Milena A Gianfrancesco1, Pernilla Stridh2, Xiaorong Shao1, Brooke Rhead3, Jennifer S Graves4, Tanuja Chitnis5, Amy Waldman6, Timothy Lotze7, Teri Schreiner8, Anita Belman9, Benjamin Greenberg10, Bianca Weinstock-Guttman11, Gregory Aaen12, Jan M Tillema13, Janace Hart14, Stacy Caillier14, Jayne Ness15, Yolanda Harris15, Jennifer Rubin16, Meghan Candee17, Lauren Krupp9, Mark Gorman18, Leslie Benson18, Moses Rodriguez13, Soe Mar19, Ilana Kahn20, John Rose21, Shelly Roalstad22, T Charles Casper22, Ling Shen23, Hong Quach1, Diana Quach1, Jan Hillert24, Anna Hedstrom24, Tomas Olsson2, Ingrid Kockum2, Lars Alfredsson25, Catherine Schaefer26, Lisa F Barcellos27, Emmanuelle Waubant4. 1. Division of Epidemiology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA. 2. Department of Clinical Neuroscience and Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden. 3. Computational Biology Graduate Group, University of California, Berkeley, Berkeley, CA, USA. 4. Department of Neurology, University of California, San Francisco, San Francisco, CA, USA. 5. Partners Pediatric Multiple Sclerosis Center, Massachusetts General Hospital for Children, Boston, MA, USA. 6. Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA. 7. Blue Bird Circle Multiple Sclerosis Center, Baylor College of Medicine, Houston, TX, USA. 8. Children's Hospital Colorado, University of Colorado, Denver, CO, USA. 9. The Lourie Center for Pediatric MS, Stony Brook Children's Hospital, Stony Brook, NY, USA. 10. Department of Neurology & Neurotherapeutics, University of Texas Southwestern, Dallas, TX, USA. 11. Pediatric Multiple Sclerosis Center, Jacobs Neurological Institute, SUNY Buffalo, Buffalo, NY, USA. 12. Pediatric MS Center, Loma Linda University Children's Hospital, Loma Linda, CA, USA. 13. Pediatric MS Center, Mayo Clinic, Rochester, MN, USA. 14. Department of Neurology and Regional Pediatric MS Center, University of California, San Francisco, San Francisco, CA, USA. 15. Center for Pediatric Onset Demyelinating Disease, University of Alabama and Children's Hospital of Alabama, Birmingham, AL, USA. 16. Division of Neurology, Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. 17. University of Utah and Primary Children's Hospital, Salt Lake City, UT, USA. 18. Boston Children's Hospital, Boston, MA, USA. 19. Pediatric-onset Demyelinating Diseases and Autoimmune Encephalitis Center, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, MO, USA. 20. Children's National Medical Center, Washington, DC, USA. 21. Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT, USA. 22. Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA. 23. Division of Research, Kaiser Permanente, Oakland, CA, USA. 24. Institute of Environmental Medicine (IMM), Karolinska Institutet, Stockholm, Sweden. 25. Institute of Environmental Medicine (IMM), Karolinska Institutet, Stockholm, Sweden/Centre for Occupational and Environmental Medicine, Stockholm County Council, Stockholm, Sweden. 26. Division of Research, Kaiser Permanente, Oakland, CA, USA/Research Program on Genes, Environment and Health, Kaiser Permanente, Oakland, CA. 27. Division of Epidemiology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA/Computational Biology Graduate Group, University of California, Berkeley, Berkeley, CA, USA; Division of Research, Kaiser Permanente, Oakland, CA, USA.
Abstract
BACKGROUND: Strong evidence supports the role of both genetic and environmental factors in pediatric-onset multiple sclerosis (POMS) etiology. OBJECTIVE: We comprehensively investigated the association between established major histocompatibility complex (MHC) and non-MHC adult multiple sclerosis (MS)-associated variants and susceptibility to POMS. METHODS: Cases with onset <18 years (n = 569) and controls (n = 16,251) were included from the United States and Sweden. Adjusted logistic regression and meta-analyses were performed for individual risk variants and a weighted genetic risk score (wGRS) for non-MHC variants. Results were compared to adult MS cases (n = 7588). RESULTS: HLA-DRB1*15:01 was strongly associated with POMS (odds ratio (OR)meta = 2.95, p < 2.0 × 10-16). Furthermore, 28 of 104 non-MHC variants studied (23%) were associated (p < 0.05); POMS cases carried, on average, a higher burden of these 28 variants compared to adults (ORavg = 1.24 vs 1.13, respectively), though the difference was not significant. The wGRS was strongly associated with POMS (ORmeta = 2.77, 95% confidence interval: 2.33, 3.32, p < 2.0 × 10-16) and higher, on average, when compared to adult cases. Additional class III risk variants in the MHC region associated with POMS were revealed after accounting for HLA-DRB1*15:01 and HLA-A*02. CONCLUSION: Pediatric and adult MS share many genetic variants suggesting similar biological processes are present. MHC variants beyond HLA-DRB1*15:01 and HLA-A*02 are also associated with POMS.
BACKGROUND: Strong evidence supports the role of both genetic and environmental factors in pediatric-onset multiple sclerosis (POMS) etiology. OBJECTIVE: We comprehensively investigated the association between established major histocompatibility complex (MHC) and non-MHC adult multiple sclerosis (MS)-associated variants and susceptibility to POMS. METHODS: Cases with onset <18 years (n = 569) and controls (n = 16,251) were included from the United States and Sweden. Adjusted logistic regression and meta-analyses were performed for individual risk variants and a weighted genetic risk score (wGRS) for non-MHC variants. Results were compared to adult MS cases (n = 7588). RESULTS:HLA-DRB1*15:01 was strongly associated with POMS (odds ratio (OR)meta = 2.95, p < 2.0 × 10-16). Furthermore, 28 of 104 non-MHC variants studied (23%) were associated (p < 0.05); POMS cases carried, on average, a higher burden of these 28 variants compared to adults (ORavg = 1.24 vs 1.13, respectively), though the difference was not significant. The wGRS was strongly associated with POMS (ORmeta = 2.77, 95% confidence interval: 2.33, 3.32, p < 2.0 × 10-16) and higher, on average, when compared to adult cases. Additional class III risk variants in the MHC region associated with POMS were revealed after accounting for HLA-DRB1*15:01 and HLA-A*02. CONCLUSION: Pediatric and adult MS share many genetic variants suggesting similar biological processes are present. MHC variants beyond HLA-DRB1*15:01 and HLA-A*02 are also associated with POMS.
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