Exploring the Role of Plasma Lipids and Statin Interventions on Multiple Sclerosis Risk and Severity: A Mendelian Randomization Study

Abstract

Background and objectives: There has been considerable interest in statins because of their pleiotropic effects beyond their lipid-lowering properties. Many of these pleiotropic effects are predominantly ascribed to Rho small guanosine triphosphatases (Rho GTPases) proteins. We aimed to genetically investigate the role of lipids and statin interventions on multiple sclerosis (MS) risk and severity.

Method: We used two-sample Mendelian randomization (MR) to investigate (1) the causal role of genetically mimic both cholesterol-dependent (through low-density lipoprotein cholesterol (LDL-C) and cholesterol biosynthesis pathway) and cholesterol-independent (through Rho GTPases) effects of statins on MS risk and MS severity, (2) the causal link between lipids (high-density lipoprotein cholesterol [HDL-C] and triglycerides [TG]) levels and MS risk and severity, and (3) the reverse causation between lipid fractions and MS risk. We used summary statistics from the Global Lipids Genetics Consortium (GLGC), eQTLGen Consortium, and the International MS Genetics Consortium (IMSGC) for lipids, expression quantitative trait loci, and MS, respectively (GLGC: n = 188,577; eQTLGen: n = 31,684; IMSGC (MS risk): n = 41,505; IMSGC (MS severity): n = 7,069).

Results: The results of MR using the inverse-variance weighted method show that genetically predicted RAC2, a member of cholesterol-independent pathway (OR 0.86 [95% CI 0.78-0.95], p-value 3.80E-03), is implicated causally in reducing MS risk. We found no evidence for the causal role of LDL-C and the member of cholesterol biosynthesis pathway on MS risk. The MR results also show that lifelong higher HDL-C (OR 1.14 [95% CI 1.04-1.26], p-value 7.94E-03) increases MS risk but TG was not. Furthermore, we found no evidence for the causal role of lipids and genetically mimicked statins on MS severity. There is no evidence of reverse causation between MS risk and lipids.

Discussion: Evidence from this study suggests that RAC2 is a genetic modifier of MS risk. Because RAC2 has been reported to mediate some of the pleiotropic effects of statins, we suggest that statins may reduce MS risk through a cholesterol-independent pathway (that is, RAC2-related mechanism(s)). MR analyses also support a causal effect of HDL-C on MS risk.

Figure 1. Statin Effects on Cholesterol and Rho GTPases

HMGCR inhibition by statins leads to (1) reduction in the synthesis of cholesterol (2) and prevention of the synthesis of isoprenoids (such as Farnesyl-PP and Geranylgeranyl-PP). Isoprenoids are essential molecules for the prenylation and functioning of the Rho GTPase family.^, After isoprenylation, the Rho proteins localize to a target cell membrane (I) and are activated by GEFs that facilitate the exchange of GDP for GTP^, (II). This enables them to pass on signals to corresponding downstream effectors and regulate numerous cellular functions.^, Finally, the Rho proteins interact with GAPs that hydrolyze GTP to GDP, thereby inactivating the Rho proteins^, (III). When the Rho proteins are inactivated (GDP-bound form), GDIs extract them from the membrane and sequester the proteins in the GDP-bound form into the cytosol^, (IV). Thus, preventing the isoprenylation of Rho GTPases by statins lead to (2a) the inhibition of Rho protein translocation to the plasma membrane and prevents the activation of their downstream effectors (2b) and disruption of GDIs-Rho GTPase binding, which causes an increase in the levels of the cytosolic GTP-bound forms of Rho GTPases.^, GAPs, GTPase-activating proteins; GDIs, guanine nucleotide dissociation inhibitors; GEFs, guanine nucleotide exchange factors; HMGCR, 3-Hydroxy-3-Methylglutaryl-CoA Reductase; Rho GTPases, Rho small guanosine triphosphatases.

Figure 2. Flow Diagram Summarizing This Study's Method and Results

The red cross symbol indicates that there is no causal association, while the green tick symbol indicates that there is a causal association (p-value < 0.05). Abbreviations: GLGC, global lipids genetics consortium; MS, multiple sclerosis; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride; IMSGC, the International Multiple Sclerosis Genetics Consortium; MHC, major histocompatibility complex.

Figure 3. Forest Plot Showing the Associations Between the Genetically Mimicked Statins' Biological Effects Through Cholesterol-Dependent (Through LDL-C and Cholesterol Biosynthesis Pathway) and Cholesterol-Independent (Through Rho GTPases) and MS Risk

Results from the Wald ratio (if the number of SNPs <2) or IVW are shown. Each point represents causal odds ratios of MS risk per one standard deviation increase in LDL-C level or gene expression in blood with a 95% confidence interval error bars. The gray vertical line (null line) indicates no effect. Abbreviations: LDL-C, low-density lipoprotein cholesterol; OR, odds ratio; FDR, false discovery rate; No. of SNPs, the number of genome-wide significant single-nucleotide polymorphisms.

Figure 4. Forest Plot Showing the Associations Between the Genetically Mimicked Statins' Biological Effects Through Cholesterol-Dependent (Through LDL-C and Cholesterol Biosynthesis Pathway) and Cholesterol-Independent (Through Rho GTPases) and MS Severity

Results from the Wald ratio (if the number of SNPs <2) or IVW are shown. Each point represents causal betas of MS severity per one standard deviation increase in LDL level or gene expression in blood with a 95% confidence interval. The gray vertical line (null line) indicates no effect. FDR, false discovery rate; LDL-C, low-density lipoprotein cholesterol; No. of SNPs, the number of genome-wide significant single-nucleotide polymorphisms.

Figure 5. Forest Plots Showing the Causal Link Between Lipids and MS

(A) Forest plot showing the associations between genetically predicted lipid fractions and MS risk that reported as causal odds ratios of MS risk per one standard deviation increase in each lipid fractions. (B) Forest plot showing the associations between genetically predicted lipid fractions and MS severity that reported as causal betas of MS severity per one standard deviation increase in each lipid fractions. (C) Forest plot showing the associations between genetically predicted MS risk and the lipid fractions which presented as causal betas per 1 unit higher log odds of MS risk. The horizontal line represents 95% confidence interval error bars. The gray vertical line (null line) indicates no effect. FDR, false discovery rate; IVW, inverse-variance weighted; MVMR, multivariable Mendelian randomization; No. of SNPs, the number of genome-wide significant single-nucleotide polymorphisms; OR, odds ratio.