Gene-environment interactions in MSThursday, October 03, 2013, 17:30 - 17:42
Interaction between adolescent obesity and HLA risk genes in the development of multiple sclerosisA.K. Hedström, I. Bomfim, L.F. Barcellos, M.A. Gianfracesco , C. Schaefer, I. Kockum, T. Olsson, L. Alfredsson (Stockholm, SE; Berkeley, US)
Background. Adolescent obesity, but not obesity in adults, is associated with increased risk of developing multiple sclerosis (MS). We investigated potential interactions between HLA genotype and body mass index (BMI) status, in relation to the risk of developing MS.
Methods. We used two case-control studies, one with incident cases (1510 cases, 2017 controls) and one with prevalent cases (937 cases, 609 controls). Subjects with different genotypes and BMI were compared with regard to incidence of MS, by calculating odds ratios with 95% confidence intervals employing logistic regression. Potential interactions between genotypes and BMI was evaluated by calculating the attributable proportion due to interaction.
Results. In both cohorts, a significant interaction was observed between HLA DRB1*15 and obesity, regardless of HLA-A*02 status. Similarly, there was a significant interaction between absence of HLA-A*02 and obesity, regardless of HLA-DRB1*15 status. In the incident cohort, obese subjects with the most susceptible genotype (carriage of HLA-DRB1*15 and absence of HLA-A*02) had an OR of 16•2 (95% CI 7•5-35•2) compared to non-obese subjects without the genetic risk factors. The corresponding OR in the prevalent study was 13•8 (95% CI 4•1-46•8).
Conclusions. We observe striking interactions between BMI status and HLA genotype with regard to MS risk. Hypothetically, a low-grade inflammatory response inherent to obesity synergizes with the adaptive, HLA-molecule-restricted arm of the immune system, causing MS. Prevention of adolescent obesity may thus lower the risk of developing MS, predominantly among people with a genetic susceptibility to MS.
Dr. Hedström, Dr. Bomfim, Dr. Barcellos, Ms. Gianfrancesca, Dr. Schaefer, and Dr. Kockum report no disclosures. Dr. Olsson served on scientific advisory boards for Merck-Serono, Biogen Idec, and SanofiAventis; served as Co-editor of Current Opinion in Immunology; received speaker honoraria from Novartis and Biogen; and receives research support from Bayer Schering, Sanofi-Aventis, Biogen Idec, the Swedish Research Council, EU fp6, EURATools, the Söderberg Foundation, Bibbi and Nils Jensens Foundation, the Montel Williams Foundation, and the Swedish Brain Foundation. Dr. Alfredsson receives research support from the Swedish Medical Research Council and Swedish Council for Working life and Social Research. The study was supported by grants from the Swedish Medical Research Council; the Swedish Council for Working Life and Social Research, Bibbi and Niels Jensens foundation, Knut and Alice Wallenberg foundation, the Söderberg foundation, the AFA foundation, the Swedish Brain foundation, the Swedish Association for Persons with Neurological Disabilities, the NIH/NINDS R01 NS049510, R01 NS0495103; NIH/NIAID R01 AI076544.