Using summary-level data for MS and BMR levels from large European populations, our study demonstrated that a genetic increase in BMR by 1 SD (a unit SD = 1358.36 KJ) was associated with a 28.3% increase in risk of MS, providing strong evidence in support of a causal role of BMR in MS susceptibility.
The success of the MR approach in MS has been demonstrated in several relevant studies; increased BMI and low serum vitamin D point to a causal association with increased MS susceptibility.(Jacobs, Noyce, Giovannoni, Dobson 2020; Mokry, Ross, Timpson, Sawcer, Davey Smith, Richards 2016) (Mokry, Ross, Ahmad, Forgetta, Smith, Goltzman, Leong et al. 2015) These epidemiological studies provide more substantial evidence than intervention studies, and account for a range of neurological diseases with significant lifestyle determinants. However, the risk factors identified in these studies only partially explain the epidemiological findings like latitude and ancestry. Epidemiological data suggest that the global distribution of MS generally increases with distance from the equator.(Walton, King, Rechtman, Kaye, Leray, Marrie, Robertson et al. 2020) In addition, although the disease is common in areas inhabited by Northern Europeans, this effect is modified according to where people live in their early lives. Migration studies show that childhood migration from low-risk areas to high-risk areas is associated with a lower risk of developing MS, and vice versa.(Dean, Kurtzke 1971) The risk factors currently identified by MR are not sufficient to systematically explain these phenomena; exposure risks may be greater than initially thought, or the better indicators that encapsulate exposure risks have not yet been identified.
BMR represents the energy expenditure necessary to maintain basic physiological functions, including the activity of the heart, respiration, conduction of nerve impulses, ion transport across membranes, and metabolic activity. Age, body size, and environmental temperature are the main factors affecting BMR.(Johnstone, Murison, Duncan, Rance, Speakman 2005),(Blakemore, Burnett, Dahl 2010) The origins of endothermy in mammals are important events in vertebrate evolution, and BMR is the most reported estimate of energy expenditure in endotherms. According to the second law of thermodynamics, the core temperature drops when the body is exposed to low temperatures, and the BMR rises in mammals to maintain the core temperature.(Jeffery, Rovelli 2020) Over the course of the evolution of mammals, climate influences have generated changes in body structure.(Avaria-Llautureo, Hernandez, Rodriguez-Serrano, Venditti 2019; Norin, Metcalfe 2019) Even after controlling for body size and composition, inhabitants living in warmer climates tend to have lower BMR values than those living in colder climates,(Froehle 2008) which is consistent with the world map representing MS incidence.(Walton, King, Rechtman, Kaye, Leray, Marrie, Robertson et al. 2020) It has been proven that BMR is positively associated with proinflammatory status among both normal weight and overweight people, suggesting that it is a marker of metabolic health, independent of obesity.(Drabsch, Holzapfel, Stecher, Petzold, Skurk, Hauner 2018) We imagine that BMR is better suited as a predictor of MS incidence.
Myelin comprises a membrane wrapped spirally around an axon, forming a sheath. This membrane is synthesized by oligodendrocytes in the CNS and interrupted at intervals by the nodes of Ranvier. Voltage-dependent sodium channels are clustered at the nodes of Ranvier, and the action potential jumps from one node to the next. This mode of saltatory conduction allows for the rapid transmission of the action potential along the axon. Accumulating evidence indicates that the increased energy demand for impulse conduction along excitable demyelinated axons and reduced axonal ATP production induces a chronic state of virtual hypoxia in chronically demyelinated axons.(Trapp, Stys 2009) The demyelinating state is associated with the inactivation of voltage-dependent potassium channels in oligodendrocytes.(Lubetzki, Zalc, Williams, Stadelmann, Stankoff 2020) It has been proven that myelination can be inhibited by blocking the action potential of neighboring axons or enhanced by increasing their electrical activity, clearly linking neuronal electrical activity to myelinogenesis.(Demerens, Stankoff, Logak, Anglade, Allinquant, Couraud, Zalc et al. 1996) Furthermore, the in vitro model has proven that a low glycolytic metabolic rate promotes oligodendrocyte survival; distinct energy utilization properties of human adult brain-derived oligodendrocytes and oligodendrocyte progenitor cells under conditions of metabolic stress can model the initial relapsing and subsequent progressive phases of MS.(Rone, Cui, Fang, Wang, Zhang, Khan, Bedard et al. 2016) In this MR study, we provide novel evidence that a high BMR is an independent causal risk factor in the demyelination of CNS; we believe that when the BMR increases beyond the compensable range, it might induce abnormal axonal electrical activity and thereby damage the myelin sheath. The specific mechanism needs to be further confirmed by scientific biophysical and biochemical experiments.
The principal determinant of BMR includes body mass and a variety of behavioral and ecological factors.(Johnstone, Murison, Duncan, Rance, Speakman 2005; Norin, Metcalfe 2019) Observational and prospective studies have demonstrated that individuals who are obese have an increased risk of MS.(Munger, Bentzen, Laursen, Stenager, Koch-Henriksen, Sorensen, Baker 2013),(Wesnes, Riise, Casetta, Drulovic, Granieri, Holmoy, Kampman et al. 2015) For smoking, our finding is consistent with the meta-analyses that have found an increased risk for MS in smokers versus nonsmokers.(Belbasis, Bellou, Evangelou, Ioannidis, Tzoulaki 2015; Degelman, Herman 2017) Our study indicates that smoking has a direct effect on BMR, which in turn increases the risk of MS, thus accounting for the lifetime effects of genetic variants on smoke. Environmental risk factors such as vitamin D deficiency might be related to reduced exposure to sunlight. Correction of vitamin D insufficiency could be important for the prevention of MS(Ascherio, Munger, White, Kochert, Simon, Polman, Freedman et al. 2014); sun exposure correlated with latitudes, which might also relate to BMR, as mentioned above. It appears that BMR and high-risk factors form part of the same causal biological pathway. The association of the selected genetic variants with these exposures might represent an example of pleiotropy due to shared biological underpinnings and thus does not bias the MR estimates. The identification of BMR as a causal susceptibility factor for MS may have important public health implications; people can change their food intake or activity patterns to counterbalance the risks in BMR elevation.
The advantages of our study include the application of two-sample MR to control for confounding factors, the use of large, novel GWAS datasets to improve power, and the alignment of our findings with previous epidemiologic risk factors and MR studies in MS. Our findings may contribute to the establishment of informed public health guidelines providing preventive measures against the adverse effects of BMR for prevention of MS. However, there are few reports focused on basic vivo experiments that can clarify how BMR mechanisms are correlated with demyelination in the CNS. In the future, basic medical experiments may pay greater attention to these aspects.
This study has some limitations. First, it focused on populations of European ancestry, which may restrict its generalizability. Second, we were unable to quantitatively analyze the factors that affect BMR to determine a precise cutoff due to the limitations of existing data.
In conclusion, there were primarily highlight from our finding that we provided evidence of an association between higher genetically predicted BMR and an increased risk of MS; specific OR values could predict the level of severity. Research on BMR will enable a greater appreciation of the genetic epidemiology of MS and has remarkable implications for preventive measures.