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AIM: We examined the combined effect of having multiple key risk factors and the interactions between the key risk factors of multiple sclerosis (MS). METHODS: We performed an incident case-control study including cases with a first clinical diagnosis of central nervous system demyelination (FCD) and population-based controls. RESULTS: Compared to those without any risk factors, those with one, two, three, and four or five risk factors had increased odds of being an FCD case of 2.12 (95% confidence interval (CI), 1.11-4.03), 4.31 (95% CI, 2.24-8.31), 7.96 (95% CI, 3.84-16.49), and 21.24 (95% CI, 5.48-82.40), respectively. Only HLA-DR15 and history of infectious mononucleosis interacted significantly on the additive scale (Synergy index, 3.78; p = 0.03). The five key risk factors jointly accounted for 63.8% (95% CI, 43.9-91.4) of FCD onset. High anti-EBNA IgG was another important contributor. CONCLUSIONS: A high proportion of FCD onset can be explained by the currently known risk factors, with HLA-DR15, ever smoking and low cumulative sun exposure explaining most. We identified a significant interaction between HLA-DR15 and history of IM in predicting an FCD of CNS demyelination, which together with previous observations suggests that this is a true interaction.

Original publication




Journal article


Mult Scler

Publication Date





461 - 469


First demyelinating event, gene-environment interaction, multiple sclerosis, population attributable fraction, risk factors, Adolescent, Adult, Antibodies, Viral, Australia, Case-Control Studies, Epstein-Barr Virus Nuclear Antigens, Female, Gene-Environment Interaction, HLA-DR Serological Subtypes, Humans, Immunoglobulin G, Incidence, Infectious Mononucleosis, Logistic Models, Male, Middle Aged, Multiple Sclerosis, Multivariate Analysis, Odds Ratio, Polymorphism, Single Nucleotide, Prevalence, Risk Assessment, Risk Factors, Seasons, Smoking, Sunlight, Time Factors, Young Adult