Previous research indicates that multiple sclerosis (MS) is the most common cause of non-traumatic neurologic disability in young adults. Both genetic and environmental factors contribute to disease susceptibility. The strongest genetic associations with MS are located within the human leukocyte antigen (HLA) complex. The primary risk allele is HLA-DRB1*15:01, whereas the class I allele HLA-A*02:01 has a protective influence on disease risk. Absence of HLA-A*02:01 is thus considered a risk factor for MS.
A synergistic effect between these genetic risk factors and tobacco smoke exposure has led to the theory that different sources of lung irritation may elicit an immune reaction in the lungs and subsequently lead to MS in people with a genetic susceptibility to the disease. My colleagues and I therefore aimed to investigate the influence of exposure to organic solvents on MS risk and a potential interaction between organic solvents and HLA genes. Environmental factors, as opposed to risk genes, are potential targets for prevention and advances in the understanding of their biological effects could also provide insight into the pathogenesis of the disease.
The Investigation
For a report published in Neurology, we completed a Swedish population-based case-control study comprising 2,042 incident cases of MS and 2,947 controls matched by age, gender, and residential area. All participants completed an extensive questionnaire on environmental and lifestyle exposures and provided a blood sample for genetic analyses. Participants with different genotypes, smoking habits, and organic solvent exposure were compared with regard to occurrence of MS, by calculating odds ratios with 95% confidence intervals employing logistic regression models.
Interaction on the additive scale, or departure from additivity of effects, occurs when the combined effect of two factors differs from the sum of the individual effect of each factor, indicating action of the two factors in the same biological pathway. A potential interaction between exposure to organic solvents and MS risk HLA genes was evaluated by calculating attributable proportion (AP) due to interaction. AP is the proportion of disease that is due to the interaction per se among individuals with both exposures. An AP greater than zero indicates the presence of interaction.
Important Findings
Overall, exposure to organic solvents increased the risk of MS by approximately 50% when compared with no exposure. The risk of the disease increased with increasing duration of exposure. An interaction between organic solvents and MS-associated HLA genes was observed with regard to MS risk, similar to findings from previous reports on gene-environment interaction involving the same MS risk HLA genes and smoke exposure.
Among participants with HLA risk factors, there was also a synergistic effect between smoking and organic solvents. Both smoking and organic solvents increased the risk of disease by 50% in the absence of the genetic risk factors, whereas the genetic risk factors were associated with a five-fold increased risk of disease among those unexposed to smoking and organic solvents. However, participants exposed to smoking, organic solvents, and the genetic risk factors had a 30-fold increased risk of developing MS when compared with non-exposed participants without the genetic risk factors. Exposure to different sources of lung irritation thus displays a considerably higher association with MS among people with a genetic susceptibility to the disease. The odds ratios of MS among participants categorized by genetic risk factors, smoking habits, and exposure to organic solvents are illustrated in the Figure.
Beyond the Study
The biological pathway through which smoking and organic solvents act to increase MS risk is not yet characterized. However, cigarette smoke and its oxidative agents initiate the inflammatory response, during which additional reactive substances are produced, causing extensive tissue damage. Smoke-induced lung inflammation induces posttranslational modifications of proteins in the lungs that may be cross-reactive with CNS antigens, promoting a CNS-directed autoimmune response. Different sources of lung irritation may thus induce an immune reaction against modified self-proteins or against potentially auto-aggressive cells resident in the lungs, and promote MS development in people with a genetic susceptibility to the disease. However, further research regarding the impact of lung irritation on MS risk and its interaction with genetics is strongly warranted.
While more than 20% of all MS cases in the Nordic population have been attributable to smoke exposure, the excess proportions may be higher in countries where smoking is more prevalent. Preventive measures in order to reduce smoking are therefore essential. Individuals with a family history of MS should be informed regarding the impact of lung-irritating agents on the risk of MS, as well as the importance of preventing their children from exposure to passive smoke and from becoming smokers.
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