Basal Metabolic Rate and Multiple Sclerosis Risk: New Genetic Evidence from Mendelian Randomization
The article, “Basal metabolic rate and risk of multiple sclerosis: a Mendelian randomization study,” investigates whether basal metabolic rate (BMR) may contribute causally to the susceptibility to multiple sclerosis (MS). MS is a chronic autoimmune and neurodegenerative disease of the central nervous system characterized by inflammatory demyelination, axonal injury, and progressive neurological disability. Although genetic predisposition and environmental exposures such as obesity, vitamin D deficiency, smoking, and physical inactivity have been implicated in MS risk, the biological pathways connecting energy metabolism to immune-mediated demyelination remain incompletely understood. By focusing on BMR, the authors examine whether intrinsic differences in resting energy expenditure may represent an additional biological determinant of MS susceptibility.
Why Basal Metabolic Rate Matters
Basal metabolic rate refers to the amount of energy expended by the body at rest to sustain essential physiological processes, including respiration, cardiac function, ion transport, thermoregulation, and neuronal activity. The authors emphasize that BMR is influenced by age, body size, body composition, endocrine status, and environmental temperature. Because MS prevalence shows geographic and environmental patterns, particularly higher occurrence at greater latitudes, the study proposes that BMR may serve as a biologically meaningful marker connecting metabolism, climate adaptation, inflammatory state, and neurological vulnerability. This approach is particularly relevant because BMR is not merely a nutritional or lifestyle measure; it reflects integrated systemic physiology.
Mendelian Randomization as the Analytical Framework
To assess causality, the authors used Mendelian randomization, an epidemiological method that employs genetic variants as instrumental variables to estimate whether an exposure has a causal effect on an outcome. This design reduces several limitations of conventional observational studies, including confounding, reverse causation, and measurement error. In this study, genetic variants associated with BMR were used to test whether genetically predicted higher BMR increases MS risk. The authors applied a two-sample Mendelian randomization design using large genome-wide association study summary statistics, thereby strengthening the inferential framework beyond simple correlation.
Data Sources and Study Design
The exposure dataset for BMR was derived from a GWAS involving 454,874 participants from the UK Biobank, accessed through the MR-Base platform. The outcome dataset for MS came from the International Multiple Sclerosis Genetics Consortium and included 115,803 individuals of European descent, comprising 47,429 MS cases and 68,374 controls. After genetic instrument selection and quality control, the authors used 378 independent single nucleotide polymorphisms associated with BMR. The study also considered potential confounding by the major histocompatibility complex region, an important genetic locus in MS, and reported no overlap between the selected BMR instruments and previously reported MHC loci.
Principal Findings
The central result was that genetically predicted higher BMR was significantly associated with increased MS susceptibility. Specifically, a one-standard-deviation increase in BMR, equivalent to 1358.32 kJ, was associated with a 28.3% higher risk of MS using the inverse-variance weighted Mendelian randomization method. The reported odds ratio was 1.283, with a 95% confidence interval of 1.108–1.486 and a statistically significant P value of 0.001. Although alternative Mendelian randomization methods, including MR-Egger, weighted median, and weighted mode, did not reach statistical significance, their effect estimates were directionally consistent with the main finding. This consistency supports the interpretation that higher BMR may be linked to increased MS risk, while also indicating that the evidence should be interpreted with appropriate methodological caution.
Biological Interpretation and Mechanistic Hypotheses
The authors propose several plausible biological explanations for the observed relationship between BMR and MS. Myelinated axons require precise energetic support for saltatory conduction, and demyelination increases the energetic cost of neuronal signaling. In MS, chronically demyelinated axons may experience a state resembling “virtual hypoxia,” in which ATP demand exceeds available energy supply. A higher BMR could therefore reflect or contribute to increased metabolic stress, inflammatory activation, or altered neuronal excitability. The article also discusses evidence that metabolic rate and inflammatory status are linked, suggesting that elevated BMR may participate in immune-metabolic pathways relevant to CNS demyelination. However, the authors appropriately note that experimental work is needed to validate these mechanisms at the cellular, biochemical, and biophysical levels.
Limitations and Scientific Significance
The study has important limitations. Its analysis was restricted to individuals of European ancestry, which may limit generalizability to other populations. In addition, although Mendelian randomization strengthens causal inference, it cannot fully establish mechanism, define a clinical BMR threshold, or replace experimental and prospective clinical validation. Nevertheless, the article provides novel evidence that higher genetically predicted BMR may be an independent causal risk factor for MS susceptibility. Its significance lies in broadening the conceptual framework of MS risk from immune genetics and environmental exposure toward systemic energy metabolism. If future studies confirm these findings, BMR-related biology may become relevant for preventive research, risk stratification, and the development of metabolism-informed approaches to MS epidemiology.
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:
Liu, C., Lu, Y., Chen, J., Qiu, W., Zhan, Y., & Liu, Z. (2022). Basal metabolic rate and risk of multiple sclerosis: a Mendelian randomization study. Metabolic Brain Disease, 37(6), 1855-1861.
