#ClinicSpeak & #ResearchSpeak: obesity comes up trumps

How do we stop the adolescent obesity crisis? It is important for MS. #ClinicSpeak #ResearchSpeak 

Adolescent obesity is a risk factor for developing MS. Is it Chicken or Egg? Is obesity simply associated with MS due to another factor or does obesity act in the MS causal pathway. An example of an association would be that its actually low vD levels, or lack of outdoor activity and less sun exposure, that is the causal factor. People who have less outdoor activity tend to be more sedentary and hence more likely to be obese. The risk factor here is less outdoor activity and not the associated obesity. Obesity could be causal if some part of adipose tissue biology interacts with the MS causal pathway. An example of this is could be one of pro-inflammatory mediators that adipose tissue produces, and there are many such mediators, may prime the immune system to develop autoimmunity. In other words if there was less adipose  tissue, and as a result less adipose tissue induced systemic inflammation, then the risk of autoimmunity will drop. 

Another way adipose tissue may interfere with the causal pathway is actually via vD metabolism. Adipose tissue may lower systemic vD levels by consuming vD as part of its metabolism. The low vitamin D level, and not the obesity, that is the risk factor here.

One way to answer the association vs. causation question is to do a randomised controlled trial of a dietary, or pharmacological intervention, which reverses or prevents adolescent obesity, and to see if the intervention reduces the risk of developing MS. This type of trial would be very difficult to do and may actually not be feasible. 

Is there a cheaper, cleverer, way to do randomised-controlled trial to prove causation? Yes, there is a clever way using Mendelian randomization and seeing if the genetic variants that are linked to obesity are risk factors for developing MS. The study below done using people from California registered with the Kaiser Permanente HMO and a replication sample from Sweden showed just that. The investigators constructed a weighted genetic risk score using genetic variants previously established to predict obesity. Subjects with higher genetically-induced obesity scores had a higher risk of developing MS. Although the investigators controlled for birth year, sex, education, smoking status, ancestry, and genetic predictors of MS they clearly couldn't control for other important con-founders that are very relevant to this analysis, for example dietary factors, exercise - in particular out-door activity - and vD levels. Despite this this study does suggest that obesity is probably part of the MS causal pathway and that if we want to reduce the incidence of MS in the population we need to tackle the problem of adolescent obesity. Now that is much easier said than done!

Gianfrancesco et al. Causal Effect of Genetic Variants Associated With Body Mass Index on Multiple Sclerosis Susceptibility. Am J Epidemiol. 2017 Jan 9. doi: 10.1093/aje/kww120.

Background: Multiple sclerosis (MS) is an autoimmune disease with both genetic and environmental risk factors. Recent studies indicate that childhood and adolescent obesity double the risk of MS, but this association may reflect unmeasured confounders rather than causal effects of obesity. 

Methods: We used separate-sample Mendelian randomization to estimate the causal effect of body mass index (BMI) on susceptibility to MS. Using data from non-Hispanic white members of the Kaiser Permanente Medical Care Plan of Northern California (KPNC) (2006-2014; 1,104 cases of MS and 10,536 controls) and a replication data set from Sweden (the Epidemiological Investigation of MS (EIMS) and the Genes and Environment in MS (GEMS) studies, 2005-2013; 5,133 MS cases and 4,718 controls), we constructed a weighted genetic risk score using 97 variants previously established to predict BMI. 

Results: Results were adjusted for birth year, sex, education, smoking status, ancestry, and genetic predictors of MS. Estimates in KPNC and Swedish data sets suggested that higher genetically induced BMI predicted greater susceptibility to MS (odds ratio = 1.13, 95% confidence interval: 1.04, 1.22 for the KPNC sample; odds ratio = 1.09, 95% confidence interval: 1.03, 1.15 for the Swedish sample). 

Conclusions: Although the mechanism remains unclear, to our knowledge, these findings support a causal effect of increased BMI on susceptibility to MS for the first time, and they suggest a role for inflammatory pathways that characterize both obesity and the MS disease process.

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