Genetic risk factors for pediatric-onset multiple sclerosis

Gianfrancesco, Milena; Stridh, Pernilla; Shao, Xiaorong; Rhead, Brooke; Graves, Jennifer; Chitnis, Tanuja; Waldman, Amy; Lotze, Timothy; Schreiner, Teri; Belman, Anita; Greenberg, Benjamin; Weinstock‐Guttman, Bianca; Aaen, Gregory; Tillema, Jan Mendelt; Hart, Janace; Caillier, Stacy J.; Ness, Jayne; Harris, Yolanda; Rubin, Jennifer; Candee, Meghan; Krupp, Lauren; Gorman, Mark; Benson, Lina; Rodriguez, Moses; Mar, Soe; Kahn, Ilana; Rose, John; Roalstad, Shelly; Casper, T. Charles; Shen, Lei; Quach, Hong; Quach, Diana; Hillert, Jan; Hedström, Anna Karin; Olsson, Tomas; Kockum, Ingrid; Alfredsson, Lars; Schaefer, Catherine; Barcellos, Lisa F.; Waubant, Emmanuelle

doi:10.1177/1352458517733551

Cited by 45 publications

(58 citation statements)

References 33 publications

(62 reference statements)

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“…Twenty‐eight non‐MHC variants studied were also significantly associated. Similar results were reported by the first genome‐wide association study in paediatric multiple sclerosis . Further studies will be required to evaluate the relevance of these single‐nucleotide polymorphisms but it is likely they will lead to an enhancement of our understanding of the pathophysiology underlying multiple sclerosis.…”

Section: Environmental and Genetic Risk Factors: The Complex Interplaysupporting

confidence: 77%

“…Genetic susceptibility has long been established in adult‐onset multiple sclerosis, the presence of HLA‐DRB1*15:01 being the strongest genetic predictor. One of the largest case–control studies (569 cases) to date identified a shared association in paediatric multiple sclerosis with HLA‐DRB1*15:01 , with an odds ratio of 2.95, suggesting similar biological processes regardless of age at onset . Twenty‐eight non‐MHC variants studied were also significantly associated.…”

Section: Environmental and Genetic Risk Factors: The Complex Interplaymentioning

confidence: 96%

“…One of the largest case-control studies (569 cases) to date identified a shared association in paediatric multiple sclerosis with HLA-DRB1*15:01, with an odds ratio of 2.95, suggesting similar biological processes regardless of age at onset. 53 Twentyeight non-MHC variants studied were also significantly associated. Similar results were reported by the first genome-wide association study in paediatric multiple sclerosis.…”

Section: Environmental and Genetic Risk Factors: The Complex Interplaymentioning

confidence: 97%

“…Similar results were reported by the first genome-wide association study in paediatric multiple sclerosis. 53 Further studies will be required to evaluate the relevance of these single-nucleotide polymorphisms but it is likely they will lead to an enhancement of our understanding of the pathophysiology underlying multiple sclerosis. A study comparing 57 novel risk alleles showed that genetic risk scores were significantly different in patients with paediatric multiple sclerosis compared with those having monophasic ADS.…”

Section: Environmental and Genetic Risk Factors: The Complex Interplaymentioning

confidence: 99%

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Paediatric multiple sclerosis: a new era in diagnosis and treatment

Duignan

Brownlee

Wassmer

et al. 2019

Develop Med Child Neuro

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Multiple sclerosis is a chronic immune‐mediated demyelinating disease of the central nervous system. The diagnosis of multiple sclerosis in children, as in adults, requires evidence of dissemination of inflammatory activity in more than one location in the central nervous system (dissemination in space) and recurrent disease over time (dissemination in time). The identification of myelin oligodendrocyte glycoprotein antibodies (MOG‐Ab) and aquaporin‐A antibodies (AQP4‐Ab), and the subsequent discovery of their pathogenic mechanisms, have led to a shift in the classification of relapsing demyelinating syndromes. This is reflected in the 2017 revised criteria for the diagnosis of multiple sclerosis, which emphasizes the exclusion of multiple sclerosis mimics and aims to enable earlier diagnosis and thus treatment initiation. The long‐term efficacy of individual therapies initiated in children with multiple sclerosis is hard to evaluate, owing to the small numbers of patients who have the disease, the relatively high number of patients who switch therapy, and the need for long follow‐up studies. Nevertheless, an improvement in prognosis with a globally reduced annual relapse rate in children with multiple sclerosis is now observed compared with the pretreatment era, indicating a possible long‐term effect of therapies. Given the higher relapse rate in children compared with adults, and the impact multiple sclerosis has on cognition in the developing brain, there is a question whether rapid escalation or potent agents should be used in children, while the short‐ and long‐term safety profiles of these drugs are being established. With the results of the first randomized controlled trial of fingolimod versus interferon‐β1a in paediatric multiple sclerosis published in 2018 and several clinical trials underway, there is hope for further progress in the field of paediatric multiple sclerosis. What this paper adds Early and accurate diagnosis of multiple sclerosis is crucial. The discovery of antibody‐mediated demyelination has changed the diagnosis and management of relapsing demyelination syndromes. Traditional escalation therapy is being challenged by induction therapy.

