Exploring Causal Links Between Lipids, Statin Pathways, and Multiple Sclerosis Risk
Multiple sclerosis (MS) is a complex immune-mediated disease in which both environmental and genetic factors shape susceptibility and clinical course. Statins—widely prescribed inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR)—have attracted interest in MS not only because they lower cholesterol, but also because they exert “pleiotropic” immunomodulatory effects that may operate independently of lipid lowering. In this context, Almramhi and colleagues (2023) used Mendelian randomization (MR) to interrogate whether (i) circulating lipid fractions contribute causally to MS risk and severity and (ii) whether genetically proxied statin mechanisms influence MS via cholesterol-dependent or cholesterol-independent pathways.
Study Design: Two-Sample Mendelian Randomization as a Causal Inference Framework
The investigators implemented a two-sample MR design, leveraging genome-wide association study (GWAS) summary statistics as instrumental variables to infer causality while reducing confounding and reverse causation typical of observational epidemiology. Exposure instruments for lipid traits were obtained from the Global Lipids Genetics Consortium (GLGC; n≈188,577), and gene-expression instruments (cis-eQTLs) were taken from eQTLGen (whole blood; n≈31,684), with replication using GTEx v8. Outcomes were derived from the International Multiple Sclerosis Genetics Consortium (IMSGC), including MS susceptibility (n≈41,505) and an MS severity dataset (n≈7,069). Methodologically, inverse-variance weighted (IVW) MR served as the primary estimator, complemented by MR-Egger and multivariable MR (MVMR) for pleiotropy assessment and adjustment (e.g., accounting for SNPs influencing multiple lipid fractions).
Dissecting Statin Biology: Cholesterol-Dependent vs Cholesterol-Independent Pathways
A central conceptual contribution of the paper is its explicit separation of statin biology into two mechanistic arms. The cholesterol-dependent arm was operationalized using genetically predicted LDL-C and cis-eQTLs for 25 genes in the cholesterol biosynthesis pathway (including HMGCR). The cholesterol-independent arm focused on Rho small guanosine triphosphatases (Rho GTPases), reflecting statins’ ability to alter isoprenoid availability and thereby affect prenylation and signaling of small G-proteins. The schematic on page 3 (Figure 1) visually summarizes this biology: HMGCR inhibition reduces cholesterol synthesis and also reduces isoprenoid intermediates, thereby perturbing Rho GTPase prenylation, membrane localization, and activation cycles (including GDI/GEF/GAP-regulated switching). This mechanistic framing is important because earlier MR studies largely proxied statin exposure solely through HMGCR variants, potentially missing non-cholesterol pathways.
Main Finding on Statin Mechanisms: RAC2 as a Protective Modifier of MS Risk
The most salient result concerns the cholesterol-independent pathway. Across MR analyses of Rho GTPase family gene-expression instruments, RAC2 emerged as the only robust signal associated with MS susceptibility: increased genetically predicted RAC2 expression in blood was linked to reduced MS risk (reported as an odds ratio ~0.86 per standard deviation increase, with results supported by sensitivity analyses and replication). By contrast, LDL-C itself and the cholesterol biosynthesis genes—including the statin target HMGCR—showed no evidence of causal association with MS risk. The flow diagram on page 5 (Figure 2) concisely depicts this pattern: “no association” markers dominate the cholesterol-dependent branch, while a “causal association” indicator appears for RAC2 within the cholesterol-independent branch. Conceptually, these findings suggest that if statins modify MS risk, they may do so through immunoregulatory signaling linked to RAC2 rather than through cholesterol reduction per se.
Plasma Lipids and MS: HDL-C Increases Risk, While LDL-C and Triglycerides Do Not
In parallel, the authors evaluated whether major lipid fractions are etiologic contributors to MS. MR results indicated that lifelong genetically elevated HDL-C is associated with increased MS risk (OR ~1.14 in the primary analysis), while triglycerides (TG) showed no causal effect. LDL-C likewise showed no causal relationship with MS susceptibility. Importantly, the investigators assessed heterogeneity and pleiotropy: while heterogeneity was observed for the HDL-C instruments, the MR-Egger intercept did not support directional horizontal pleiotropy, and MVMR adjusting for LDL-C and TG remained consistent with a causal HDL-C signal. The forest plots on page 9 (Figure 5A) summarize these lipid–risk estimates and visually emphasize the directionality: HDL-C shifts risk upward, whereas TG does not. This pattern is scientifically provocative because HDL-C is often interpreted as “protective” in cardiovascular contexts; the MS finding underscores that lipid fractions can have disease-specific immunometabolic consequences.
Severity vs Susceptibility: No Genetic Evidence for Lipids or Statin Pathways in MS Progression
A notable negative result is that neither genetically proxied statin mechanisms (cholesterol-dependent or Rho GTPase–mediated) nor lipid fractions (HDL-C, TG, LDL-C) showed evidence of causal association with MS severity in this analysis. The MR estimates for severity clustered around the null across both pathways, as displayed in page 8 (Figure 4) and page 9 (Figure 5B). The authors discuss plausible explanations, including limitations of available severity GWAS data (cross-sectional nature, heterogeneity of severity measures, and potentially limited stability as a proxy for long-term outcomes). The implication is clinically relevant: genetic architecture influencing risk of developing MS may differ from that influencing disease course once MS is established, and therapeutic targets for prevention may not translate to targets for progression.
Reverse Causation and Interpretation: What This Does—and Does Not—Imply for Statin Use
Finally, the authors explicitly tested reverse causation for MS susceptibility on lipid levels and found no evidence that genetic liability to MS alters HDL-C, LDL-C, or TG (see page 9, Figure 5C), strengthening directional inference that HDL-C influences MS risk rather than the reverse. Nevertheless, the translational interpretation requires precision. MR provides evidence consistent with causal effects of genetically proxied exposures but does not establish the exact molecular mechanisms, dose–response relationships, or clinical efficacy of pharmacologic interventions in established disease. The RAC2 finding supports the hypothesis that statins might reduce MS risk via cholesterol-independent pathways tied to immune regulation, yet the authors appropriately caution that RAC2’s protective association may be independent of statin biology and that mechanistic validation is needed. In sum, this study refines the biological narrative: cholesterol lowering is unlikely to mediate MS protection, whereas RAC2-linked immunomodulatory pathways and HDL-C–associated risk merit deeper functional and clinical investigation.
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.
