Environmental risk factors associated with pediatric MS: The role of remote viral infections and vitamin D revisited.

Objective: To confirm our preliminary findings of association between EBV, CMV and HSV-1 remote infections, serum25(OH)vitamin D levels and pediatric MS in a large national case-control study. Background: Prior studies have suggested associations between viral infections acquired during childhood and MS development. Design/Methods: Patients with pediatric-onset MS or CIS and frequency-matched controls were recruited at 16 pediatric MS centers across the US. Batched Epstein-Barr virus (EBV)-viral capsid antigen (VCA), Epstein-Barr nuclear antigen-1 (EBNA-1), EBV-early antigen (EA), CMV, HSV-1 and −2 serostatus were tested by ELISA. 25-(OH)-vitamin D levels were determined by chemoluminescence. The rates of viral seropositivity and serum levels of vitamin D were compared between cases and controls in analyses adjusted for possible confounders such as age, sex, race and ethnicity. DRB1*1501 status was determined using SNP typing. Results: Samples from 360 pediatric cases (mean age: 15.2±3.2 years, 64% females, mean disease duration 354±321 days) and 496 controls (mean age: 14.3±3.8 years, 52% females) were tested for EBV, CMV and HSV antibodies and 25-(OH)-vitamin D. Adjusting for age, sex, race/ethnicity, a remote infection with EBV (anti-EBNA1+) was strongly associated with higher risk of pediatric-onset MS (OR:3.6, 95%CI 2.1–6.3). HSV-1 seropositivity was also associated with pediatric-onset MS (OR:1.4, 95%CI 1.001–2.011). For vitamin D analyses, we compared controls with 42 cases who were recruited within 45 days of onset as serum levels could not yet be substantially altered by supplementation. There was a trend towards an association between lower serum levels of vitamin D and the risk of developing pediatric MS. For each 1 ng increase in 25-(OH)-vitamin D serum levels, there was a 3% reduction in the risk of pediatric MS onset (OR:0.77, 95%CI 0.93–1.01). Analyses stratifying by DRB1*1501 status are ongoing. Conclusions: Our preliminary results support an association between prior EBV and HSV-1 infection, and vitamin D deficiency and development of pediatric-onset MS. Disclosure: Dr. Taleb has nothing to disclose. Dr. Nourbakhsh has received research support from the American Brain Foundation. Dr. Graves has received research support from Genentech, Biogen and S3 Group. Dr. Casper has nothing to disclose. Dr. Waldman has received royalty payments from UpToDate. Dr. Lulu has received research support from National Multiple Sclerosis Society and Biogen Idec. Dr. Belman has received personal compensation for activities with Biogen Idec as a consultant. Dr. Guttman has received research support from NMSS, NIH, ITN, Teva Neuroscience, Biogen Idec, EMD Serono, Aspreva, Novartis, and Acorda. Dr. Greenberg has received personal compensation for activities with Novartis Boston Pharmaceuticals, and MSAA. Dr. Greenberg has received personal compensation in an editorial capacity for JAMA Neurology. Dr. Greenberg has received research support from Medimmune, Acorda, and Chugai. Dr. Aaen has nothing to disclose. Dr. Hart has nothing to disclose. Dr. Ness has received research support from Novartis Pharmaceuticals. Dr. Rubin has nothing to disclose. Dr. Tillema 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 received personal compensation for activities with Roche-Genentech and Sanofi-Genzyme. Dr. Chitnis received research support from EMD Serono, Biogen, Novartis and Verily. Dr. Rose has received research support from Biogen Idec, AbbieVie Biotherapeutics, Teva, and National Multiple Sclerosis Society. Dr. Barcellos has nothing to disclose. Dr. Waubant has received research support from Roche, Biogen Idec and Novartis.