Dataset Information

Genetic risk factors for pediatric-onset multiple sclerosis.

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.

SUBMITTER: Gianfrancesco MA

PROVIDER: S-EPMC5878964 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genetic risk factors for pediatric-onset multiple sclerosis.

Gianfrancesco Milena A MA Stridh Pernilla P Shao Xiaorong X Rhead Brooke B Graves Jennifer S JS Chitnis Tanuja T Waldman Amy A Lotze Timothy T Schreiner Teri T Belman Anita A Greenberg Benjamin B Weinstock-Guttman Bianca B Aaen Gregory G Tillema Jan M JM Hart Janace J Caillier Stacy S Ness Jayne J Harris Yolanda Y Rubin Jennifer J Candee Meghan M Krupp Lauren L Gorman Mark M Benson Leslie L Rodriguez Moses M Mar Soe S Kahn Ilana I Rose John J Roalstad Shelly S Casper T Charles TC Shen Ling L Quach Hong H Quach Diana D Hillert Jan J Hedstrom Anna A Olsson Tomas T Kockum Ingrid I Alfredsson Lars L Schaefer Catherine C Barcellos Lisa F LF Waubant Emmanuelle E

Multiple sclerosis (Houndmills, Basingstoke, England) 20171005 14

<h4>Background</h4>Strong evidence supports the role of both genetic and environmental factors in pediatric-onset multiple sclerosis (POMS) etiology.<h4>Objective</h4>We comprehensively investigated the association between established major histocompatibility complex (MHC) and non-MHC adult multiple sclerosis (MS)-associated variants and susceptibility to POMS.<h4>Methods</h4>Cases with onset <18 years (<i>n</i> = 569) and controls (<i>n</i> = 16,251) were included from the United States and Swe ...[more]

PMID: 28980494

Similar Datasets

Project description:ImportanceAvailability of new disease-modifying therapies (DMTs) and changes of therapeutic paradigms have led to a general improvement of multiple sclerosis (MS) prognosis in adults. It is still unclear whether this improvement also involves patients with pediatric-onset MS (POMS), whose early management is more challenging.ObjectiveTo evaluate changes in the prognosis of POMS over time in association with changes in therapeutic and managing standards.Design, setting, and participantsRetrospective, multicenter, observational study. Data were extracted and collected in May 2019 from the Italian MS Registry, a digital database including more than 59 000 patients. Inclusion criteria were MS onset before age 18 years, diagnosis before January 2014, and disease duration of at least 3 years. Exclusion criteria were primary progressive MS, Expanded Disability Status Scale (EDSS) score of at least 8 one year after onset, unavailability of diagnosis date, and less than 2 EDSS score evaluations. Eligible patients were 4704 patients with POMS. According to these criteria, we enrolled 3198 patients, excluding 1506.ExposuresWe compared time to reach disability milestones by epoch of MS diagnosis (<1993, 1993-1999, 2000-2006, and 2007-2013), adjusting for possible confounders linked to EDSS evaluations and clinical disease activity. We then analyzed the difference among the 4 diagnosis epochs regarding demographic characteristics, clinical disease activity at onset, and DMTs management.Main outcomes and measuresDisability milestones were EDSS score 4.0 and 6.0, confirmed in the following clinical evaluation and in the last available visit.ResultsWe enrolled 3198 patients with POMS (mean age at onset, 15.2 years; 69% female; median time to diagnosis, 3.2 years; annualized relapse rate in first 1 and 3 years, 1.3 and 0.6, respectively), with a mean (SD) follow-up of 21.8 (11.7) years. Median survival times to reach EDSS score of 4.0 and 6.0 were 31.7 and 40.5 years. The cumulative risk of reaching disability milestones gradually decreased over time, both for EDSS score of 4.0 (hazard ratio [HR], 0.70; 95% CI, 0.58-0.83 in 1993-1999; HR, 0.48; 95% CI, 0.38-0.60 in 2000-2006; and HR, 0.44; 95% CI, 0.32-0.59 in 2007-2013) and 6.0 (HR, 0.72; 95% CI, 0.57-0.90; HR, 0.44; 95% CI, 0.33-0.60; and HR, 0.30; 0.20-0.46). In later diagnosis epochs, a greater number of patients with POMS were treated with DMTs, especially high-potency drugs, that were given earlier and for a longer period. Demographic characteristics and clinical disease activity at onset did not change significantly over time.Conclusions and relevanceIn POMS, the risk of persistent disability has been reduced by 50% to 70% in recent diagnosis epochs, probably owing to improvement in therapeutic and managing standards.

Dataset Information

Genetic risk factors for pediatric-onset multiple sclerosis.

Background

Objective

Methods

Results

Conclusion

Publications

Genetic risk factors for pediatric-onset multiple sclerosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets