降脂药物与肌肉疏松症风险的关系:一项药物靶点孟德尔随机化研究和荟萃分析。

IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Human Genomics Pub Date : 2024-07-03 DOI:10.1186/s40246-024-00643-3
Jiaxin Li, Chenyang Zang, Hui Lv, Zheng Xiao, Peihong Li, Bo Xiao, Luo Zhou
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引用次数: 0

摘要

背景:降脂药在老年人中被广泛使用,一些研究表明它与肌肉相关症状有关。然而,其因果关系仍不确定:方法:我们使用孟德尔随机化(MR)方法,评估了通过抑制羟甲基戊二酰-CoA 还原酶(HMGCR)、9 型枯草蛋白酶/kexin 型丙蛋白转换酶(PCSK9)和 Niemann-Pick C1-like 1(NPC1L1)来降低低密度脂蛋白胆固醇(LDL-C)对肌肉疏松症相关特征的因果效应,包括低手握力、阑尾瘦体重和通常步行速度。我们进行了一项荟萃分析,以合并来自不同联盟的因果关系估计值:结果:利用主要来自英国生物库的低密度脂蛋白胆固醇集合数据,HMGCR的基因替代抑制与较高的闌尾瘦体重(β=0.087,P=7.56 × 10-5)和较慢的步行速度(OR=0.918,P=6.06 × 10-9)相关。与此相反,抑制 PCSK9 可减少阑尾瘦体重(β = -0.050,P = 1.40 × 10-3),而抑制 NPC1L1 则对肌肉疏松症相关特征没有因果影响。这些结果通过全球血脂遗传学联合会的低密度脂蛋白胆固醇数据得到了验证,表明抑制 HMGCR 可增加阑尾瘦体重(β = 0.066,P = 2.17 × 10-3)并减慢步行速度(OR = 0.932,P = 1.43 × 10-6),而抑制 PCSK9 可减少阑尾瘦体重(β = -0.048,P = 1.69 × 10-6)。元分析进一步证实了这些因果关系的稳健性:结论:基因替代的 HMGCR 抑制可增加肌肉质量,但会损害肌肉功能;PCSK9 抑制可导致肌肉质量减少;而 NPC1L1 抑制与肌肉疏松症相关特征无关。
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Association of lipid-lowering drugs with risk of sarcopenia: a drug target mendelian randomization study and meta-analysis.

Background: Lipid-lowering drugs are widely used among the elderly, with some studies suggesting links to muscle-related symptoms. However, the causality remains uncertain.

Methods: Using the Mendelian randomization (MR) approach, we assessed the causal effects of genetically proxied reduced low-density lipoprotein cholesterol (LDL-C) through inhibitions of hydroxy-methyl-glutaryl-CoA reductase (HMGCR), proprotein convertase subtilisin/kexin type 9 (PCSK9), and Niemann-Pick C1-like 1 (NPC1L1) on sarcopenia-related traits, including low hand grip strength, appendicular lean mass, and usual walking pace. A meta-analysis was conducted to combine the causal estimates from different consortiums.

Results: Using LDL-C pooled data predominantly from UK Biobank, genetically proxied inhibition of HMGCR was associated with higher appendicular lean mass (beta = 0.087, P = 7.56 × 10- 5) and slower walking pace (OR = 0.918, P = 6.06 × 10- 9). In contrast, inhibition of PCSK9 may reduce appendicular lean mass (beta = -0.050, P = 1.40 × 10- 3), while inhibition of NPC1L1 showed no causal impact on sarcopenia-related traits. These results were validated using LDL-C data from Global Lipids Genetics Consortium, indicating that HMGCR inhibition may increase appendicular lean mass (beta = 0.066, P = 2.17 × 10- 3) and decelerate walking pace (OR = 0.932, P = 1.43 × 10- 6), whereas PCSK9 inhibition could decrease appendicular lean mass (beta = -0.048, P = 1.69 × 10- 6). Meta-analysis further supported the robustness of these causal associations.

Conclusions: Genetically proxied HMGCR inhibition may increase muscle mass but compromise muscle function, PCSK9 inhibition could result in reduced muscle mass, while NPC1L1 inhibition is not associated with sarcopenia-related traits and this class of drugs may serve as viable alternatives to sarcopenia individuals or those at an elevated risk.

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来源期刊
Human Genomics
Human Genomics GENETICS & HEREDITY-
CiteScore
6.00
自引率
2.20%
发文量
55
审稿时长
11 weeks
期刊介绍: Human Genomics is a peer-reviewed, open access, online journal that focuses on the application of genomic analysis in all aspects of human health and disease, as well as genomic analysis of drug efficacy and safety, and comparative genomics. Topics covered by the journal include, but are not limited to: pharmacogenomics, genome-wide association studies, genome-wide sequencing, exome sequencing, next-generation deep-sequencing, functional genomics, epigenomics, translational genomics, expression profiling, proteomics, bioinformatics, animal models, statistical genetics, genetic epidemiology, human population genetics and comparative genomics.
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