Gene Variants Linked to High Childhood BMI Point to Higher MS Risk, Study Finds

Genetic variations that increase body mass index (BMI) in childhood are associated with a higher risk of multiple sclerosis (MS) regardless of a person’s vitamin D levels, a study found.

The study, “BMI and low vitamin D are causal factors for multiple sclerosis,” was published in the journal Neurology Neuroimmunology & Neuroinflammation.

An individual’s risk of developing MS is influenced by both genetics and environmental factors. Among the known environmental factors are low levels of vitamin D, exposure to the Epstein-Barr virus, obesity, and smoking.

Researchers used Mendelian randomization (MR) to evaluate the effects of adult BMI, childhood BMI, and vitamin D on MS risk. MR is a type of analysis used to explore possible associations between genetic variants and certain physical traits to identify causal relationships between these traits and particular outcomes.

The term gene variant describes any change — benign, disease-causing, or not-yet-known — in the DNA sequences that compose a gene. Often, a variant is a mutation. 

MR involves constructing a genetic risk score for a given trait — such as BMI — based on information from all genetic variations associated with that trait. The score, rather than the trait itself, is then used to determine causal associations between traits and a particular outcome of interest, such as MS risk.

“Previous MR studies have shown causal relationships between low vitamin D, adult body mass index (BMI), and MS risk, with conflicting results for childhood BMI,” the researchers wrote.

To reassess the causality between these two traits associated with MS risk, researchers at the Wolfson Institute of Preventive Medicine in the U.K. constructed MR models based on genetic scores of BMI and vitamin D levels.

The study included data from more than 800,000 people of European ancestry obtained from different genetic datasets.

Genetic scores associated with a high BMI in childhoodwere linked to a higher risk for MS (increase of 24% by each genetically determined unit), the researchers found. Genetic scores linked to a high adult BMI were also associated with a higher MS risk (increase of 14%).

There were 16 genetic variants in the adult BMI score that were also found to be associated with childhood BMI. When these variants were removed from the analysis, the adult BMI genetic score was no longer linked to a greater MS risk.

When information from these 16 genetic variants was used to create a separate genetic risk score, the new score was associated with an even higher risk of MS.

In contrast, genetic scores associated with higher levels of 25(OH)D3, a metabolite of vitamin D, were linked to a lower MS risk (reduction of 43% by each genetically determined unit). Adjusting for vitamin D scores generally did not affect BMI scores, or vice versa, though a small but significant effect of vitamin D scores on adult BMI was noted.

While there were no significant associations between genetic risk scores for MS itself and for BMI, there was a very small, but statistically significant, decrease in 25(OH)D3 associated with the MS genetic risk score, “implying that MS may reduce vitamin D levels,” the researchers said.

“We showed that genetically determined increased childhood BMI is a causal risk factor for MS, independent of vitamin D,” the researchers said, adding that the data also strengthen the “evidence for the causal role of vitamin D in the pathogenesis [or, origin and development] of MS.”

Although the effects detected in the study are small relative to the MS population, interventions aimed at those with high BMI or low vitamin D levels might be helpful for people at high risk for the disease because of other factors, the researchers said.

“[I]t is likely that addressing these risk factors in early life among high-risk individuals (e.g., those with strong family history and therefore have a higher baseline incidence) will have a more pronounced effect,” they wrote.