Genetic risk factors for pediatric-onset multiple sclerosis

Milena A Gianfrancesco; Pernilla Stridh; Xiaorong Shao; Brooke Rhead; Jennifer S Graves; Tanuja Chitnis; Amy Waldman; Timothy Lotze; Teri Schreiner; Anita Belman; Benjamin Greenberg; Bianca Weinstock-Guttman; Gregory Aaen; Jan M Tillema; Janace Hart; Stacy Caillier; Jayne Ness; Yolanda Harris; Jennifer Rubin; Meghan Candee; Lauren Krupp; Mark Gorman; Leslie Benson; Moses Rodriguez; Soe Mar; Ilana Kahn; John Rose; Shelly Roalstad; T Charles Casper; Ling Shen; Hong Quach; Diana Quach; Jan Hillert; Anna Hedstrom; Tomas Olsson; Ingrid Kockum; Lars Alfredsson; Catherine Schaefer; Lisa F Barcellos; Emmanuelle Waubant; Network of Pediatric Multiple Sclerosis Centers

doi:10.1177/1352458517733551

Genetic risk factors for pediatric-onset multiple sclerosis

Mult Scler. 2018 Dec;24(14):1825-1834. doi: 10.1177/1352458517733551. Epub 2017 Oct 5.

Authors

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; Network of Pediatric Multiple Sclerosis Centers

Affiliations

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 (OR_avg = 1.24 vs 1.13, respectively), though the difference was not significant. The wGRS was strongly associated with POMS (OR_meta = 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.

Keywords: Multiple sclerosis; epidemiology; genetics; pediatrics.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Female
Genetic Predisposition to Disease / genetics*
Genetic Testing
HLA-DRB1 Chains / genetics*
Humans
Logistic Models
Male
Multiple Sclerosis / genetics*
Polymorphism, Single Nucleotide / genetics*
Risk Factors
Sweden

Substances

HLA-DRB1 Chains

Abstract

Publication types

MeSH terms

Substances

Grants and funding