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.
Prof G or Alison why don't you include a obesity in your Digesting Science course. I know its obvious, but all it is important for my children to know about these other risk factors. Thanks.
I was sporty as a child, but they were indoor sports mainly – gymnastics then swimming and waterpolo. I had very bad hay fever, so I didn't see the point in spending much time outside, unless there was a specific reason. I wonder if this meant I didn't get enough vitamin d.
Here in the US we should have a sky rocketing increase in MS incidence. Obesity is a national epidemic.
I'm an MD in the field of genetic epidemiology, mainly focusing on cardiovascular endpoints. (On a side-note, I have MS, thankfully well controlled by Gilenya). I just wish to commend Dr. Giovanni for this clear summary of the MS/BMI-study, and of the Mendelian randomization-method in general. In my experience, it's rare that scientists outside of the Mendelian randomization field truly appreciate the method.
Prof G any other Mendelian randomization studies done in MS in relation to other risk factors, in particular vD, EBV and smoking?
What would be really interesting to know is does the mother's BMI during pregnancy affect the child's risk of MS even if the child does not have a high BMI.
Maybe it's really Vitamin D, its "floating" rate in the body the "link" among several other risk factors. I can speak for myself, which is not science: I have always been athletic, been playing sports since I was 5 years old, and even after my illness I continue to exercise and maintain normal BMI. Now I have always used a lot of sunscreen, and I have always preferred to exercise indoors, because I'm very white, the rates of melanomas in Brazil are very high. And when I had my first relapse my vit D rate was below normal, well below. And I know several people with MS with similar history, always had physical activity, normal BMI, balanced nutrition, now little or no exposure to sunlight, always with a lot of sunscreen.
Best way to take tumeric is to heat in a glass of full fat milk, first frying turmeric in cooking oil, since It's not water soluble. Before I was diagnosed with MS, I suspected I had ms, and started taking tumeric milk, world most powerfull antioxidant made from krill oil, 10000 iu units of vitamin d, lipoic acid. 6 months before I was diagnosed and put on tecfidera, my fatigue went away, my fastest walking speed went up from 4.5 km/hr to 6 km / hr. Given all ms patients are being monitored yearly, and blood tests every 3 months. Instead of speculating on the benefits of turmeric, given tumeric costs nothing why can't Bart recommend their patients to take the supplement. If there's any efficacy surely it will show up on MRI and disability profession within a year? and put the argument to bed once and for all?