Genetic modifiers of multiple sclerosis progression, severity and onset

Sadovnick, A. Dessa; Traboulsee, Anthony; Zhao, Yinshan; Bernales, Cecily Q.; Encarnacion, Mary Joy; Ross, Jay P.; Yee, Irene M.; Criscuoli, Maria; Vilariño‐Güell, Carles

doi:10.1016/j.clim.2017.05.009

Cited by 19 publications

(25 citation statements)

References 28 publications

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“…Similarly inconsistent results were also obtained in studies examining the influence of rs4149584 SNP on disease onset or severity. In the current study, we found no evidence of association between the R92Q SNP and the age of MS onset, severity or rate of disability progression, what is in agreement with several other retrospective studies (IMSGC, a; Kauffman et al, ; Kümpfel et al, ; Sadovnick et al, ). In contrast, a study in Belgians reported a not quite significant trend towards a more severe disease in A allele carriers (Goris et al, ), whereas a study in the Spanish population detected an association of A allele with lower MS severity and lower age at MS onset (Comabella et al, ).…”

Section: Discussionsupporting

confidence: 94%

TNFRSF1A polymorphisms and their role in multiple sclerosis susceptibility and severity in the Slovak population

Javor

Shawkatová

Ďurmanová

et al. 2018

Int J Immunogenetics

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Tumour necrosis factor (TNF)-mediated signalling plays a key role in inflammatory and neurodegenerative processes leading to the development of multiple sclerosis (MS). Recent studies have highlighted the role of tumour necrosis factor receptor superfamily member 1A (TNFRSF1A) gene encoding the type 1 TNF receptor in the genetic predisposition to MS. This study aimed to validate the association of TNFRSF1A rs1800693 and rs4149584 polymorphisms with susceptibility to MS in the Slovak population and analyse their influence on age at disease onset, severity, and disability progression. Polymerase chain reaction-restriction fragment length polymorphism method was used to genotype both TNFRSF1A polymorphisms in 541 MS patients and 724 healthy controls. Logistic regression analysis revealed a significantly increased risk of developing MS for the carriers of rs1800693 C allele (TC + CC vs. TT: pcorr = 0.005; OR = 1.61; 95% CI = 1.23-2.12), irrespective of sex and carriage of the major MS risk allele HLA-DRB1*15:01. On the other hand, no association could be found between rs4149584 and MS risk (GA + AA vs. GG: pcorr = 1.00; OR = 1.25; 95% CI = 0.71-2.21). Moreover, neither polymorphism was significantly associated with age at disease onset, MS Severity Score (MSSS) or MS Progression Index (PI) in any of the inheritance models. In conclusion, our results provide support for a sex- and HLA-DRB1*15:01-independent association of TNFRSF1A rs1800693 SNP with MS susceptibility, but not with age at disease onset, severity or rate of disability accumulation.

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Section: Discussionsupporting

confidence: 94%

TNFRSF1A polymorphisms and their role in multiple sclerosis susceptibility and severity in the Slovak population

Javor

Shawkatová

Ďurmanová

et al. 2018

Int J Immunogenetics

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“…24 Increased expression of PMS2 ( Z -score=4.05) was associated with later age of HD onset and could potentially play a role in mediating the somatic instability of the CAG repeat. The EIF2AK1 and CHCHD2 genes are relevant for neurological phenotypes, since genetic variants have been respectively associated with modulating multiple sclerosis 12 progression, as well as risk for Parkinson disease and Lewy body disorders respectively. 25…”

Section: Resultsmentioning

confidence: 99%

“…Recent studies have started to make progress in identifying modifier genetic variants, both for HD, 7–11 and other neurological disorders. 12–14 For example, genetic variants in the interrupting sequence between the pathogenic CAG repeat and the polymorphic CCG repeat have been shown to influence age of onset of HD patients, and are particularly relevant for patients that carry reduced penetrance alleles. 10, 11 Additionally, genome-wide association studies (GWAS) have identified trans -modifiers of clinical age of onset in HD, 7, 8, 10 and have highlighted the important role of DNA repair genes in modulating age of onset, potentially through altering the somatic instability of the CAG repeat.…”

Section: Introductionmentioning

confidence: 99%

Gene expression profiles complement the analysis of genomic modifiers of the clinical onset of Huntington disease

Wright

Caron

et al. 2019

Preprint

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Huntington disease (HD) is a neurodegenerative disorder that is caused by a CAG repeat expansion in the HTT gene. In an attempt to identify genomic modifiers that contribute towards the age of onset of HD, we performed a transcriptome wide association study assessing heritable differences in genetically determined expression in diverse tissues, employing genome wide data from over 4,000 patients. This identified genes that showed evidence for colocalization and replication, with downstream functional validation being performed in isogenic HD stem cells and patient brains. Enrichment analyses detected associations with various biologically-relevant gene sets and striatal coexpression modules that are mediated by CAG length. Further, cortical coexpression modules that are relevant for HD onset were also associated with cognitive decline and HD-related traits in a longitudinal cohort. In summary, the combination of population-scale gene expression information with HD patient genomic data identified novel modifier genes for the disorder.

