Obesity a Key Driver of Multiple Sclerosis Risk

Adil Harroud, MD

Obesity is a more important driver of multiple sclerosis (MS) risk than early age at puberty, new research shows.

"Earlier age at puberty and increased body weight have both been proposed as possible risk factors for MS based on observational research but it wasn't clear whether these were independent risk factors or whether they somehow interacted with one another," Adil Harroud, MD, of McGill University in Montreal, Quebec, Canada, told Medscape Medical News.

"In this study, people with earlier age at puberty were in fact more likely to develop MS, but once we factor in their body weight the results were no longer significant, meaning that it's really obesity that is the major determinant and that age at puberty alone is not a direct risk factor for MS," said Harroud.

The study was published online March 20 in Neurology.

Modifiable Risk Factor

For the study, researchers used 372 genetic variants strongly associated with age at puberty in a genome-wide association study (GWAS) of 329,245 women.

The genetic architecture of pubertal timing across both sexes is highly correlated, such that these variants provide reliable insights into pubertal timing in males as well, they note in their article.

The researchers used Mendelian randomization to determine whether pubertal timing exerts direct effects on MS susceptibility independently of body mass index (BMI) using a GWAS of 14,802 MS cases and 26,703 controls.

They found a 1-year increase in genetically predicted age at puberty decreased the odds of MS by 8% (odds ratio [OR], 0.92; 95% CI, 0.86 - 0.99; P = .03).

After accounting for effects on adult BMI, the association of age at puberty with MS susceptibility was attenuated and no longer significant (OR, 0.96; 95% CI, 0.88 - 1.04; P = .36). Repeating the multivariate analysis after adjusting for genetic effects of childhood BMI yielded similar results (OR, 0.97; 95% CI, 0.89 - 1.05; P = .40).

"Prior studies have been observational, which we know are susceptible to confounding. This study used Mendelian randomization that limits the risk of confounding and perhaps gets us closer to being able to estimate causal effect," Harroud told Medscape Medical News.

"Our findings do not support a substantial role for the effect of the timing of puberty on the risk of MS independent of BMI," coauthor J. Brent Richards, MD, also of McGill University, added in a news release. "More research is needed to determine whether decreasing rates of obesity could help to reduce the prevalence of MS," said Richards.

"Obesity is something we can modify and this is especially important in MS," Harroud said.

"There are now several medications that can slow down the disease but there isn't a cure so prevention is really important. We know that MS rates are on the rise and one reason may be that our society is becoming more obese.

"This study might provide a sense of urgency for us as a society to help younger individuals control their weight because the consequences of obesity are not just later in life," said Harroud.

"Striking Changes" in MS Demographics

The authors of an accompanying editorial note "striking changes" in the demographic pattern of MS with increasing prevalence and incidence over time, especially in women, strongly indicate an influence of modifiable exposures on the disease.

"The current study attributes the inverse association between pubertal timing and MS essentially to BMI. It does not support a substantial role for effects of pubertal timing independent of weight status," write An Goris, PhD, and Benedicte Dubois, MD, PhD, of KU Leuven and Leuven Brain Institute, Belgium.

"Modifiable exposures lend themselves well to intervention, they add, and Mendelian randomization is 'an elegant genetic tool' to prioritize randomized controlled trials to inform intervention strategies for improving public health.

"Extending the current Mendelian randomization approach to other autoimmune diseases would establish whether the influence of modifiable exposures is shared across these diseases, as is the case for shared genetic risk factors.

"If so, this would highlight the importance at the public health level of prevention strategies aimed at decreasing obesity rates, reducing not only the well-recognized cardiovascular consequences but also rates of autoimmunity affecting a substantial proportion of the population," Goris and Dubois conclude.

The study was supported by the Canadian Institutes of Health Research, Canadian Foundation for Innovation, and Quebec Health Research Fund (FRSQ). Harroud has reported no relevant disclosures. Richards has reported receiving research support from Eli Lilly, MSD, and GlaxoSmithKline. Dubois has reported receiving consulting fees and/or funding from Biogen Idec, Sanofi-Aventis, and Teva. Dubois and Goris have reported receiving travel or consulting fees and/or research funding from Merck, Novartis, and Roche.

Neurology. Published online March 20, 2019. Abstract, Editorial

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