DRB1-environment interactions in multiple sclerosis etiology: results from two Swedish case-control studies.

Abstract

We aimed to investigate the influence of environmental risk factors for multiple sclerosis (MS) in different genetic contexts, and study if interactions between environmental factors and human leucocyte antigen (HLA) genes differ in magnitude according to heterozygocity and homozygocity for <i>HLA-DRB1*15:01</i>. Using population-based case-control studies (6985 cases, 6569 controls), subjects with different genotypes and smoking, EBNA-1 status and adolescent Body Mass status, were compared regarding MS risk, by calculating OR with 95% CI employing logistic regression. The interaction between different genotypes and each environmental factor was evaluated on the additive scale. The effect of each <i>DRB1*15:01</i> allele on MS risk was additive on the log-odds scale for each additional allele. Interaction between <i>DRB1*15:01</i> and each assessed environmental factor was of similar magnitude regardless of the number of <i>DRB1*15:01</i> alleles, although ORs were affected. When any of the environmental factors were present in <i>DRB1*15:01</i> carriers without the protective <i>A*02:01</i> allele, a three-way interaction occurred and rendered high ORs, especially among <i>DRB1*15:01</i> homozygotes (OR 20.0, 95% CI 13.1 to 30.5 among smokers, OR 21.9, 95% CI 15.0 to 31.8 among those with elevated EBNA-1 antibody levels, and OR 44.3, 95% CI 13.5 to 145 among those who reported adolescent overweight/obesity). The strikingly increased MS risk among <i>DRB*15:01</i> homozygotes exposed to any of the environmental factors is a further argument in favour of these factors acting on immune-related mechanisms. The data further reinforce the importance of preventive measures, in particular for those with a genetic susceptibility to MS.