Saturday, 20 January 2018

What is causing the MS pandemic?

Is it not the time to do something about the obesity pandemic? What has obesity got to do with MS? 




The latest data from Canada indicates that the prevalence and incidence of MS continues to increase; this is a trend across the world. Importantly, Canada may have just surpassed Scotland as the highest prevalence region of the world. Why is this happening? Why has MS become a pandemic? Is there anything we can do about this?

MS and other autoimmune diseases were very uncommon 150+ years ago. Our genetics haven't changed and therefore there must be an environmental factor driving the increased incidence. Could it be the macroenvironment (climate, latitude, etc.) or the microenvironment (diet, smoking, exercise, etc.)? Many of the migration and genetic studies, particularly from Canada, would argue against the microenvironment being responsible. However, I am not so sure. 

Well known non-genetic risk factors for developing MS are EBV infection, particularly late infection, low vD levels or sunlight exposure and smoking. More recent factors that have emerged are child obesity and organic solvent exposure. 

I am particularly interested in obesity, which seems to be a real risk factor as it is supported by two Mendelian randomization studies. These show that those who are genetically predisposed to being obese have a  higher risk of getting MS. What is it about obesity that raises your risk of getting MS? Is it because adipose tissue is pro-inflammatory and stimulates autoimmunity secondarily? Could adipose tissue soak up circulating vD as it is a fat-soluble vitamin and lower vD levels? Or could obesity be the smoking gun and represent something in our diets that have triggered the epidemic? These are only a few of the hypotheses floating about amongst academic who think MS is a preventable disease. 

As always these observations are associations and not causal. To prove obesity is in the causal pathway will be a gargantuan task. But linking obesity to an increasing incidence of MS and other autoimmune diseases may help public health officials and politician do something about the obesity pandemic that threatens the planet. 

Multiple sclerosis: Prevalence and impact. The Daily, Wednesday, January 17, 2018.

Estimates from individual provinces suggest that the prevalence of multiple sclerosis (MS) among Canadians may be one of the highest in the world. A new study released today in the publication Health Reports provides information on the impact MS has on people's lives, such as mobility, pain, sleep and cognition. About two-thirds of those diagnosed reported that their lives were affected moderately, quite a bit, or extremely by MS. Although 57% of people with MS could walk without aid, almost one-third (31%) required a wheelchair, a mechanical aid such as a cane or walker, or the help of another person, and 12% could not walk at all. Just over half (53%) were usually pain-free, with the rest reporting pain that prevented a few activities (21%) or some/most activities (25%). Close to two-thirds (62%) experienced difficulty getting a good night's sleep. Half (50%) of people whose only neurological condition was MS had difficulty remembering most things and/or thinking and solving problems. MS can be limiting in other ways. Close to one-third reported that it had prevented them from driving (30%), or compromised their educational opportunities (32%). More than half (58%) experienced at least some limitations in job opportunities. As well, 43% reported that MS had a negative impact on their social interactions, such as feeling left out, embarrassed, or that others felt uncomfortable around them or avoided them. This study also provides the most recent national prevalence estimates of MS. An estimated 93,500 Canadians living in private households and 3,800 in long-term care institutions reported a diagnosis of MS. At 290 cases per 100,000 in the household population, prevalence exceeded that in many other countries and was higher than reported in earlier Canadian studies. Women are two to three times more likely than men to have MS (2.6 women reported MS for every man with the condition). Unlike neurological disorders such as dementia and Parkinson's disease that tend to develop at older ages, MS is more prevalent in younger adults. MS was diagnosed between the ages of 20 and 49 for 82% of those with the disorder.


Mokry et al. Obesity and Multiple Sclerosis: A Mendelian Randomization Study. PLoS Med. 2016 Jun 28;13(6):e1002053.


BACKGROUND: Observational studies have reported an association between obesity, as measured by elevated body mass index (BMI), in early adulthood and risk of multiple sclerosis (MS). However, bias potentially introduced by confounding and reverse causation may have influenced these findings. Therefore, we elected to perform Mendelian randomization (MR) analyses to evaluate whether genetically increased BMI is associated with an increased risk of MS.

