Cholesterol, Statins, and Multiple Sclerosis: What Genetics Suggests Beyond the Lipid Story

Statins are best known for lowering cholesterol, yet neurologists have long been intrigued by something else: their “pleiotropic” effects—immune-modulating and anti-inflammatory actions that may matter in autoimmune disease. Almramhi and colleagues tackled a clean version of this question in multiple sclerosis (MS): if statins help, is it because they lower LDL cholesterol, or because they affect immune signaling pathways that happen to be touched by statins? A Genetics-First Strategy: Mendelian Randomization
Rather than relying on observational associations (which can be distorted by confounding and reverse causality), the authors used two-sample Mendelian randomization (MR). In MR, genetic variants that influence an exposure—here, lipid fractions and gene-expression proxies for statin-related pathways—serve as instruments to estimate causal effects on outcomes. They drew lipid GWAS data from the Global Lipids Genetics Consortium, gene-expression instruments from eQTLGen, and MS risk/severity data from the International MS Genetics Consortium, giving the analysis substantial statistical weight. Cholesterol-Lowering Was Not the Main Story
If statins reduce MS risk mainly by lowering cholesterol, you would expect genetically proxied LDL-C reduction (and variants in cholesterol biosynthesis genes such as HMGCR) to show a protective causal signal for MS risk. They did not. The MR results found no evidence that LDL-C—or genetic proxies for the cholesterol biosynthesis pathway—causally influences MS risk, which argues against a simple “lower LDL, lower MS risk” narrative. A Surprising Protective Signal Points to RAC2
The most striking mechanistic clue emerged from the cholesterol-independent side of statin biology: the Rho GTPase network. The study found that genetically predicted expression of RAC2 (a Rho-family GTPase member tied to immune cell behavior) was causally associated with reduced MS risk (OR ≈ 0.86). This does not prove statins prevent MS, but it does sharpen the hypothesis that any potential benefit could flow through immunologic pathways linked to Rho GTPase biology, rather than through cholesterol reduction per se. HDL-C: “Good Cholesterol,” Not Necessarily Good for MS Risk
In a result that will make many readers pause, the MR analyses suggested that lifelong higher HDL-C increases MS risk (OR ≈ 1.14), while triglycerides showed no causal signal for MS risk. The authors also tested reverse causation and found no evidence that genetic liability to MS risk causes changes in HDL-C, LDL-C, or triglycerides—strengthening the directionality of the HDL-C finding. Practically, this does not mean clinicians should try to lower HDL-C; it means HDL biology may be entangled with immune pathways in ways that differ from cardiovascular disease frameworks. Severity Is a Different Endpoint—and the Door Stays Open
When the authors turned from risk to severity, the signals largely disappeared: genetically proxied lipid fractions and genetically mimicked statin-pathway effects showed no clear causal association with MS severity in their analyses. They are also careful about limitations—MS severity GWASs are often cross-sectional and may not fully capture long-term disability trajectories, and lipid measures are heterogeneous mixtures of subfractions that MR using “total HDL-C/LDL-C/TG” cannot resolve. The most constructive takeaway is forward-looking: the genetics highlight RAC2 and cholesterol-independent immunologic mechanisms as a plausible research lane, while ongoing clinical trials (such as MS-STAT2) remain essential for establishing real-world therapeutic impact. Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.

References:
Almramhi, M. M., Finan, C., Storm, C. S., Schmidt, A. F., Kia, D. A., Coneys, R., ... & Wood, N. W. (2023). Exploring the role of plasma lipids and statin interventions on multiple sclerosis risk and severity: a mendelian randomization study. Neurology, 101(17), e1729-e1740.