Unraveling the Impact of Lifestyle, Genetics on MS

A series of presentations at the MSVirtual2020: 8th Joint ACTRIMS-ECTRIMS Meeting, taking place this weekend, focused on the environmental and lifestyle risk factors of multiple sclerosis (MS), including obesity, metabolic syndrome, smoking and genetics, and the role of common viruses.

To the extent that some factors are modifiable, the takeaway for clinicians is to encourage their patients to adopt healthy habits, presenters said. For instance, smoking can hasten progression of the disease and obesity may have a negative impact on the effectiveness of disease-modifying therapy (DMT).

Obesity and metabolic syndrome

Adiposity obesity, particularly when it begins in childhood and late adolescence, was identified as leading to a 2-fold risk of developing MS in one study, according to Ruth Ann Marrie, MD, PhD, FRCPC, director of the Multiple Sclerosis Clinic at the University of Manitoba. Central obesity, or visceral adipose fatty deposits in the abdominal area, is a key component of metabolic syndrome, a cluster of abnormalities that includes hypertension, dyslipidemia, and insulin resistance and is linked to a higher risk of cardiac disease and diabetes.

In the Nurses Health Study, which examined risk factors for chronic disease, women with a body mass index (BMI) of 30 or more had a 2-fold increased risk of subsequently developing MS. And a study using data from the Copenhagen School Health Records Register found that children aged 7 to 13 years with a BMI equivalent to 30 in adults had an increased risk of developing MS later in life.

Obesity is more common even before MS diagnosis, Marrie said. In an effort to look at other aspects of metabolic syndrome, researchers used Canadian claims data of about 20,000 individuals with newly diagnosed MS and found that by the time of diagnosis, more than 15% had hypertension and nearly 10% had dyslipidemia.

There is also evidence that obesity and components of metabolic syndrome are associated with longer diagnostic delays, greater disability at diagnosis, as well as an increased relapse rate and accelerated disability progression. One “key question” she said, is whether treating metabolic syndrome might improve MS outcomes and multiple sclerosis.

In one small, nonrandomized cohort study of 50 individuals with MS, obesity, and metabolic syndrome, they were treated either with metformin or pioglitazone, or they declined treatment.

Before treatment, researchers measured the number of newer enlarging T2 lesions in the 24-month period before intervention as well as gadolinium-enhancing lesions; all 3 groups looked similar.

After treatment with either metformin or pioglitazone, the number of newer T2 lesions as well as gadolinium-enhancing lesions dropped over 24 months. Patients who declined treatment did not see a decrease.

“I think the growing body of evidence suggests that clinical trials are needed to really test whether treating obesity and metabolic syndrome may improve outcomes in MS and to test whether we need to be using different strategies for managing disease-modifying therapy, including dosing in individuals who are obese or extremely obese with multiple sclerosis,” Marrie said.

Smoking and genetics

Another presentation focused on the interactions between modifiable risk factors—namely smoking—and genetics.

“People with a genetic susceptibility to the disease may be at a substantially increased risk of developing MS if you’re exposed to certain environmental factors,“ said Anna Hedström, MD, PhD, from the Karolinska Institute Stockholm, Sweden in the Department of Clinical Neuroscience.

Smoking and the chemicals from tobacco creates a cascade of problems, including systemic inflammation, local inflammation in the lungs, oxidative stress, damaged neural tissue, and epigenetic changes.

Smoking increases the risk of MS by about 50%, she said, with men more affected than women; in addition, there is also a dose response relationship between the accumulated dose of smoking and the risk of developing the disease.

In 2005, the Karolinska Institute began a study called the Epidemiological Investigation of Multiple Sclerosis, which uses the country’s national MS registry. As an ongoing study, it now includes 9000 cases and 12,000 matched controls.

In 2011, Hedström and colleagues published a study that found a significant interaction between 2 genetic risk factors and smoking: HL ADRB1*15, the key genetic risk factor for MS, and HLA A*02, the absence of which carries a reduced risk of MS. The research looked at the interaction of these genes in both smokers and non-smokes.

Smokers with both genes had an odds ratio (OR) of 13.5 (8.1-22.6) for MS, compared with nonsmokers with the same makeup.

Compared with non-smokers with neither of the genetic risk factors, the OR for smokers without genetic risk was 1.4 (0.9-2.1); the OR for non-smokers with both genetic risk factors was 4.9 (3.6-6.6).

Among those with both genetic risk factors, smoking increased the risk by a factor of 2.8 in comparison with a factor of 1.4 among those without the genetic risk factors.

Passive smoking (ie, never smokers exposed to second-hand smoke) also increases MS risk (OR 1.3-1.6) and the risk increases along with the length of exposure, she said.

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Similarly, exposure to organic solvents, she said, also raises the rise of MS in people with the same genetic profile.

MS and Epstein-Barr virus (EBV) infection

No virus has been discovered as a cause of MS, but the hypothesis that a virus may be involved in MS has been around for some time, said Kassandra Munger, ScD, of the Department of Nutrition in the Harvard TH Chan School of Public Health. Current knowledge, she said, points to Epstein-Barr.

“From environmental risk factor perspective, MS is likely a rare complication of Epstein-Barr virus infection, with risk further modified by inadequate vitamin D levels, being overweight or obese in early life and cigarette smoking,” she said.

Early studies attempting to look at the issue through antibody testing could not determine if EBV infection proceeded MS or if it was a complication.

Using blood samples collected by the Department of Defense of US military members, Munger and colleagues found preliminary evidence that EBV infection does happen before MS. They identified 305 MS cases and 610 matched controls. In cases where serum samples were collected before the onset of MS symptoms and measured EBV titers, they found that 38 were EBV negative at the time they went on active duty. During follow up, up until MS onset, 20 of the 38 became EBV positive. Eighteen remained EBV negative and did not develop MS.

This is a preliminary finding that needs to be replicated in a larger study, she said.

References

Hedström AK, Sundqvist E, Bäärnhielm M, et al. Smoking and two human leukocyte antigen genes interact to increase the risk for multiple sclerosis. Brain. 2011;134(3):653-64. doi:10.1093/brain/awq371