The Multifaceted Role of Genes and Metabolism in Multiple Sclerosis Pathogenesis

Multiple sclerosis (MS) is a chronic, debilitating neurodegenerative inflammatory disease of the central nervous system (CNS). While the exact causes of MS remain unknown, researchers believe the condition is triggered by a complex interplay of genetic factors, environmental exposures, and immunological processes. Recent scientific investigations leveraging advanced metabolomics and genetic techniques have begun to map the molecular landscape of MS, revealing critical insights into disease risk, severity, and progression.

Genetic and Environmental Interplay: The Vitamin D – HLA Link
One of the most profound observations in MS epidemiology is its remarkable geographic distribution, which inversely mirrors regional ultraviolet radiation levels. This observation strongly supports the hypothesis that Vitamin D plays a central role in the disease etiology. Research indicates that genetic risk is tied directly to environmental factors, specifically demonstrating a direct biological interaction between the active form of Vitamin D (1,25-dihydroxyvitamin D3) and the main MS susceptibility locus, the HLA-DRB1 allele. Crucially, a Vitamin D Response Element (VDRE) found in the HLA-DRB1 promoter region is highly conserved in the MS-associated DR2 haplotype (HLA-DRB1*15), conferring sensitivity to active Vitamin D. This gene-environment interaction may partially explain the geographical distribution of MS and the higher incidence observed in women.

Metabolome-Wide Insights into MS Risk
The circulating metabolome, positioned at the intersection of the genome and environmental exposures, offers unique insights into MS pathophysiology. A metabolome-wide Mendelian randomization study, employing two-sample Mendelian randomization (MR) analysis across 571 circulating metabolites, prioritized specific compounds likely contributing to MS risk. The study found that genetically instrumented levels of serine, lysine, acetone, and acetoacetate were associated with a higher MS risk. Conversely, total cholesterol and phospholipids in large very-low-density lipoprotein (VLDL) were associated with a lower MS risk. However, paradoxically, risk-increasing associations were observed for these same two lipids when found in very large high-density lipoprotein (HDL).

Folate Metabolism and Homocysteine Dynamics
Metabolic alterations related to folate and one-carbon metabolism are also implicated in MS risk. A study focusing on the Turkish population investigated polymorphisms of key enzymes in folate metabolism (MTHFR, MTRR, MTR) and essential cofactors (Homocysteine (Hcy), Cysteine (Cys), and Vitamin B12 (VitB12)). Results showed that MS patients had statistically significantly lower levels of Hcy and VitB12 and higher levels of Cys compared to healthy controls. The simultaneous decrease in Hcy and increase in Cys suggests that the methionine synthesis pathway is not working adequately, thereby directing Hcy toward Cys formation via the transsulfuration pathway. Furthermore, decreased VitB12 and increased Cys levels were associated with a statistically significant increase in the risk of MS.

Discerning Progressive MS Subtypes Through Lipids
Lipid metabolism plays a significant role in MS pathophysiology, particularly concerning myelin components. Utilizing lipidomics on post-mortem CNS tissues, specifically Normal-Appearing White Matter (NAWM), researchers differentiated between Primary Progressive MS (PPMS) and Secondary Progressive MS (SPMS) based on their distinct lipidomic profiles. The workflow identified 44 lipids as significant markers distinguishing PPMS from SPMS, with phospholipids, sphingolipids, and glycerolipids being the key differentiating classes. Most of these lipids (65.9%) were decreased in SPMS compared to PPMS. Metabolic pathway analysis revealed that the most significantly altered pathways between these progressive forms were glycerophospholipid metabolism, glycosylphosphatidylinositol (GPI)-anchor biosynthesis, and linoleic acid metabolism.

Decoding MS Susceptibility: Mitochondrial-Nuclear Interactions
The complexity of MS genetics has prompted investigations into "missing heritability"—the unexplained portion of genetic risk. A study conducted on Russian patients explored the combined effect of nuclear gene polymorphisms (involved in immune system functioning) and mitochondrial DNA (mtDNA) polymorphisms on MS risk. Researchers successfully identified five protective biallelic combinations (Odds Ratio 0.67–0.75) that affected MS development risk. These combinations included mitochondrial variants (m.4580, m.13368, and m.13708 mtDNA) paired with nuclear variants (CXCR5, TNFRSF1A, and CD86). The interaction between these mitochondrial and nuclear components was determined to be additive rather than epistatic (synergistic).

New Therapeutic Avenues Through Metabolic Targeting
Understanding these metabolic aberrations has begun to reveal new therapeutic targets. For instance, bile acid metabolism is altered in MS, with reduced levels of multiple bile acids observed in both adults and children. Bile acid receptors (like GPBAR1) are present in MS lesions on immune and glial cells, suggesting that reduced bile acid signaling could predispose to greater neuroinflammation. In vitro treatment with the endogenous bile acid tauroursodeoxycholic acid (TUDCA) ameliorated inflammatory polarization in astrocytes and microglia. Similarly, supplementation with the short-chain fatty acid propionate, which is reduced in MS patients, enhanced regulatory T cells and reduced inflammatory disease activity. These findings highlight the potential for interventions like metabolite supplementation to modulate the disease course, ushering in the possibility of precision medicine for MS.

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:
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