Zhang Ronghuai, Wu Min, Ma Meijuan, Liu Bo, Zhang Xuejun, Wei Na, Wang Ting, Lv Ying, Xu Cuixiang, Wang Junkui, Zhang Yulian, Liu Fuqiang
Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, P. R. China.
Shaanxi Provincial Key Laboratory of Infection and Immune Diseases, Shaanxi Provincial People's Hospital, Xi'an, P. R. China.
Eur J Clin Invest. 2023 Nov;53(11):e14056. doi: 10.1111/eci.14056. Epub 2023 Jul 1.
Evidence of a clear causal relationship between telomere length and aortic aneurysms is limited by the potential for confounding or reverse causation effects. In this study, we used a Mendelian randomisation (MR) approach to investigate this putative causal association.
In total, 118 telomere length-associated single-nucleotide polymorphisms, identified in 472,174 individuals of European ancestry, were used as the instrumental variables. Summary statistics for genome-wide association studies of aortic aneurysms were obtained from the FinnGen consortium. For the primary MR analyses, the inverse-variance weighted random-effects method was used and was supplemented with multivariable MR, weighted median and MR-Egger approaches. The MR-Egger intercept test, Cochran's Q test and 'leave-one-out' sensitivity analysis were performed to evaluate the horizontal pleiotropy, heterogeneity and stability of the genetic variants. Forward and reverse MR analyses were performed.
All forward univariable MR analyses showed that longer telomere lengths decreased aortic aneurysm risks (total aortic aneurysms: OR = 0.80, 95% CI 0.67-0.96, p = .015; thoracic aortic aneurysms: OR = 0.82, 95% CI 0.68-0.98, p = .026; abdominal aortic aneurysms: OR = 0.525, 95% CI 0.398-0.69, p < .001), whereas all reverse MR analyses suggested the absence of aortic aneurysm liability on telomere length. The sensitivity analysis results were robust, and no evidence of horizontal pleiotropy was observed.
Our results support a possible causal association between telomere length and aortic aneurysms, providing new insights into the involvement of telomere biology in this condition and offering a potential avenue for targeted therapeutic interventions.
端粒长度与主动脉瘤之间明确的因果关系证据受到混杂或反向因果效应可能性的限制。在本研究中，我们采用孟德尔随机化（MR）方法来研究这种假定的因果关联。
总共118个在472174名欧洲血统个体中鉴定出的与端粒长度相关的单核苷酸多态性被用作工具变量。主动脉瘤全基因组关联研究的汇总统计数据来自芬兰基因联盟。对于主要的MR分析，使用了逆方差加权随机效应方法，并辅以多变量MR、加权中位数和MR-Egger方法。进行了MR-Egger截距检验、 Cochr an's Q检验和“留一法”敏感性分析，以评估基因变异的水平多效性、异质性和稳定性。进行了正向和反向MR分析。
所有正向单变量MR分析均显示，端粒长度越长，主动脉瘤风险越低（总主动脉瘤：OR = 0.80，95%CI 0.67 - 0.96，p = 0.015；胸主动脉瘤：OR = 0.82，95%CI 0.68 - 0.98，p = 0.026；腹主动脉瘤：OR = 0.525，95%CI 0.398 - 0.69，p < 0.001），而所有反向MR分析表明主动脉瘤对端粒长度无影响。敏感性分析结果稳健，未观察到水平多效性的证据。
我们的结果支持端粒长度与主动脉瘤之间可能存在因果关联，为端粒生物学在这种疾病中的作用提供了新的见解，并为靶向治疗干预提供了潜在途径。
