Wang Junkui, Hao Yan, Zhu Zhanfang, Liu Bo, Zhang Xuejun, Wei Na, Wang Ting, Lv Ying, Xu Cuixiang, Ma Meijuan, Zhang Yulian, Liu Fuqiang
Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, China.
Shaanxi Provincial Key Laboratory of Infection and Immune Diseases, Shaanxi Provincial People's Hospital, Xi'an, China.
Front Med (Lausanne). 2022 Dec 12;9:1077686. doi: 10.3389/fmed.2022.1077686. eCollection 2022.
Observational studies have shown that calcific aortic valve stenosis (CAVS) is associated with a shorter telomere length (TL). However, the results of observational studies are often influenced by confounding factors and reverse causal associations; it is unclear whether there is a causal relationship between TL and CAVS. This study aimed to investigate the causal relationship between TL and CAVS.
Genome-wide association study (GWAS) data on TL ( = 472,174) and CAVS ( = 311,437) were used to assess the effect of TL on CAVS. All the participants were of European ancestry. Three Mendelian randomization (MR) methods, namely, MR-Egger, weighted median, and inverse variance weighted (IVW), were used to assess the potential causal effect of TL on CAVS. Heterogeneity was assessed using Cochran's statistic. Leave-one-out and MR-Egger regression methods were used for sensitivity and pleiotropy analyses. Forward and reverse MR analyses were performed.
In total, 118 valid and independent TL genetic instrumental variants were extracted from the GWAS dataset. MR analysis showed that TL was negatively associated with CAVS (odds ratios [OR] = 0.727, 95% confidence interval [CI]: 0.565-0.936, and = 0.013 by weighted median; OR = 0.763, 95% CI: 0.634-0.920, and = 0.005 by IVW; OR = 0.757, 95% CI: 0.549-1.044, and = 0.055 by MR-Egger). Sensitivity and pleiotropy analyses showed that the results of this study were relatively stable and that there was no significant pleiotropy. Reverse MR analyses consistently suggested the absence of causal effects of CAVS liability on TL levels.
A causal relationship between the shortening of TL and the development of CAVS in the European population was suggested in this study, and a theoretical basis was provided to investigate the pathogenesis of CAVS.
观察性研究表明，钙化性主动脉瓣狭窄（CAVS）与较短的端粒长度（TL）相关。然而，观察性研究的结果常受混杂因素和反向因果关联的影响；TL与CAVS之间是否存在因果关系尚不清楚。本研究旨在探讨TL与CAVS之间的因果关系。
利用关于TL（n = 472,174）和CAVS（n = 311,437）的全基因组关联研究（GWAS）数据，评估TL对CAVS的影响。所有参与者均为欧洲血统。采用三种孟德尔随机化（MR）方法，即MR-Egger、加权中位数和逆方差加权（IVW），来评估TL对CAVS的潜在因果效应。使用 Cochr an's Q统计量评估异质性。采用留一法和MR-Egger回归方法进行敏感性和多效性分析。进行了正向和反向MR分析。
总共从GWAS数据集中提取了118个有效且独立的TL基因工具变量。MR分析表明，TL与CAVS呈负相关（加权中位数法的优势比[OR] = 0.727，95%置信区间[CI]：0.565 - 0.936，P = 0.013；IVW法的OR = 0.763，95% CI：0.634 - 0.920，P = 0.005；MR-Egger法的OR = 0.757，95% CI：0.549 - 1.044，P = 0.055）。敏感性和多效性分析表明，本研究结果相对稳定，且不存在显著的多效性。反向MR分析一致表明，CAVS易感性对TL水平不存在因果效应。
本研究提示在欧洲人群中TL缩短与CAVS发生之间存在因果关系，为研究CAVS的发病机制提供了理论依据。