METHODS AND FINDINGS: Employing a two-sample MR approach, we used summary statistics from the Genetic Investigation of Anthropometric Traits (GIANT) consortium and the International MS Genetics Consortium (IMSGC), the largest genome-wide association studies for BMI and MS, respectively (GIANT: n = 322,105; IMSGC: n = 14,498 cases and 24,091 controls). Seventy single nucleotide polymorphisms (SNPs) were genome-wide significant (p < 5 x 10-8) for BMI in GIANT (n = 322,105) and were investigated for their association with MS risk in the IMSGC. The effect of each SNP on MS was weighted by its effect on BMI, and estimates were pooled to provide a summary measure for the effect of increased BMI upon risk of MS. Our results suggest that increased BMI influences MS susceptibility, where a 1 standard deviation increase in genetically determined BMI (kg/m2) increased odds of MS by 41% (odds ratio [OR]: 1.41, 95% CI 1.20-1.66, p = 2.7 x 10-5, I2 = 0%, 95% CI 0-29). Sensitivity analyses, including MR-Egger regression, and the weighted median approach provided no evidence of pleiotropic effects. The main study limitations are that, while these sensitivity analyses reduce the possibility that pleiotropy influenced our results, residual pleiotropy is difficult to exclude entirely.

CONCLUSION: Genetically elevated BMI is associated with risk of MS, providing evidence for a causal role for obesity in MS etiology. While obesity has been associated with many late-life outcomes, these findings suggest an important consequence of childhood and/or early adulthood obesity.

Gianfrancesco et al. Causal Effect of Genetic Variants Associated With Body Mass Index on Multiple Sclerosis Susceptibility. Am J Epidemiol. 2017 Feb 1;185(3):162-171.


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. We used separate-sample Mendelianrandomization 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 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). 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.

ProfG    

36 comments:

  1. How do you stop children getting obese? Surely this is a public health and not an MS problem?

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    Replies
    1. You need to remove processed carbohydrates from their diets (sugar, high fructose corn syrup, too much bread and pasta, etc.) and get them to exercise. Yes, it is a public health problem, but that means it is everyones problem.

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  2. Aren't you being reactionary calling the increase in MS a pandemic?

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    1. Maybe, maybe not! The incidence is going up globally and low reisk areas are becoming high-risk areas. We have a problem we need to do something about it.

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  3. Maybe the people that develop MS are susceptible to develop obesity aswell! Maybe as both can be affected or triggered by hormones, the person could have a flaw in that part of things? My partner who has rrms has had meningitus, glandular fever, obesity

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  4. Re: MS and other autoimmune diseases were ver uncommon 150+ years ago.

    How do we know this? Comparing diagnostic criteria from then to now is apples and oranges. Even 100 years ago the practice of medicine was rudimentary at best.

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    1. Fully agree with this point. Life expectancy was not that good to a 100 years ago. Plus MS is not easy to diagnose

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    2. Agree. Plus MS is hard to diagnose and life expectancy has jumped for the last 100 years. These are much more likely causd to the MS pandemic.

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  5. My two friends with MS (one male and one female) are the thinnest people you are likely to meet + neither have ever smoked. Both got glandular fever in mid-teens. Stick to EBV Prof G. Otherwise, you'll need to explain to me why clinically obese, smoking, vit D depleted females who haven't got MS, haven't got it!

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  6. I have always been ideal weight / borderline underweight. Maybe that predisposed me to develop PPMS as opposed to RRMS. Being overweight might not be the cause, but perhaps it has a bearing on MS type/presentation. It might make MS damage/inflammation more visible, and earlier on.

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    1. Many think MS is one disease, not two or three. Perhaps PPMSers had a clinically silent RRMS phase or relapses were not reported/diagnosed during the RRMS phase.

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    2. Yes. So maybe I'd have developed aggressive RRMS if I'd been fat.

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  7. Prof G, you're blog needs more podcasts with fellow Team G scientists to discuss topics like this. It will contemporise your blog, which is getting rusty and is in danger of being forgotten.

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    1. Maybe, but the numbers tell a different story. We have never had more average pageviews per day than we are getting now and that is excluding the the people who follow the blog via email, RSS feeds or other social network feeds.

      Podcasts take time and energy, which we don't have much of.

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  8. What about testosterone levels? Women and men. What if women who have higher testosterone levels fared better than those with lower levels?

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  9. Interesting, I got away without any symptoms of MS for 53 years despite spending much of that time as overweight. In 2011 I developed type 2 diabetes and my GP told me to lose weight. I lost 5.5 stones over the following year and maintained an ideal weight for a year. Then I had an attack of optic neuritis which led to a diagnosis of MS. I had been gaining a little bit of weight over the preceding months. Is it possible that those reactivated adipose cells triggered the attack?

