Cigarette smoking and an Epstein–Barr virus infection together represent a significant risk factor for multiple sclerosis (MS), suggesting that at least one path to this disease involves two factors working synergistically, a study reports.
The study, “Smoking and Epstein–Barr virus infection in multiple sclerosis development,” was published in the journal Nature Scientific Reports.
Among the environmental factors associated with a likelihood of MS are smoking and infectious mononucleosis, caused by the Epstein–Barr virus (EBV).
However, previous studies into how smoking might interact with different aspects of EBV infection have reported conflicting results.
A team led by researchers at the Karolinska Institutet used two Swedish population-based case-control studies, involving 6,340 MS patients and 6,219 matched healthy people as controls, to investigate the interplay between smoking and EBV infection on the risk of this disease.
These two studies were the Epidemiological Investigation of Multiple Sclerosis (EIMS) and Genes and Environment in Multiple Sclerosis (GEMS), composed of people ages 16 to 70.
Participants in both studies answered a questionnaire regarding lifestyle factors and environmental exposures, and provided blood samples. Based on self-reported information, they either had a history of infectious mononucleosis or they did not.
Blood tests were to identify the presence of antibodies that target EBV, called EBNA-1 antibodies. Based on their results, patients were classified as having either high or low levels of EBNA-1. The presence of a gene variant associated with MS risk, known as DRB1*15:01, was also determined by genetic analysis.
Information about current and previous smoking was collected, including the duration of smoking and the average number of cigarettes smoked each day.
Smoking habits were only considered before the year of disease onset. Participants who smoked at disease onset were classified as current smokers, while those who had stopped before disease onset were past smokers. Patients who had never smoked before or during the year of disease onset were defined as never smokers.
Analysis revealed that people who had smoked at any time (ever smokers) were 1.4 times more likely to develop MS regardless of their EBNA-1 antibody levels.
Compared with never smokers in both the MS and control groups, ever smokers also had significantly higher levels of EBNA-1 antibodies.
An additive interaction was also found between current smokers and high EBNA-1 levels that was not evident in former smokers.
“Interaction on the additive scale between smoking and aspects of EBV infection (EBNA-1 status and IM [infectious mononucleosis] respectively) was assessed by calculating the attributable proportion due to interaction,” the study noted.
These findings suggest that the combined effect of smoking and high EBNA-1 antibody levels from an EBV infection was greater on MS risk than were the individual effects of either smoking or high EBNA-1 levels. This connection remained after adjusting these data for age at EBV assessment or DRB1*15:01 gene status.
A significant additive interaction was also observed between current smoking and a history of infectious mononucleosis. Again, the combined effect on MS risk of both smoking and infection was higher than either of these risk factors alone. These results also remained consistent even when smoking was considered two years before disease onset.
“Our results demonstrate a significant interaction on the additive scale between current smoking and both high EBNA-1 IgG levels and [infectious mononucleosis] history, with regard to MS risk. The interactions remained similar regardless of DRB1*15:01 status,” the researchers wrote.
Based on the results, they suggested that “current smoking increases EBNA-1 antibody levels and acts synergistically with both aspects of EBV infection to increase MS risk, indicating that there is at least one pathway to disease in which both risk factors are involved.”
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