Multiple sclerosis (MS) has a “striking” association with obesity at age 20 that strongly interacts with genetic susceptibility, according to an analysis of data from two case–control studies that examined environmental and genetic risk factors for MS and was published online ahead of print February 5 in Neurology.
This relationship between adolescent obesity and MS is of the same magnitude as the separate associations between MS and carriage of the high-risk HLA-DRB1*15 allele, absence of the protective HLA-A*02 allele, and smoking, according to Anna Karin Hedström, MD, of the Institute of Environmental Medicine, Karolinska Institutet, Stockholm, and colleagues.
“The biologic explanations for these interactions are far from clear, but the data open [the way] for mechanistically oriented studies,” the study authors stated.
Three previous studies have suggested that obesity in early life may be linked to an increased risk of developing MS later. Dr. Hedström and her colleagues examined this association using data from a Swedish population-based, case–control study and from a separate American case–control study.
In the Swedish study, 1,510 adults with incident MS who were treated at 40 clinics across the country during a seven-year period and 2,017 control subjects completed detailed questionnaires concerning environmental exposures and other factors. The controls were matched for age, sex, and area of residence, and all the participants gave blood samples for HLA typing.
The American study involved 937 white adults with prevalent MS who were members of a single large health maintenance organization covering northern California and 609 white control subjects matched for age, sex, and area of residence. All the participants completed computer-assisted telephone interviews regarding environmental exposures and lifestyle factors.
All the subjects in both studies reported what their height and weight had been at age 20, from which the investigators calculated BMI.
In both studies, participants whose BMI at age 20 was 27 kg/m2 or greater showed an increased risk of developing MS later in life, compared with those whose BMI was 18.5 to 21 kg/m2. The odds ratios (ORs) were 2.2 for subjects in the Swedish study and 1.8 for those in the American study, Dr. Hedström and her associates said.
Similarly, participants with a slightly lower but still above-normal BMI of 25 to 27 kg/m2 had a modestly increased risk of developing MS later in life. The ORs were 1.4 in the Swedish study and 1.3 in the American study.
These ORs were unchanged when a sensitivity analysis was performed, including only the study subjects who had been genotyped.
Participants who carried the high-risk HLA-DRB1*15 gene, did not carry the protective HLA-A*02 gene, and had a BMI of 27 kg/m2 or greater at age 20 had an OR of 16.2 for developing later MS, compared with those who had none of those risk factors. In contrast, subjects who had the same HLA profile but had not been obese at age 20 had an OR of 5.1.
The investigators proposed that the low-grade chronic inflammation associated with obesity, together with obesity’s adverse effects on autoimmunity, may increase the risk of HLA-related activation of T cells that attack the CNS.
Both studies were limited in that they were retrospective and relied on participants’ self-reports. In addition, Dr. Hedström and her associates modified the usual definition of obesity for the purposes of their study. The typical standard for obesity is a BMI of greater than 30 kg/m2, not greater than 27 kg/m2. However, the number of subjects at this level of BMI was too small in the Swedish cohort to allow accurate analysis, so the researchers combined the top two categories of BMI into one designation of obese.
—Mary Ann Moon