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  10. I love this blog! It is a great source of information. But, I don’t think that obesity can be a cause for MS. I don’t remember meeting obese MS-ers. In my case, I’ve always had a healthy BMI and I have always been physically active, but when I was eighteen I had a bad case of glandular fever, I have Hashimoto’s thyroiditis and, I don’t know why, my calcium levels had been low until I started taking vitamin D. When I developed MS symptoms and, consequently diagnosed with MS I was in an excellent physical shape.

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  11. Thanks...

    I thought that adipose tissue was largely associated with macrophage activation hence diabetes. In the context of the"Pro inflammatory state", are there well characterised pathways between adipose and B/T cells (and then MS) or has this not really been shown?



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    1. Not really shown. How adiposity is linked to MS and other autoimmune diseases is unknown. It may not be causal, but simply an association. Although the Mendelian Randomization studies suggest causastion it can still be an association. This is why we need more research in this area.

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    2. This comment has been removed by the author.

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  12. MS and other autoimmune diseases were very uncommon 150+ years ago

    How do you know that? Do you got data suporting that?

    Obrigado

    Luis

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    1. Yep, there are publications in the historical literature on this. It is not only MS but also type 1 diabetes, athma, etc.

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    2. "MS and autoimmune diseases were very uncommon 150+ years ago"

      What about EBV rates 150+ years ago ?

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    3. EBV rates would I suspect be high, the big problem for EBV is that we are getting infected later in life.
      For many in their teens. Therefore we now have different B cell repertoire.

      But profG can answer this

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    4. " the big problem for EBV is that we are getting infected later in life."

      Yes..there is a too clean/sterile environment theory I believe.

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  13. Pandemic

    A pandemic (from Greek πᾶν pan "all" and δῆμος demos "people") is an epidemic of infectious disease that has spread through human populations across a large region; for instance multiple continents, or even worldwide.

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  14. Rates of MS appear to be increasing; this, however, may be explained simply by better diagnosis.[2] Studies on populational and geographical patterns have been common[39] and have led to a number of theories about the cause.

    https://en.wikipedia.org/wiki/Multiple_sclerosis

    Obrigado

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    1. The Scandinavians (Danes and Swedes) have excluded ascertainment bias (better diagnosis) as a cause for the increasing incidence. Simililarly in Iran the cause is not better diagnosis. They have had access to MRI scanners for the last 25 years.

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    2. I think it's probable that in the age before dmt and internet, doctors who suspected MS may have not told the patient. So only those with severe relapses that couldn't be put down to 'one of those things' or 'sometimes these odd things happen, we'll keep an eye on it'(days before patients demanded answers and everyone trusted their Dr) were diagnosed. For everyone else there would have been a good chance of patient dying before MS worsened significantly. I know of a long retired family Dr who told me he used to do that 'I didn't used to tell them'. Going back even further think of women who died in childbirth, no antibiotics, TB etc etc people died young!

      It's only now we have dmt it's important to diagnose early

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    3. Also the increase appears sex selective

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  15. How about following. People are avoiding the sun due to skin cancer or in asian/ African countries to remain fairer. You may well notice the demographic profile of MS patients also changing. Nahh that sounds too far fetched. Let's stick with
    Obesity.

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    1. The obesity theory is totally consistent with the Bit D theory mate. Overweight people tend to have lower Vit D levels as the fat tissue stores/locks up Vit D.

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  16. Whether part of the cause of MS or not: obesity is pertinent to all of us health wise: avoid it if you can!

    Prof G I see you raised via twitter the question of diet and I recall your commitment to providing us,on this site, advice and guidance on diet. As you're now proposing a potential connection between obesity and MS can I politely request you get on and do the post about diet - beyond eat Med style.
    Thanks.

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  17. I find it hard to believe that there is a strong correlation between BMI and obesity.

    Simply because I have never seen an obese person with MS, and haven't even seen many overweight ones (and I have seen quite a few)

    When MS first hit my family, it was to an extremely thin child

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  18. Adipose tissue is an inflammatory environment for innate and adaptive immune activity. Will liposuction be the next CCSVI?:-)

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  19. Dear Prof,
    Good stuff, why not connect dots and speculate? To me, three things are different today: 1) antibiotics 2) vaccines 3) processed food. MS could be caused by an impaired immune (2) system interacting with bad digestion (1, 3) caused by the change of the microbiome of the society as well as an individual after antibiotic therapy, sugary food could contribute to this. Furthermore, the immune attack on the brain is that subtle that it must be secondary to another immune process. I speculate that the immune attack is mainly directed against the intestinal tissue (second brain). Why not chuck EAE and try FT?

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