Overview of data sources.

BackgroundNumerous observational studies have reported an association between frailty and atherosclerosis. However, the causal relationship between frailty and the occurrence of atherosclerosis in different anatomical sites remains unclear. we conducted a bidirectional Mendelian randomization (MR) study to evaluate the causal relationship between the frailty index (FI), and both systemic atherosclerosis and lipids.MethodsWe obtained summary statistics from large-scale genome-wide association studies (GWAS) of various phenotypes, including frailty (n = 175,226), coronary atherosclerosis (n = 56,685), cerebral atherosclerosis (n = 150,765), peripheral arterial disease (PAD) (n = 361,194), atherosclerosis at other sites (n = 17,832), LDL-C (n = 201,678), HDL-C (n = 77,409), and triglycerides (n = 78,700). The primary MR analysis employed the inverse variance weighted (IVW) method. Furthermore, to assess reverse causality, we employed inverse MR and multivariate MR analysis.ResultsGenetically predicted FI showed positive associations with the risk of coronary atherosclerosis (OR = 1.47, 95% CI 1.12–1.93) and cerebral atherosclerosis (OR = 1.99, 95% CI 1.05–3.78), with no significant association (p >0.05) applied to peripheral arterial disease and atherosclerosis at other sites. Genetically predicted FI was positively associated with the risk of triglycerides (OR = 1.31, 95% CI 1.08–1.59), negatively associated with the risk of LDL-C (OR = 0.87, 95% CI 0.78–0.97), and showed no significant association with the risk of HDL-C (p >0.05). Furthermore, both reverse MR and multivariate MR analyses demonstrated a correlation between systemic atherosclerosis, lipids, and increased FI.ConclusionOur study elucidated that genetically predicted FI is associated with the risk of coronary atherosclerosis and cerebral atherosclerosis by the MR analysis method, and they have a bidirectional causal relationship. Moreover, genetically predicted FI was causally associated with triglyceride and LDL-C levels. Further understanding of this association is crucial for optimizing medical practice and care models specifically tailored to frail populations.背景 既往多项观察性研究均已报道衰弱与动脉粥样硬化之间存在关联，但衰弱与不同解剖部位动脉粥样硬化发生之间的因果关系仍未明确。为此，本研究开展双向孟德尔随机化（Mendelian randomization, MR）研究，以评估衰弱指数（frailty index, FI）与系统性动脉粥样硬化及血脂之间的因果关联。 方法 本研究从涵盖多种表型的大规模全基因组关联研究（genome-wide association studies, GWAS）中获取汇总统计数据，涉及的表型包括衰弱（样本量n=175226）、冠状动脉粥样硬化（n=56685）、脑动脉粥样硬化（n=150765）、外周动脉疾病（peripheral arterial disease, PAD，n=361194）、其他部位动脉粥样硬化（n=17832）、低密度脂蛋白胆固醇（low-density lipoprotein cholesterol, LDL-C，n=201678）、高密度脂蛋白胆固醇（high-density lipoprotein cholesterol, HDL-C，n=77409）及甘油三酯（n=78700）。本研究的主要孟德尔随机化分析采用逆方差加权（inverse variance weighted, IVW）法；此外，为评估反向因果关系，我们还开展了反向孟德尔随机化及多变量孟德尔随机化分析。 结果 遗传预测的FI与冠状动脉粥样硬化（OR=1.47，95%CI：1.12~1.93）及脑动脉粥样硬化（OR=1.99，95%CI：1.05~3.78）的发病风险呈显著正相关，而与外周动脉疾病及其他部位动脉粥样硬化无统计学关联（P>0.05）。遗传预测的FI与甘油三酯升高风险呈正相关（OR=1.31，95%CI：1.08~1.59），与低密度脂蛋白胆固醇升高风险呈负相关（OR=0.87，95%CI：0.78~0.97），与高密度脂蛋白胆固醇风险无显著关联（P>0.05）。此外，反向孟德尔随机化及多变量孟德尔随机化分析均证实，系统性动脉粥样硬化、血脂异常与FI升高存在相关性。 结论 本研究通过孟德尔随机化分析明确，遗传预测的FI与冠状动脉粥样硬化及脑动脉粥样硬化发病风险相关，且二者存在双向因果关系；同时，遗传预测的FI与甘油三酯及低密度脂蛋白胆固醇水平存在因果关联。进一步阐明此类关联的内在机制，对于优化针对衰弱人群的医疗实践与个性化照护模式具有重要的临床意义。