Exploring the Link Between Basal Metabolic Rate and Multiple Sclerosis Risk: A Mendelian Randomization Approach

Multiple sclerosis (MS) is a complex immune-mediated neurodegenerative disease of the central nervous system (CNS), influenced by a combination of genetic and environmental factors. While various lifestyle risks for MS have been identified, such as obesity, vitamin D deficiency, and smoking, the role of basal metabolic rate (BMR) as a contributing factor remains underexplored. This study leverages a Mendelian randomization (MR) framework to investigate whether BMR, a measure of energy expenditure at rest, may have a causal relationship with MS susceptibility​.

Study Approach and Methodology
The researchers conducted a two-sample Mendelian randomization analysis to evaluate the potential causal link between BMR and MS risk. Using genome-wide association study (GWAS) data from the International Multiple Sclerosis Genetics Consortium (IMSGC) involving 115,803 participants of European descent (47,429 MS cases and 68,374 controls), they identified 378 genetic variants strongly associated with BMR. These variants were selected as instrumental variables to determine if genetically predicted higher BMR is associated with a greater risk of developing MS​.

Data and Statistical Analyses
The GWAS data used for the BMR analysis included nearly 10 million single nucleotide polymorphisms (SNPs) from 454,874 participants in the UK Biobank. The instrumental variables were selected based on a significance threshold of p < 5×10−8p < 5×10−8 and a minimum minor allele frequency of 5%. The Mendelian randomization was performed using inverse-variance weighting (IVW) as the primary method, complemented by MR-Egger, weighted median, and weighted mode methods to assess the consistency of the findings​.

Sensitivity analyses further confirmed the robustness of these findings. Using the lasso penalization method to account for heterogeneity and a leave-one-out test to examine the influence of each SNP individually, the researchers ensured that their results were not significantly biased by any single variant​.

Key Findings
The results demonstrated that a genetically predicted higher BMR is significantly associated with an increased risk of MS. Specifically, an increase in BMR by one standard deviation (approximately 1358.32 kJ) correlated with a 28.3% higher risk of developing MS (odds ratio [OR]: 1.283, 95% confidence interval [CI]: 1.108–1.486, p = 0.001). Notably, while the MR-Egger and weighted median methods produced similar trends, only the IVW method yielded statistically significant results, underscoring its robustness in this context​.

Biological Implications
The elevated energy demands associated with higher BMR could increase oxidative stress and inflammation, factors known to exacerbate neurodegenerative processes in MS. BMR reflects essential physiological functions like cardiac activity, nerve impulse conduction, and ion transport, all of which are energy-intensive processes that may contribute to a chronic state of “virtual hypoxia” in demyelinated axons. This hypoxic environment is believed to lead to further nerve damage and impede myelin repair in MS​.

Limitations and Future Directions
While this study establishes BMR as a novel independent risk factor for MS, it is essential to consider its limitations. First, the study focuses solely on participants of European ancestry, potentially limiting its applicability to broader populations. Additionally, the precise mechanisms through which BMR influences MS pathogenesis remain unclear. Future research should aim to validate these findings across diverse populations and explore in vivo models to elucidate the underlying biophysical and biochemical interactions​.

Conclusion
This Mendelian randomization study provides compelling evidence that higher BMR is a causal risk factor for MS. The findings suggest that interventions aimed at managing BMR through lifestyle modifications could potentially play a role in MS prevention strategies. This study emphasizes the importance of energy metabolism in MS pathology and opens new avenues for exploring metabolic interventions as part of MS management​.

Reference:
Liu, C., Lu, Y., Chen, J. et al. Basal metabolic rate and risk of multiple sclerosis: a Mendelian randomization study. Metab Brain Dis 37, 1855–1861 (2022).