How Genetics Reveal Immune Pathways Linking Statins, Lipids, and Multiple Sclerosis
Multiple sclerosis (MS) is a complex immune-mediated disease of the central nervous system, and its risk factors remain incompletely understood. Over the past two decades, statins—widely prescribed cholesterol-lowering drugs—have attracted interest in MS research because of their anti-inflammatory and immunomodulatory properties. The article by Almramhi et al. (2023) tackles a central unresolved question: do statins influence MS risk and severity through cholesterol reduction, or through alternative, cholesterol-independent biological pathways? Using Mendelian randomization (MR), a genetic approach designed to infer causality, the authors provide important new insights into this debate.
Mendelian Randomization as a Causal Lens
Traditional observational studies of lipids and MS are vulnerable to confounding and reverse causation—for example, inflammation altering lipid profiles rather than the reverse. Mendelian randomization overcomes these limitations by using genetic variants as proxies for lifelong exposure to traits such as lipid levels or gene expression. In this study, the authors applied a two-sample MR framework using large genome-wide association datasets for plasma lipids, gene expression (eQTLs), MS risk, and MS severity. This design allowed them to disentangle cholesterol-dependent effects of statins from cholesterol-independent pathways, particularly those involving immune signaling molecules.
Testing the Cholesterol Hypothesis: LDL-C Falls Flat
A key finding of the study is the lack of evidence that low-density lipoprotein cholesterol (LDL-C) plays a causal role in MS risk or severity. Genetic proxies for LDL-C, as well as variants in genes involved in cholesterol biosynthesis (including the canonical statin target HMGCR), showed no association with MS outcomes. This strongly suggests that any beneficial effects of statins observed in clinical trials are unlikely to be driven by cholesterol lowering itself. In other words, reducing LDL-C does not appear to reduce the likelihood of developing MS or slow disease progression.
A Cholesterol-Independent Signal: The Role of RAC2
In contrast, the cholesterol-independent analysis yielded a striking result. Among genes encoding Rho family GTPases—key regulators of immune cell migration and activation—genetically increased expression of RAC2 was associated with a significantly reduced risk of MS. This association was robust across sensitivity analyses and replicated in an independent dataset. RAC2 is predominantly expressed in hematopoietic cells and plays a dual role in immune activation and immune tolerance, making it biologically plausible as a modifier of autoimmune disease risk.
Statins, RAC2, and Immune Modulation
The identification of RAC2 provides a potential mechanistic bridge between statins and MS. Statins inhibit the prenylation of Rho GTPases, altering their localization and activity within immune cells. Previous experimental studies have shown that statins can influence Rac signaling, oxidative stress, and inflammatory responses. The MR evidence presented here supports the hypothesis that statins may reduce MS risk through modulation of RAC2-related immune pathways rather than through lipid lowering per se. Importantly, the authors caution that MR cannot prove that statins act directly through RAC2, but it highlights this pathway as a compelling candidate for further investigation.
HDL Cholesterol: An Unexpected Risk Factor
Beyond statins, the study also examined the causal role of major lipid fractions in MS. Surprisingly, lifelong genetically elevated high-density lipoprotein cholesterol (HDL-C) was associated with an increased risk of MS, while triglycerides showed no effect. This finding challenges the conventional view of HDL-C as uniformly protective and underscores the complexity of lipid biology in immune-mediated diseases. The authors suggest that HDL-C may act as a marker for underlying immunometabolic pathways rather than being directly pathogenic.
Implications and Future Directions
Taken together, this study reshapes our understanding of how lipids and statins intersect with MS biology. It argues against a cholesterol-centric view and instead highlights immune signaling pathways—particularly those involving RAC2—as potential modifiers of disease risk. Clinically, these findings suggest that if statins are beneficial in MS, it is likely through pleiotropic, cholesterol-independent mechanisms. Scientifically, the work motivates deeper functional studies of RAC2 and related pathways, as well as a more nuanced exploration of lipid subfractions in neuroinflammation. Ultimately, this genetic evidence brings us closer to targeted, mechanism-based strategies for MS prevention and therapy.
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:
Jacobs, B. M., Schalk, L., Tregaskis-Daniels, E., Scalfari, A., Nandoskar, A., Dunne, A., ... & Dobson, R. (2025). Genetic determinants of Multiple Sclerosis susceptibility in diverse ancestral backgrounds. medRxiv, 2025-01.
