Increased body mass index is causally associated with pediatric MS onset: A Mendelian randomization study (P1.375)

Objective: We utilized Mendelian randomization to estimate the causal relationship between increasing body mass index (BMI) and pediatric MS susceptibility using a weighted BMI genetic risk score (BMI GRS). Background: Childhood and adolescent obesity are associated with a two-fold increased risk of pediatric and adult-onset MS. However, the relationship between obesity and MS may be confounded by lifestyle and/or socioeconomic factors that have not been appropriately adjusted for in previous studies. Methods: The BMI GRS incorporates the cumulative effect of 97 variants associated with BMI identified from the largest genome-wide association study (GWAS), to date (Locke et al, 2015). A split-sample instrumental variable (IV) analysis was used by summing all risk alleles multiplied by the estimated effect of each risk allele on the phenotype derived from the GWAS. Participants included non-Hispanic white pediatric MS cases and controls from over 15 sites across the U.S. (total sample size: 394 MS cases, 10,875 controls). Results: A significant association between BMI GRS and pediatric MS was demonstrated (causal odds ratio [OR] = 1.20, 95[percnt] CI 1.06, 1.36; p=0.004) after adjusting for sex, ancestry, HLA-DRB1*15:01 (the strongest genetic predictor of MS) and a weighted genetic risk score comprised of 110 non-HLA MS risk variants. Evidence of interaction between BMI GRS and HLA-DRB1*15:01 was also present (p-interaction=0.04); individuals carrying 1-2 DRB1* 15:01 risk alleles demonstrated a stronger association (OR=1.39, 95[percnt] CI 1.16, 1.37) compared to non-carriers (OR=1.05, 95[percnt] CI 0.88, 1.26). Conclusions: For the first time, we provide evidence supporting increased BMI is causally associated with pediatric MS and interacts with HLA-DRB1*15:01 status. Further, pediatric MS risk conferred by obesity may involve predisposing genetic factors for increased BMI, suggesting that specific inflammatory mechanisms involved in the obesity pathway may mediate disease onset. Disclosure: Dr. Gianfrancesco has nothing to disclose. Dr. Shao has nothing to disclose. Dr. Rhead has nothing to disclose. Dr. Graves has nothing to disclose. Dr. Waldman has received royalty payments from UpToDate. Dr. Lotze has nothing to disclose. Dr. Schreiner has received personal compensation for activities with Biogen Idec and MSAA as a consultant. Dr. Belman has nothing to disclose. Dr. Greenberg has received personal compensation for activities with EMD Serono, Novartis, Amarantus, and MSAA for honoria and consulting. Dr. Greenberg has received personal compensation in an editorial capacity for JAMA Neurology. Dr. Greenberg has rece Dr. Weinstock-Guttman has received personal compensation for activities with Biogen Idec, Teva Neurosciences, EMD Serono, Pfizer, Novartis, Genzyme & Sanofi, Mylan, and Acorda. Dr. Aaen has nothing to disclose. Dr. Tillema has nothing to disclose. Dr. Hart has nothing to disclose. Dr. Ness has nothing to disclose. Dr. Harris has nothing to disclose. Dr. Rubin has nothing to disclose. Dr. Candee has nothing to disclose. Dr. Krupp has received licensing and/or royalty fees from Johnson and Johnson, AbbVie, and Grifols. Dr. Gorman has nothing to disclose. Dr. Benson has nothing to disclose. Dr. Rodriguez has received research support from Acorda Therapeutics, Inc. Dr. Chitnis has received personal compensation for activities with Novartis and Biogen. Dr. Chitnis has received research support from Merck-Serono and Novartis Pharmaceuticals. Dr. Mar has nothing to disclose. Dr. Kahn has nothing to disclose. Dr. Rose has received research support from Biogen Idec, AbbieVie Biotherapeutics, Teva, Cumming Foundation, National Multiple Sclerosis Society, VA and NIH. Dr. Roalstad has nothing to disclose. Dr. Casper has nothing to disclose. Dr. Shen has nothing to disclose. Dr. Quach has nothing to disclose. Dr. Metayer has nothing to disclose. Dr. Schaefer has nothing to disclose. Dr. Waubant has received personal compensation for activities with Roche Diagnostics Corporation, Genzyme Corporation, and Novartis. Dr. Waubant has received research support from Roche Diagnostics Corporation, Biogen Idec, and Novartis. Dr. Barcellos has nothing to disclose.