背景:降脂药在老年人中广泛使用,一些研究表明与肌肉相关的症状有关。然而,因果关系仍然不确定。
方法:使用孟德尔随机化(MR)方法,我们通过抑制羟甲基戊二酰辅酶A还原酶(HMGCR)评估了遗传代理降低的低密度脂蛋白胆固醇(LDL-C)的因果效应,前蛋白转化酶枯草杆菌蛋白酶/kexin9型(PCSK9),和Niemann-PickC1样1(NPC1L1)在肌肉减少症相关性状上,包括低握力,阑尾瘦体重,通常的步行速度。进行了荟萃分析,以结合来自不同联盟的因果估计。
结果:使用主要来自英国生物银行的LDL-C汇总数据,遗传代理抑制HMGCR与较高的阑尾瘦体重(β=0.087,P=7.56×10-5)和较慢的步行速度(OR=0.918,P=6.06×10-9)有关。相比之下,抑制PCSK9可降低阑尾瘦体重(β=-0.050,P=1.40×10-3),而NPC1L1的抑制对肌肉减少症相关性状没有因果关系。这些结果使用全球血脂遗传学联盟的LDL-C数据进行了验证,表明抑制HMGCR可能会增加四肢瘦体重(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可以降低阑尾瘦体重(β=-0.048,P=1.69×10-6)。荟萃分析进一步支持了这些因果关联的稳健性。
结论:基因代理抑制HMGCR可能会增加肌肉质量,但损害肌肉功能,PCSK9抑制可导致肌肉质量减少,而NPC1L1抑制与肌肉减少症相关性状无关,这类药物可作为肌肉减少症个体或高危人群的可行替代药物.
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.