Multiple sclerosis (MS) is a disabling chronic disease with complex susceptibility factors, such as genetic factors and environmental exposures during early life. Although the disease predominantly affects adults, MS is now increasingly recognized in children. Our pilot data suggest that prior Epstein-Barr virus (EBV) infection, and carrying the HLA-DRB1*1501 allele increase susceptibility to MS in children. Intriguingly, the risk conferred by prior EBV infection may be much higher in HLA-DRB1*1501/1503 negative patients, suggesting a possible gene-environment interaction. The primary advantage of the proposed work is to identify risk factors and their respective contribution to developing MS, some of which are potentially modifiable. In addition, identifying interactions between risk factors in this very informative population will enhance our understanding of the molecular mechanisms that lead to developing the disease. Finally, confirming that risk factors are similar in both age groups will provide support for the extension of conventional management strategies from adults to children. The primary objective of this study is to determine if risk factors identified for adult MS such as HLA- DRB1*1501/1503, EBV, 25(OH) vitamin D3 insufficiency, and exposure to cigarette smoking are also risk factors for pediatric MS, and if there are interactions between them. This objective will be addressed in a prospective study of 640 early pediatric-onset MS cases and 1280 matched controls recruited through the Pediatric MS Network, and its Data Coordinating and Analysis Center.
The specific aims of this project are:
Aim I : To investigate whether genes known to increase MS susceptibility in adults also increase susceptibility in children.
Aim II : To investigate whether remote infections with EBV and other common viruses increase susceptibility to pediatric-onset MS.
Aim III : To investigate if vitamin D insufficiency increases the risk of developing pediatric-onset MS.
Aim I V: To determine if exposure to cigarette smoking increases the risk of developing pediatric-onset MS.
Aim V : To develop predictive models for susceptibility to pediatric-onset MS. Pediatric cases with early MS and matched controls will provide blood for genotyping, and viral and 25(OH) vitamin D3 status. In addition, comprehensive data will be gathered regarding environmental exposures in utero and during childhood. Studying the role of viruses and other environmental insults in the pediatric MS population provides a unique opportunity given the close temporal relationship between exposure and MS onset. In addition, we anticipate that subjects in whom the disease develops before adulthood are likely to have a higher load of risk factors, thus allowing for an easier detection of their effects and interactions.

Public Health Relevance

Multiple sclerosis (MS), a disabling chronic disease, is thought to be caused by a combination of genetic and environmental risk factors. The purpose of this study is to investigate potentially important risk factors for MS in children.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS071463-04
Application #
8460902
Study Section
Neurological, Aging and Musculoskeletal Epidemiology (NAME)
Program Officer
Utz, Ursula
Project Start
2010-08-15
Project End
2016-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
4
Fiscal Year
2014
Total Cost
$539,694
Indirect Cost
$32,230
Name
University of California San Francisco
Department
Neurology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Graves, Jennifer S; Barcellos, Lisa F; Simpson, Steve et al. (2018) The multiple sclerosis risk allele within the AHI1 gene is associated with relapses in children and adults. Mult Scler Relat Disord 19:161-165
Aaen, Gregory; Waltz, Michael; Vargas, Wendy et al. (2018) Acquisition of Early Developmental Milestones and Need for Special Education Services in Pediatric Multiple Sclerosis. J Child Neurol :883073818815041
Nourbakhsh, Bardia; Rutatangwa, Alice; Waltz, Michael et al. (2018) Heterogeneity in association of remote herpesvirus infections and pediatric MS. Ann Clin Transl Neurol 5:1222-1228
Azary, Saeedeh; Schreiner, Teri; Graves, Jennifer et al. (2018) Contribution of dietary intake to relapse rate in early paediatric multiple sclerosis. J Neurol Neurosurg Psychiatry 89:28-33
Suleiman, Leena; Waubant, Emmanuelle; Aaen, Gregory et al. (2018) Early infectious exposures are not associated with increased risk of pediatric-onset multiple sclerosis. Mult Scler Relat Disord 22:103-107
Nourbakhsh, Bardia; Bhargava, Pavan; Tremlett, Helen et al. (2018) Altered tryptophan metabolism is associated with pediatric multiple sclerosis risk and course. Ann Clin Transl Neurol 5:1211-1221
Lavery, Amy M; Waubant, Emmanuelle; Casper, T Charles et al. (2018) Urban air quality and associations with pediatric multiple sclerosis. Ann Clin Transl Neurol 5:1146-1153
Pakpoor, Julia; Seminatore, Brandon; Graves, Jennifer S et al. (2018) Dietary factors and pediatric multiple sclerosis: A case-control study. Mult Scler 24:1067-1076
Lavery, Amy M; Waldman, Amy T; Charles Casper, T et al. (2017) Examining the contributions of environmental quality to pediatric multiple sclerosis. Mult Scler Relat Disord 18:164-169
Gianfrancesco, Milena A; Stridh, Pernilla; Rhead, Brooke et al. (2017) Evidence for a causal relationship between low vitamin D, high BMI, and pediatric-onset MS. Neurology 88:1623-1629

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