Department of Geriatrics, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Key Laboratory of Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases of Zhejiang Province, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
BMC Geriatr. 2024 May 18;24(1):438. doi: 10.1186/s12877-024-05039-5.
Appendicular lean mass (ALM) is a good predictive biomarker for sarcopenia. And previous studies have reported the association between ALM and stroke or Alzheimer's disease (AD), however, the causal relationship is still unclear, The purpose of this study was to evaluate whether genetically predicted ALM is causally associated with the risk of stroke and AD by performing Mendelian randomization (MR) analyses.
A two-sample MR study was designed. Genetic variants associated with the ALM were obtained from a large genome-wide association study (GWAS) and utilized as instrumental variables (IVs). Summary-level data for stroke and AD were generated from the corresponding GWASs. We used random-effect inverse-variance weighted (IVW) as the main method for estimating causal effects, complemented by several sensitivity analyses, including the weighted median, MR-Egger, and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods. Multivariable analysis was further conducted to adjust for confounding factors, including body mass index (BMI), type 2 diabetes mellitus (T2DM), low density lipoprotein-C (LDL-C), and atrial fibrillation (AF).
The present MR study indicated significant inverse associations of genetically predicted ALM with any ischemic stroke ([AIS], odds ratio [OR], 0.93; 95% confidence interval [CI], 0.89-0.97; P = 0.002) and AD (OR, 090; 95% CI 0.85-0.96; P = 0.001). Regarding the subtypes of AIS, genetically predicted ALM was related to the risk of large artery stroke ([LAS], OR, 0.86; 95% CI 0.77-0.95; P = 0.005) and small vessel stroke ([SVS], OR, 0.80; 95% CI 0.73-0.89; P < 0.001). Regarding multivariable MR analysis, ALM retained the stable effect on AIS when adjusting for BMI, LDL-C, and AF, while a suggestive association was observed after adjusting for T2DM. And the estimated effect of ALM on LAS was significant after adjustment for BMI and AF, while a suggestive association was found after adjusting for T2DM and LDL-C. Besides, the estimated effects of ALM were still significant on SVS and AD after adjustment for BMI, T2DM, LDL-C, and AF.
The two-sample MR analysis indicated that genetically predicted ALM was negatively related to AIS and AD. And the subgroup analysis of AIS revealed a negative causal effect of genetically predicted ALM on LAS or SVS. Future studies are required to further investigate the underlying mechanisms.
附肢瘦体重（ALM）是肌少症的良好预测生物标志物。先前的研究报告了 ALM 与中风或阿尔茨海默病（AD）之间的关联，然而，因果关系仍不清楚。本研究旨在通过进行孟德尔随机化（MR）分析来评估遗传预测的 ALM 是否与中风和 AD 的风险存在因果关系。
设计了两样本 MR 研究。从大型全基因组关联研究（GWAS）中获得与 ALM 相关的遗传变异，并将其用作工具变量（IVs）。中风和 AD 的汇总水平数据来自相应的 GWAS。我们使用随机效应逆方差加权（IVW）作为估计因果效应的主要方法，并辅以几种敏感性分析，包括加权中位数、MR-Egger 和 MR-偏倚残差和异常值（MR-PRESSO）方法。进一步进行多变量分析以调整混杂因素，包括体重指数（BMI）、2 型糖尿病（T2DM）、低密度脂蛋白-C（LDL-C）和心房颤动（AF）。
本 MR 研究表明，遗传预测的 ALM 与任何缺血性中风（[AIS]，比值比[OR]，0.93；95%置信区间[CI]，0.89-0.97；P=0.002）和 AD（OR，0.90；95%CI 0.85-0.96；P=0.001）呈显著负相关。关于 AIS 的亚型，遗传预测的 ALM 与大动脉中风（[LAS]，OR，0.86；95%CI 0.77-0.95；P=0.005）和小血管中风（[SVS]，OR，0.80；95%CI 0.73-0.89；P<0.001）的风险相关。在多变量 MR 分析中，当调整 BMI、LDL-C 和 AF 时，ALM 对 AIS 的影响仍然稳定，而在调整 T2DM 后则观察到提示性关联。并且，在调整 BMI 和 AF 后，ALM 对 LAS 的估计效应具有显著性，而在调整 T2DM 和 LDL-C 后则发现提示性关联。此外，在调整 BMI、T2DM、LDL-C 和 AF 后，遗传预测的 ALM 对 SVS 和 AD 的估计效果仍然显著。
两样本 MR 分析表明，遗传预测的 ALM 与 AIS 和 AD 呈负相关。AIS 的亚组分析显示，遗传预测的 ALM 对 LAS 或 SVS 具有负向因果关系。需要进一步的研究来探讨潜在的机制。
