Genetically determined change in weight tied to increased risk of multiple sclerosis
Individuals with genetically increased body mass indexes were at a greater risk for developing multiple sclerosis (MS), according to analyses performed on two genome-wide association datasets.
For every one standard deviation increase in genetically determined body mass index (BMI), there was a 41% increase in odds of being diagnosed with MS (OR 1.41, 95% CI 1.20-1.66, P=2.7 x 10-5), reported graduate student Lauren Mokry of McGill University in Montreal, and colleagues.
They used statistics from both the Genetic Investigation of Anthropometric Traits (GIANT) and the International MS Genetics Consortium (IMSGC) to carry out various Mendelian Randomization (MR) analyses, they explained in PLOS Medicine.
However, genetic factors contributing to the development of MS did not play a role in determining BMI, based on a bidirectional MR analysis, the authors said.
“These results provide evidence supporting a causal role for elevated BMI in MS etiology,” Mokry’s group stated, adding that the results provide “further rationale for individuals at risk for MS to maintain a healthy BMI.” But they cautioned that they could not “conclude whether BMI influences MS progression.”
They identified seventy single nucleotide polymorphisms (SNPs) that all had genome-wide significant in relation to BMI in the GIANT study. The SNPs were validated by ruling out linkage disequilibrium, pleiotropy (production of multiple, unrelated effects by a single gene), and population stratification.
The researchers tested for an association between these SNPs and risk of MS in using the IMSGC data. Then, the impact of individual SNPs on risk of MS were weighted by their individual impact on BMI, so that the resulting estimates could be pooled in order to determine the effect that increased BMI had on risk of MS.
Based on the results of the GIANT consortium, the mean standard deviation for BMI across cohorts was 4.70, which is the approximate difference between what the World Health Organization considers to be an overweight BMI (> 25) and an obese BMI (> 30). In the current study, a single standard deviation was associated with a 41% increased likelihood of developing MS, the authors wrote, leading them to conclude that a change in BMI status from overweight to obese could make an individual more susceptible to MS.
The group pointed out that most of the known consequences of increased BMI do not manifest themselves until individuals reach their 40s or 50s, but onset of MS commonly occurs between ages 28 and 31.
They noted that “our findings may demonstrate a more immediate consequence of elevated BMI. This provides further rationale to combat increasing youth obesity rates by implementing community and school-based interventions that promote physical activity and nutrition.”
The authors outlined some of the potential ways that weight status may relate to MS, such as vitamin D levels, which decrease as BMI increases. Low vitamin D levels are one of the risk factors for MS, they noted.
Another possibility is that obesity’s proinflammatory effect might somehow relate to autoimmunity, thereby linking the two conditions. Finally, there’s obesity’s impact on “metabolite, lipoprotein, and hormone profiles,” as certain adipose-derived hormones that are influenced by weight status were previously associated with MS.
Obesity’s ability to alter the levels of these hormones sometimes leads to a reduction in T-cells and anti-inflammatory cytokines, they explained.
Study limitations included the inability to fully eliminate the influence of pleiotropy, and the inability to determine if there was overlap between GIANT and IMSGC participants.
Mokry’s group pointed out that results from the National Health and Nutrition Examination Survey (NHANES) suggested that nearly 20% of U.S. youth and more than a third of adults are considered to be obese.
“The identification of elevated BMI as a susceptibility factor for MS places a high proportion of the population at a relatively higher risk for MS. Mean population BMI has increased in many Western countries over the past several decades, which coincides with rising MS incidence rates,” they said.
Future research should use cohort studies and additional MR analyses in order to better understand the connection between obesity and MS, the authors stated.
The study was supported by the Canadian Institute of Health Research, Fonds de la recherche en sante du Quebec (FRSQ), Merck, the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, and Cambridge NIHR Biomedical Research Centre.
Mokry disclosed no relevant relationships with industry. One co-author disclosed a relevant relationship with Merck.
