Plasma Lipids, Statin Biology, and Multiple Sclerosis: Mendelian Randomization Evidence for Cholesterol-Independent Mechanisms
Statins have long been considered plausible candidates for multiple sclerosis (MS) prevention or modification because they exhibit effects that extend beyond LDL-cholesterol reduction, including immunomodulatory and anti-inflammatory actions. The motivating clinical backdrop includes the phase 2 MS-STAT trial, in which high-dose simvastatin was associated with reduced brain atrophy and slower disability progression in secondary progressive MS, raising the question of whether any benefit is driven by cholesterol lowering or by so-called “pleiotropic” mechanisms. Almramhi and colleagues address this question using human genetics to separate cholesterol-dependent from cholesterol-independent pathways, focusing specifically on Rho-family small GTPases that are mechanistically linked to statin biology.
Conceptual Framework: Two Pathways by Which Statins Could Influence MS
The authors formalize two mechanistic hypotheses: (i) a cholesterol-dependent pathway mediated by HMGCR inhibition, downstream cholesterol biosynthesis genes, and LDL-C reduction; and (ii) a cholesterol-independent pathway mediated by effects on Rho GTPases. The biological logic is summarized in the paper’s schematic (Figure 1, page 3), where HMGCR blockade reduces cholesterol synthesis but also prevents generation of isoprenoid intermediates needed for prenylation of Rho GTPases—thereby altering their membrane localization and activation state. This framing is important because earlier Mendelian randomization (MR) studies that instrumented only the HMGCR region effectively tested the cholesterol-lowering component of statins and could have missed non-lipid immunobiology.
Study Design: Two-Sample Mendelian Randomization as a Causal Inference Strategy
This is a two-sample MR study integrating large, independent summary-statistic datasets: lipid GWAS from the Global Lipids Genetics Consortium (GLGC), whole-blood cis-eQTL instruments from eQTLGen (with replication using GTEx), and MS outcomes from the International Multiple Sclerosis Genetics Consortium (IMSGC) for both MS risk and MS severity. The analytic plan (Figure 2, page 5) includes: (a) genetic proxies for statin-like perturbation via expression instruments near cholesterol biosynthesis genes and Rho GTPase genes; (b) conventional lipid instruments for LDL-C, HDL-C, and triglycerides (TG); and (c) reverse-causation testing from MS risk liability to lipid traits. Primary causal estimates rely on inverse-variance weighted MR, with sensitivity analyses including MR-Egger and multivariable MR (to address correlation among lipid fractions).
Main Finding on Statin Biology: RAC2 Emerges as a Cholesterol-Independent Protective Signal
Across the statin-mimicking analyses, the central positive result is not in the cholesterol axis but within the Rho GTPase family: genetically predicted higher blood expression of RAC2 is associated with a lower odds of MS risk (reported as an odds ratio of approximately 0.86 per standard deviation increase in genetically predicted expression, with statistical support in IVW and consistency in MR-Egger). The forest plot (Figure 3, page 6) visually distinguishes this signal from null effects across the cholesterol biosynthesis genes and LDL-C instruments, and the authors further note that the RAC2 association survives multiple testing at the borderline threshold and replicates in an independent whole-blood cis-eQTL dataset (Table 2, page 7). Interpreted biologically, this result is consistent with the proposition that statins could reduce MS risk through pathways linked to Rho GTPase regulation rather than through cholesterol lowering per se.
Lipid Fractions and MS Risk: A Causal Signal for HDL-C, Not for LDL-C or Triglycerides
When MS risk is treated as the outcome and lipid fractions as exposures, the study reports a notable and potentially counterintuitive result: lifelong higher HDL-C is associated with increased MS risk, while TG shows no evidence of a causal relationship, and LDL-C similarly shows no causal association with MS risk in the primary and sensitivity analyses. This pattern is summarized in the lipid-to-MS forest plot (Figure 5A, page 9) and supported by the instrument characteristics in Table 1 (page 7), which indicate strong genetic instruments (mean F-statistics well above conventional weak-instrument thresholds). The authors also emphasize that the HDL-C finding replicates using independent HDL-C summary statistics (Table 2, page 7), strengthening the interpretation that the HDL-C–MS association is not an artifact of a single dataset.
MS Severity: No Genetic Evidence That Lipids or Statin-Mimicked Pathways Modify Severity Metrics
A key negative result is that neither lipid fractions nor genetically mimicked statin-related pathways show evidence of causal effects on MS severity in this analysis. This includes null effects for LDL-C instruments and for expression instruments across cholesterol biosynthesis genes and Rho GTPase family members (Figure 4, page 8; Figure 5B, page 9). The authors interpret this cautiously, noting that severity GWAS resources are smaller and more methodologically challenging than risk GWAS, and that severity measures—often cross-sectional—may not fully capture the long-term dynamics of progression. As such, the absence of evidence should not be overread as definitive evidence of no effect, especially given clinical heterogeneity and measurement limitations in disability phenotyping.
Implications, Limitations, and Next Steps: From Genetic Signals to Mechanistic and Clinical Translation
The study’s synthesis is that RAC2 may act as a genetic modifier of MS susceptibility, aligning with immunologic roles of RAC2 in blood cell lineages and inflammatory response regulation, and potentially connecting to statin pleiotropy through prenylation-dependent signaling. At the same time, the authors explicitly caution that MR supports a causal relationship but does not establish the precise molecular mechanism, nor does it prove that statin exposure itself will necessarily change RAC2 expression in clinically meaningful ways. Additional limitations include the coarse granularity of total lipid fractions (which subsume heterogeneous particle subtypes), incomplete ability to test alternative non-HMGCR/non–Rho GTPase statin pathways, and constraints of cross-sectional severity GWAS that may not reflect stable long-term progression. Practically, these results prioritize follow-up work: mechanistic studies to map RAC2-regulated immune processes to MS initiation, and carefully designed trials or pharmacogenetic analyses that evaluate whether any statin benefit—if present—is better explained by cholesterol-independent immunobiology than by LDL-C reduction.
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.
