From the Department of Clinical and Movement Neurosciences (M.M.A., C.S.S., D.A.K., R.R.C., N.W.W.), University College London Queen Square Institute of Neurology, United Kingdom; Department of Medical Technology (M.M.A.), Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia; Institute of Cardiovascular Science (C.F., A.F.S., S.C., A.D.H.), Faculty of Population Health, and Health Data Research UK London (A.D.H.), University College London; British Heart Foundation University College London Research Accelerator (C.F., A.F.S., S.C., A.D.H.), United Kingdom; and Department of Cardiology (C.F., A.F.S.), Division Heart and Lungs, University Medical Center Utrecht, the Netherlands.
Neurology. 2023 Oct 24;101(17):e1729-e1740. doi: 10.1212/WNL.0000000000207777. Epub 2023 Sep 1.
There has been considerable interest in statins because of their pleiotropic effects beyond their lipid-lowering properties. Many of these pleiotropic effects are predominantly ascribed to Rho small guanosine triphosphatases (Rho GTPases) proteins. We aimed to genetically investigate the role of lipids and statin interventions on multiple sclerosis (MS) risk and severity.
We used two-sample Mendelian randomization (MR) to investigate (1) the causal role of genetically mimic both cholesterol-dependent (through low-density lipoprotein cholesterol (LDL-C) and cholesterol biosynthesis pathway) and cholesterol-independent (through Rho GTPases) effects of statins on MS risk and MS severity, (2) the causal link between lipids (high-density lipoprotein cholesterol [HDL-C] and triglycerides [TG]) levels and MS risk and severity, and (3) the reverse causation between lipid fractions and MS risk. We used summary statistics from the Global Lipids Genetics Consortium (GLGC), eQTLGen Consortium, and the International MS Genetics Consortium (IMSGC) for lipids, expression quantitative trait loci, and MS, respectively (GLGC: n = 188,577; eQTLGen: n = 31,684; IMSGC (MS risk): n = 41,505; IMSGC (MS severity): n = 7,069).
The results of MR using the inverse-variance weighted method show that genetically predicted , a member of cholesterol-independent pathway (OR 0.86 [95% CI 0.78-0.95], -value 3.80E-03), is implicated causally in reducing MS risk. We found no evidence for the causal role of LDL-C and the member of cholesterol biosynthesis pathway on MS risk. The MR results also show that lifelong higher HDL-C (OR 1.14 [95% CI 1.04-1.26], -value 7.94E-03) increases MS risk but TG was not. Furthermore, we found no evidence for the causal role of lipids and genetically mimicked statins on MS severity. There is no evidence of reverse causation between MS risk and lipids.
Evidence from this study suggests that is a genetic modifier of MS risk. Because has been reported to mediate some of the pleiotropic effects of statins, we suggest that statins may reduce MS risk through a cholesterol-independent pathway (that is, RAC2-related mechanism(s)). MR analyses also support a causal effect of HDL-C on MS risk.
由于他汀类药物具有降脂作用以外的多种作用，因此人们对其产生了浓厚的兴趣。这些多效性作用主要归因于 Rho 小分子鸟苷三磷酸酶（Rho GTPases）蛋白。我们旨在从遗传角度研究脂质和他汀类药物干预对多发性硬化症（MS）风险和严重程度的影响。
我们使用两样本孟德尔随机化（MR）来研究（1）通过胆固醇依赖性（通过低密度脂蛋白胆固醇（LDL-C）和胆固醇生物合成途径）和胆固醇非依赖性（通过 Rho GTPases）模拟他汀类药物对 MS 风险和 MS 严重程度的遗传作用，（2）脂质（高密度脂蛋白胆固醇[HDL-C]和甘油三酯[TG]）水平与 MS 风险和严重程度之间的因果关系，以及（3）脂质分数与 MS 风险之间的反向因果关系。我们分别使用来自全球脂质遗传学联盟（GLGC）、eQTLGen 联盟和国际多发性硬化症遗传学联盟（IMSGC）的脂质、表达数量性状基因座和 MS 的汇总统计数据（GLGC：n=188577；eQTLGen：n=31684；IMSGC（MS 风险）：n=41505；IMSGC（MS 严重程度）：n=7069）。
使用逆方差加权法进行 MR 的结果表明，遗传预测的胆固醇非依赖性途径的成员 （OR 0.86 [95% CI 0.78-0.95]，-值 3.80E-03）与降低 MS 风险有关。我们没有发现 LDL-C 和胆固醇生物合成途径成员在 MS 风险中的因果作用的证据。MR 结果还表明，终生较高的 HDL-C（OR 1.14 [95% CI 1.04-1.26]，-值 7.94E-03）会增加 MS 风险，但 TG 则不会。此外，我们没有发现脂质和遗传模拟他汀类药物对 MS 严重程度的因果作用的证据。MS 风险与脂质之间没有证据表明存在反向因果关系。
本研究的证据表明 是 MS 风险的遗传调节剂。由于已报道 可介导他汀类药物的一些多效性作用，因此我们认为他汀类药物可能通过非胆固醇依赖性途径（即 RAC2 相关机制）降低 MS 风险。MR 分析也支持 HDL-C 对 MS 风险的因果作用。
