Now you see it, Now you don’t!


Obesity or high BMI and raised cholesterol have all been linked to an increased risk of multiple sclerosis. This is of particular concern in the Western world as obesity is fast becoming the single major determinant of an individuals health quotient.

But, how far should we take this in MS?

In a large study of 14802 MS cases and 26703 control, a group in San Francisco set about looking for a link between MS and obesity. After some sophisticated modelling (see Figure below) what they found was that the odds of developing MS increased slightly but consistently with elevated BMI. The bizarre extra piece of finding, however, was that this was in part driven by low vitamin D levels! In short around 5% (and up to a third) of the association with obesity and MS susceptibility could be explained by low vitamin D.

Figure: Forest plot showing the MR estimates investigating the effect of BMI and its potential mediators on the risk of MS.

This is no magician’s trick, but what we in the scientific land call confounding. I often suspect this when the odds ratio of a particular association is low in the face of such a large sample size. For those of you who haven’t come across odds ratio before, to give you a comparator to mull over, the odds of developing lung cancer in smoker vs. non-smoker is a whopping 40.4 in the US. There is no doubt in this scenario that smoking causes lung cancer.

Confounding is a distortion of the association between an exposure and an outcome that occurs when the study groups differ with respect to other factors that influence the outcome. Unlike selection and information bias, which can be introduced by the investigator or by the subjects, confounding is a type of bias that can be adjusted for in the analysis, provided that the investigators have information on the status of study subjects with respect to potential confounding factors. (from Sph.web)
Figure: Increased BMI may affect the risk of MS through lowering 25OHD levels (indirect pathways in red), or independently from 25OHD (pathway in blue). The indirect effect can be calculated by multiplying α times β, where α is the effect of BMI on 25OHD levels, and β the effect of 25OHD levels on MS adjusted for BMI using multivariable MR. The proportion mediated can be estimated by dividing the indirect effect by the total effect of BMI on MS. MR: Mendelian randomization; BMI: body mass index; 25OHD: 25-hydroxyvitamin D; MS: multiple sclerosis; SNP: single-nucleotide polymorphism.


The relative contributions of obesity, vitamin D, leptin, and adiponectin to multiple sclerosis risk: A Mendelian randomization mediation analysis

Adil Harroud Despoina Manousaki Guillaume Butler-Laporte Ruth E Mitchell George Davey Smith J Brent Richards Sergio E Baranzini

Background: Obesity is associated with increased risk of multiple sclerosis (MS); however, the underlying mechanisms remain unclear.

Objective: To determine the extent to which decreased vitamin D bioavailability and altered levels of adiponectin and leptin mediate the association between obesity and MS.

Methods: We performed Mendelian randomization (MR) analyses to estimate the effects on MS of body mass index (BMI), 25-hydroxyvitamin D (25OHD), adiponectin, and leptin levels in a cohort of 14,802 MS cases and 26,703 controls. We then estimated the proportion of the effect of obesity on MS explained by these potential mediators.

Results: Genetic predisposition to higher BMI was associated with increased MS risk (odds ratio (OR) = 1.33 per standard deviation (SD), 95% confidence interval (CI) = 1.09-1.63), while higher 25OHD levels reduced odds of MS (OR = 0.72 per SD, 95% CI = 0.60-0.87). In contrast, we observed no effect of adiponectin or leptin. In MR mediation analysis, 5.2% of the association between BMI and MS was attributed to obesity lowering 25OHD levels (95% CI = 0.3%-31.0%).

Conclusions: This study found that a minority of the increased risk of MS conferred by obesity is mediated by lowered vitamin D levels, while leptin and adiponectin had no effect. Consequently, vitamin D supplementation would only modestly reverse the effect of obesity on MS.

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Neuro Doc Gnanapavan




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