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Section: Environmental and Genetic Risk Factors: The Complex Interplaysupporting

confidence: 77%

Section: Environmental and Genetic Risk Factors: The Complex Interplaymentioning

confidence: 96%

Section: Environmental and Genetic Risk Factors: The Complex Interplaymentioning

confidence: 97%

Section: Environmental and Genetic Risk Factors: The Complex Interplaymentioning

confidence: 99%

See 2 more Smart Citations

Paediatric multiple sclerosis: a new era in diagnosis and treatment

Duignan

Brownlee

Wassmer

et al. 2019

Develop Med Child Neuro

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“…Participants were asked to give blood samples, which were genotyped on an Illumina custom array, the MS replication chip 14. Genotypes in the major histocompatibility complex region from the custom array were used to impute human leucocyte antigen ( HLA)-DRB1 and HLA-A alleles with HLA*IMP02 ,15 described in detail elsewhere 16. Single nucleotide polymorphisms with <2% minor allele frequency, genotyped in <98% of individuals or not in Hardy Weinberg equilibrium among controls (p<0.0001) were excluded.…”

Section: Methodsmentioning

confidence: 99%

Factors associated with and long-term outcome of benign multiple sclerosis: a nationwide cohort study

Crielaard

Kavaliūnas

Ramanujam

et al. 2019

J Neurol Neurosurg Psychiatry

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ObjectiveBenign multiple sclerosis (BMS) is often defined by the Expanded Disability Status Scale (EDSS) score of ≤3.0 after ≥15 years of disease duration. This classification’s clinical relevance remains unclear as benign patients may suffer other impairments and advance towards a progressive course, prompting our objective to holistically investigate factors associated with BMS and its long-term prognosis.MethodsBenign cases were identified in the Swedish Multiple Sclerosis registry. Baseline clinical data, demographic features and influence of multiple sclerosis (MS) major risk alleles on likelihood of benign course were investigated. Physical disability (EDSS), cognitive function (Symbol Digit Modalities Test; SDMT) and self-reported and socioeconomic differences between benign and non-benign patients were evaluated using generalised estimation equations models.Results11222 patients (2420 benign/8802 non-benign) were included. Benign patients were more likely to be female and younger at MS onset, have fewer relapses within the first two and 5 years from onset and fully recover from the first relapse (p<0.001). No association between human leucocyte antigen (HLA) DRB1*15:01 carriership (OR: 0.97, 95% CI: 0.86 to 1.09) or HLA-A*02:01 lacking (OR: 0.99, 95% CI: 0.87 to 1.11) and benign/non-benign was found. Non-benign patients accumulated an extra 0.04 (95% CI 0.03 to 0.04, p<0.001) EDSS score/year, lost an extra 0.3 (95% CI − 0.39 to − 0.18, p<0.001) SDMT score/year and deteriorated faster in self-reported impact and socioeconomic measures (p<0.001).ConclusionPatients with BMS have a better disease course as they progress more slowly at the group level in all respects. Lack of an association with major genetic risk factors indicates that MS course is most likely influenced by either environmental factor(s) or genetic factors outside the HLA region.

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Association of Obesity With Multiple Sclerosis Risk and Response to First-line Disease Modifying Drugs in Children

et al. 2019

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IMPORTANCE Obesity reportedly increases the risk of pediatric multiple sclerosis (MS), but little is known about its association with disease course. OBJECTIVE To investigate the association of obesity with pediatric MS risk and with first-line therapy response among children with MS. DESIGN, SETTING, AND PARTICIPANTS This single-center retrospective study used the medical records and database at the Center for MS in Childhood and Adolescence, Göttingen, Germany. The study included 453 patients with relapsing-remitting pediatric MS and body mass index (BMI) measurement taken within 6 months of diagnosis.

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Genetic risk factors for pediatric-onset multiple sclerosis

Abstract: Pediatric and adult MS share many genetic variants suggesting similar biological processes are present. MHC variants beyond HLA-DRB115:01 and HLA-A02 are also associated with POMS.

Cited by 45 publications

References 33 publications

Paediatric multiple sclerosis: a new era in diagnosis and treatment

Paediatric multiple sclerosis: a new era in diagnosis and treatment

Factors associated with and long-term outcome of benign multiple sclerosis: a nationwide cohort study

Association of Obesity With Multiple Sclerosis Risk and Response to First-line Disease Modifying Drugs in Children

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Genetic risk factors for pediatric-onset multiple sclerosis

Abstract: 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.

Cited by 45 publications

References 33 publications

Paediatric multiple sclerosis: a new era in diagnosis and treatment

Paediatric multiple sclerosis: a new era in diagnosis and treatment

Factors associated with and long-term outcome of benign multiple sclerosis: a nationwide cohort study

Association of Obesity With Multiple Sclerosis Risk and Response to First-line Disease Modifying Drugs in Children

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Abstract: Pediatric and adult MS share many genetic variants suggesting similar biological processes are present. MHC variants beyond HLA-DRB115:01 and HLA-A02 are also associated with POMS.