总级数据来源于多组GWAS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）、最大似然估计、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）等多种方法，探究TL与心血管疾病的关联。
结果：研究结果显示，较长的TL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，却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）。但TL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（MR-PRESSO）的原始估计与离群值校正后的估计结果均与逆方差加权（IVW）结果一致。敏感性分析未发现多效性证据（MR-Egger截距项，P>0.05），但科克伦Q检验与MR-Egger结果提示存在不同程度的异质性。
结论：本孟德尔随机化研究表明，较长的端粒与多种心血管疾病发病风险降低相关，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以验证本研究结果，并探究这些关联背后的潜在机制。