Interactions between genetic, lifestyle/environmental risk factors for multiple sclerosis

Tomas Olsson Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

There is solid evidence for variants of genes and lifestyle/environmental factors influencing the risk for multiple sclerosis (MS), each of which has low or modest impact on the disease. Association to an increasing number of lifestyle/environmental factors has been demonstrated recently. The epidemiological and genetic fields have mostly operated separately, despite the fact that gene-environment interactions may be important. Detailed knowledge on these may allow more precise therapy and prevention. We combine studies of genetics and environmental factors in nation-wide studies of MS case control materials. Around 200 gene variants have been associated to MS risk. HLA class II and I gene variants coding for molecules presenting antigens to T cells, display the strongest associations. Non-HLA gene variants each provide ORs in the range 1.1-1.3. Despite the small influence of each variant, they denote the starting point for functional analysis, which in turn may provide targets for therapy. Nearly all risk gene variants relate to aspects of the innate and adaptive immunity; a strong argument for MS being a primary inflammatory disease.  Studies of lifestyle/environmental factors have demonstrated associations to smoking (OR~1.6), exposure to organic solvents (OR~1.5), use of oral tobacco (OR~0.5), lack of sun exposure/vitamin D (OR~1.5), Epstein Barr virus (EBV) infection (OR~2, high EBNA1 fragment serology: (OR~4), obesity (OR~2 at age 20), night shift work (OR~1.7), and head concussion (OR~1.3). Most of these factors act during adolescence. Many of these interact with the strongest MS risk genes: HLA-class II (HLA DRB1*15:01) and HLA class I (A2 status). Smoking interacted with carriage of HLA-DRB1*15 and absence of HLA-A*02. The risk of developing MS was substantially increased among smokers with both genetic risk factors (OR 13) compared to non-smokers with neither of these factors, similar to organic solvent exposure. Similar interactions prevailed with measures of EBV infection, obesity and exposure to organic solvents. Hypothetically, inflammatory irritation in the lung in context with MS risk genes may trigger MS. The low grade systemic inflammation in obesity may lower the threshold for activation of CNS autoreactive immunocompetent cells. The data will have implications both for prevention, but also for the search for more precise therapy in MS.

Disclosures: Tomas Olsson has received unrestricted MS research grants and compensation for advisory boards and/or lectures from Biogen, Genzyme, Novartis, AstraZeneca and Allmiral. Research funding has been obtained from the Swedish Research Council, the AFA foundation, Knut and Alice Wallenberg foundation, the Swedish Brain Foundation