The following is a summary of “Exploring the Role of Plasma Lipids and Statins Interventions on Multiple Sclerosis Risk and Severity: A Mendelian Randomization Study,” published in the September 2023 issue of Neurology by Almramhi et al.

Statins have garnered interest for their pleiotropic effects, mainly attributed to Rho small guanosine triphosphatases (Rho GTPases) proteins. Researchers performed a retrospective study investigating the genetic link between lipids, statin interventions, and multiple sclerosis (MS) risk and severity.

They utilized two-sample Mendelian randomization (MR) with data from the Global Lipids Genetics Consortium (GLGC: n = 188,577), eQTLGen Consortium (n = 31,684), and the International MS Genetics Consortium (IMSGC) for lipids, expression quantitative trait loci, and MS (IMSGC MS risk: n = 41,505; IMSGC MS severity: n = 7,069). This enabled the investigation of the causal role of genetically mimicking both cholesterol-dependent (via low-density lipoprotein cholesterol (LDL-C) and cholesterol biosynthesis pathway) and cholesterol-independent (via Rho GTPases) effects of statins on MS risk and severity, the causal link between lipids (high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG)) levels and MS risk and severity, as well as reverse causation between lipid fractions and MS risk.

The results showed that genetically predicted RAC2, a member of the cholesterol-independent pathway, was causally implicated in reducing MS risk (OR 0.86, 95% CI 0.78 to 0.95, P-value 3.80E-03), while no evidence supported the causal role of LDL-C and the cholesterol biosynthesis pathway in MS risk. Lifelong higher HDL-C levels were associated with increased MS risk (OR 1.14, 95% CI 1.04 to 1.26, P-value 7.94E-03), but TG did not—no causal role of lipids or statins on MS severity. There is no reverse causation between MS risk and lipids.

They concluded that RAC2 is a genetic modifier of MS risk, and statins may reduce MS risk via a cholesterol-independent pathway.

Source: n.neurology.org/content/early/2023/09/01/WNL.0000000000207777