IL12A, MPHOSPH9/CDK2AP1 and RGS1 are novel multiple sclerosis susceptibility loci

Esposito, Federica; Patsopoulos, Nikolaos A.; Cepok, Sabine; Kockum, Ingrid; Leppä, Virpi; Booth, David R.; Heard, Robert; Stewart, Graeme J.; Cox, Mathew; Scott, Rodney J.; Lechner-Scott, J.; Goris, An; Dobosi, Rita; Dubois, Bénédicte; Rioux, John D.; Oturai, Annette Bang; Søndergaard, Helle Bach; Sellebjerg, Finn; Sørensen, P. S.; Reunanen, Mauri; Koivisto, Keijo; Cournu-Rebeix, Isabelle; Fontaine, Bertrand; Winkelmann, Juliane; Gieger, Christian; Infante-Duarte, Carmen; Zipp, Frauke; Bergamaschi, Laura; Leone, Maurizio; Bergamaschi, Roberto; Cavalla, Paola; Lorentzen, Åslaug R.; Mero, Inger-Lise; Celius, Elisabeth Gulowsen; Harbo, Hanne F.; Spurkland, Anne; Comabella, Manuel; Bryneda, B.; Alfredsson, Lars; Bernardinelli, Luisa; Robertson, Neil; Hawkins, Clive; Barcellos, Lisa F.; Beecham, Gary W.; Bush, William S.; Cree, Bruce A.C.; Daly, Mark J.; Ivinson, Adrian J.; Aubin, Cristin; Compston, Alastair; D’Alfonso, Sandra; Haines, Jonathan L.; Hauser, Stephen L.; Hemmer, Bernhard; Hillert, Jan; McCauley, Jacob L.; Oksenberg, Jorge R.; Olsson, Tomas; Palotie, Aarno; Peltonen, Leena; Pericak‐Vance, Margaret A.; Saarela, Janna; Sawcer, Stephen; Stranger, Barbara Elaine; Boneschi, Filippo Martinelli; Comı, Gıancarlo; Hafler, David A.; Bakker, Paul I. W. de; Jager, Philip L. De

doi:10.1038/gene.2010.28

Cited by 73 publications

(29 citation statements)

References 42 publications

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“…Nonetheless, from a mechanistic standpoint, the results are intriguing. MPHOSPH9 , which has unknown function [12], was associated with greater attack severity. One hypothesis regarding its function is that this SNP is associated with reduced expression of the nearby CDK2AP1 gene, a cell cycle regulator [27].…”

Section: Discussionmentioning

confidence: 94%

Multiple Sclerosis Susceptibility Genes: Associations with Relapse Severity and Recovery

et al. 2013

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ObjectivePatients with early multiple sclerosis (MS) have stereotyped attack severity and recovery. We sought to determine if polymorphisms in MS susceptibility genes are associated with these attack features or with the risk of a second attack.Methods503 white subjects evaluated within a year of MS onset were included in the study. The severity of and recovery from the first two attacks were determined based on published definitions. Seventeen MS susceptibility genes were genotyped at the UCSF MS Genetics laboratory. Each polymorphism was evaluated in multivariate ordinal models, adjusted for the other polymorphisms, for its association with attack severity and recovery. We also assessed if these polymorphisms were associated with increased risk of a second attack.ResultsThe MPHOSPH9 polymorphism was associated with greater attack severity (odds ratios [OR] = 1.47, 95% CI [1.11, 1.94], p = 0.008), while the RGS1 and TNFRSF1A polymorphisms tended to be associated with reduced attack severity. The CD6 polymorphism tended to be associated with increased odds of worse attack recovery (OR = 1.25, 95% CI [0.93, 1.68], p = 0.13). In those who were HLA-DRB1-negative, the EVI5 polymorphism was associated with attacks of less severity; in HLA-DRB1 positive patients, EVI5 was associated with attacks of greater severity and worse recovery. The IL7R, TNFRSF1A, and GPC5 polymorphisms tended to be associated with having a second event within a year.ConclusionsSome MS susceptibility polymorphisms may be associated with attack severity, recovery, or frequency. Further characterization of these genes may lead to a better understanding of MS pathogenesis and to a more individualized treatment approach.

