|HLA-DRB1*15:01/03 modifies association of vitamin D level with relapse rate in pediatric MS|| |
|J Graves1, L Barcellos2, M Milazzo3, E Mowry4, A Belman3, M Rodriguez5, B Weinstock-Guttman6, M Gorman7, L Benson8, J Ness9, T Lotze10, G Aaen11, T Chitnis12, J Rose13, TC Casper13, L Krupp3, E Waubant14, U.S. Network of Pediatric MS Centers|
|1UCSF, San Francisco, CA, United States, 2University of California, Berkeley, Berkeley, CA, United States, 3Stonybrook University, Stonybrook, NY, United States, 4Johns Hopkins University, Baltimore, MD, United States, 5Mayo Clinic, Rochester, NY, United States, 6The Pediatric MS Center of the Jacobs Neurological Institute at the University of Buffalo, Buffalo, NY, United States, 7Children's Hospital Boston, Boston, MA, United States, 8Boston Children's Hospital, Boston, MA, United States, 9The Center for Pediatric-Onset Demyelinating Diseases at Children's Hospital of Alabama, Birmingham, AL, United States, 10Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, United States, 11Loma Linda University, San Bernadino, CA, United States, 12The Partners Pediatric MS Center at the Massachusetts General Hospital for Children, Boston, MA, United States, 13Department of Pediatrics, University of Utah, Salt Lake City, UT, United States, 14The Regional Pediatric MS Center at the University of California at San Francisco, San Francisco, CA, United States|
|Background: The strongest genetic risk factor for multiple sclerosis is presence of at least one copy of HLA-DRB1*15:01 (or 15:03 in those of African descent). Vitamin D level is one of the strongest environmental risk factors consistently identified for MS risk and severity in children and adults. The effect of genetic risk factors on relapse rate is largely unknown, though a recent study in adults suggests susceptibility alleles may modify the association of vitamin D level and relapse rate (Lin et al, MSJ 2013).|
Objectives: To determine if HLA-DRB1*15 status modifies the association of vitamin D level with relapse rate in children with MS.
Methods: HLA-DRB1*15:01/03 carrier allele status was determined by Taqman assay for 185 MS or clinically isolated syndrome patients from the Pediatric MS Centers at Stony Brook and UCSF who had received prospective clinical follow-up for relapses. HLA-DRB1*15 status modification of the 25-OH vitamin D level association with relapse hazard was assessed using repeated events Cox regression models. Adjustments were made for disease-modifying therapy use, genetic markers of ancestry and gender. Schoenfeld's residuals test was used to verify assumption of proportional hazards.
Results: : Over 511 patient-years of follow-up, 435 relapses were captured. HLA-DRB1*15 status modified the association of vitamin D level with relapse rate (p=0.006). A 10 unit lower vitamin D level was only associated with increased hazard to relapse in those carrying at least one copy of 15:01 or 15:03 (HR 1.53, 95% CI 1.19-1.98, p=0.001), adjusting for gender and genetic ancestry. In those with negative HLA-DRB1*15 status, there was no association of vitamin D level with relapse hazard (HR 0.96, 95% CI 0.85-1.09, p=0.55). Addition of disease modifying therapy use to the models did not change results.
Conclusions: Ours is the first study to suggest an interaction of the strongest genetic risk factor with vitamin D level in effect on relapse rate in children with MS. Vitamin D level may be most relevant to disease course in those with positive HLA-DRB1*15 status. These data support a previous finding in adults that HLA-DRB1*15 status modifies the association of vitamin D level with development of new MRI lesions (Mowry et al., Ann Neurol 2012).
MD, PhD Jennifer Graves , UCSF , San Francisco , US
Assigned in sessions:
11.09.2014, 17:00-17:45, Hot topic sessions, HT1, Genetics of MS (HT1.1-HT1.3), Grand Ballroom