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“…Of interest, some of these genes have been reported implicated in diseases with cognitive impairment, for example, BRI3, RGS6, DIP2A, ZBTB16, BACE2, SIRBP1, IGF2BP2, FCRL5, RTN3, FAM46A, MCF2L, SPI1, and TREM1 in Alzheimer's disease (Abd‐Elrahman, Hamilton, Vasefi, & Ferguson, ; Chung et al, ; Comabella et al, ; Dashinimaev, Artyuhov, Bolshakov, Vorotelyak, & Vasiliev, ; De Jager et al, ; Gaikwad et al, ; Gasparoni et al, ; Matsuda, Matsuda, & D'Adamio, ; Moon et al, ; Replogle et al, ; Schott et al, ; Shi, Ge, He, Hu, & Yan, ); or in clinical conditions characterized by behavioral changes, such as NTNG2 in cognitive abnormalities associated with defective axonal amygdalar projections (Huang et al, ) or bipolar disorders (Egger et al, ), or RAB11FIP5, WARS, and HES6 in depression and other mood disorders (Bacaj, Ahmad, Jurado, Malenka, & Sudhof, ; Glubb, Joyce, & Kennedy, ; Musante et al, ). Furthermore, the experimental ablation of CACNA1H , a gene already associated with the RR course of MS (Sadovnick et al, ), was able to trigger affective disorders including anxiety and hippocampus‐dependent recognition memories (Gangarossa, Laffray, Bourinet, & Valjent, ).…”

Section: Discussionmentioning

confidence: 99%

“…Of interest, some of these genes have been reported implicated in diseases with cognitive impairment, for example, (Huang et al, 2014) or bipolar disorders (Egger et al, 2014), or RAB11FIP5, WARS, and HES6 in depression and other mood disorders (Bacaj, Ahmad, Jurado, Malenka, & Sudhof, 2015;Glubb, Joyce, & Kennedy, 2009;Musante et al, 2017). Furthermore, the experimental ablation of CACNA1H, a gene already associated with the RR course of MS (Sadovnick et al, 2017), was able to trigger affective disorders including anxiety and hippocampus-dependent recognition memories (Gangarossa, Laffray, Bourinet, & Valjent, 2014).…”

Section: Discussionmentioning

confidence: 99%

Association between miRNAs expression and cognitive performances of Pediatric Multiple Sclerosis patients: A pilot study

et al. 2019

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Introduction The Pediatric onset of Multiple Sclerosis (PedMS) occurs in up to 10% of all cases. Cognitive impairment is one of the frequent symptoms, exerting severe impact in patients’ quality of life and school performances. The underlying pathogenic mechanisms are not fully understood, and molecular markers predictive of cognitive dysfunctions need to be identified. On these grounds, we searched for molecular signature/s (i.e., miRNAs and target genes) associated with cognitive impairment in a selected population of PedMS patients. Additionally, changes of their regional brain volumes associated with the miRNAs of interest were investigated. Methods Nineteen PedMS subjects received a full cognitive evaluation; total RNA from peripheral blood samples was processed by next‐generation sequencing followed by a bioinformatics/biostatistics analysis. Results The expression of 11 miRNAs significantly correlated with the scores obtained at different cognitive tests; among the others, eight miRNAs correlated with the Trail Making Tests. The computational target prediction identified 337 genes targeted by the miRNAs of interest; a tangled network of molecular connections was hypothesized, where genes like BST1, NTNG2, SPTB, and STAB1 , already associated with cognitive dysfunctions, were nodes of the net. Furthermore, the expression of some miRNAs significantly correlated with cerebral volumes, for example, four miRNAs with the cerebellum cortex. Conclusions As far as we know, this is the first evaluation exploring miRNAs in the cognitive performances of PedMS. Although none of these results survived the multiple tests’ corrections, we believe that they may represent a step forward the identification of biomarkers useful for monitoring and targeting the onset/progression of cognitive impairments in MS.

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Genetic modifiers of multiple sclerosis progression, severity and onset

Cited by 19 publications

References 28 publications

TNFRSF1A polymorphisms and their role in multiple sclerosis susceptibility and severity in the Slovak population

TNFRSF1A polymorphisms and their role in multiple sclerosis susceptibility and severity in the Slovak population

Gene expression profiles complement the analysis of genomic modifiers of the clinical onset of Huntington disease

Association between miRNAs expression and cognitive performances of Pediatric Multiple Sclerosis patients: A pilot study

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