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Section: Discussionmentioning

confidence: 94%

Multiple Sclerosis Susceptibility Genes: Associations with Relapse Severity and Recovery

et al. 2013

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“…5,60 None of the reported variants showed any evidence for association with severity (Supplementary Table 1). However, over 1100 SNPs in 13 of the 21 susceptibility loci had an association with MSSS at P <0.05 in at least one of the three meta-analyses (Supplementary Table 2).…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association study of severity in multiple sclerosis

Briggs¹,

Shao²,

Goldstein³

et al. 2011

Genes Immun

106

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Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system with a strong genetic component. Several lines of evidence support a strong role for genetic factors influencing both disease susceptibility and clinical outcome in MS. Identification of genetic variants that distinguish particular disease subgroups and/or predict a severe clinical outcome is critical to further our understanding of disease mechanisms and guide development of effective therapeutic approaches. We studied 1470 MS cases and performed a genome-wide association study of more than 2.5 million single-nucleotide polymorphisms to identify loci influencing disease severity, measured using the MS severity score (MSSS), a measure of clinical disability. Of note, no single result achieved genome-wide significance. Furthermore, variants within previously confirmed MS susceptibility loci do not appear to influence severity. Although bioinformatic analyses highlight certain pathways that are over-represented in our results, we conclude that the genetic architecture of disease severity is likely polygenic and comprised of modest effects, similar to what has been described for MS susceptibility, to date. However, a role for major effects of rare variants cannot be excluded. Importantly, our results also show the MSSS, when considered as a binary or continuous phenotype variable is by comparison a stable outcome.

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“…In addition, multi-gene RNA signatures measured before treatment provide an advantage over genome-wide association study biomarkers because the latter yield odds ratios often too low for predicative engineering. 36, 37 An obvious advantage to RNA signatures measured during treatment is that these characterize actual treatment-mediated changes in patients.…”

Section: Discussionmentioning

confidence: 99%

Interferon-beta-1b-induced short- and long-term signatures of treatment activity in multiple sclerosis

Croze

Yamaguchi²,

Knappertz

et al. 2012

Pharmacogenomics J

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Interferon beta (IFNβ) reduces disease burden in relapsing-remitting multiple sclerosis (MS) patients. In this study, IFNβ-1b-treated MS patient gene expression profiles and biological knowledgebases were integrated to study IFNβ's pleiotropic mechanisms of action. Genes involved in immune regulation, mitochondrial fatty acid metabolism and antioxidant activity were discovered. Plausible mediators of neuronal preservation included NRF2, downregulation of OLA1, an antioxidant suppressor, and the antioxidant gene ND6, implicated in optic neuropathy and MS-like lesions. Network analysis highlighted IKBKE, which likely has a role in both viral response and energy metabolism. A comparative analysis of therapy-naive MS- and IFNβ-associated gene expression suggests an IFNβ insufficiency in MS. We observed more gene expression changes in long-term treatment than during acute dosing. These distinct short- and long-term effects were driven by different transcription factors. Multi-gene biomarker signatures of IFNβ treatment effects were developed and subsequently confirmed in independent IFNβ-1b-treated MS studies, but not in glatiramer acetate-treated patients.

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IL12A, MPHOSPH9/CDK2AP1 and RGS1 are novel multiple sclerosis susceptibility loci

Cited by 73 publications

References 42 publications

Multiple Sclerosis Susceptibility Genes: Associations with Relapse Severity and Recovery

Multiple Sclerosis Susceptibility Genes: Associations with Relapse Severity and Recovery

Genome-wide association study of severity in multiple sclerosis

Interferon-beta-1b-induced short- and long-term signatures of treatment activity in multiple sclerosis

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