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Recent association studies in multiple sclerosis (MS) have identified and replicated several single nucleotide polymorphism (SNP) susceptibility loci including CLEC16A, IL2RA, IL7R, RPL5, CD58, CD40 and chromosome 12q13-14 in addition to the well established allele HLA-DR15. There is potential that these genetic susceptibility factors could also mo...
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Citations
... Earlier studies assessing MS disability failed to find genetic associations, partially due to the relatively low number of pwMS included. 22,23 Several studies found that HLA-DRB1*1501 is associated with a lower age at onset, and that age at onset on itself is associated with the development of long-term disability. 24,25 Of interest, in the present study, HLA-DRB1*1501 carriership was significantly higher in rs10191329 A carriers (Table 1) and, therefore, it would be of interest to assess in the IMSGC study whether HLA-DRB1*1501 may affect age at onset and, thereby, the development of disease severity. ...
Objective
Currently, 233 genetic loci are known to be associated with susceptibility to multiple sclerosis (MS). Two independent pivotal severity genome wide association studies recently found the first genome wide significant single nucleotide variant (SNV, rs10191329 A ) and several other suggestive loci associated with overall disability outcomes. It is now important to understand if these findings can influence individual patient management.
Methods
We assessed whether these progression SNVs are associated with detailed clinical phenotypes in a well‐characterized prospective cohort of 1455 MS patients. We used logistic regression, survival analysis and propensity score matching to predict relevant long‐term clinical outcomes.
Results
We were unable to detect any association between rs10191329 A and a range of clinically relevant outcomes (e.g. time to EDSS milestones, age‐related MS severity score, anatomical localization at onset or during subsequent relapses, annualized relapse rate). In addition, an extremes of outcome case‐control analysis using a propensity score matching for genotype detected no association between disease severity and rs10191329 A . However, we were able to replicate association of two suggestive SNVs (rs7289446 G and rs868824 C ) with development of fixed disability, albeit with modest effect sizes, and the association of HLA‐DRB1*1501 with age at onset.
Interpretation
Identification of rs10191329 A and other suggestive SNVs are of considerable importance in understanding pathophysiological processes associated with MS severity. However, it is unlikely that individual genotyping can currently be used in a clinical setting to guide disease management. This study shows the importance of independent replication of genome wide association studies associated with disease progression in neurodegenerative disorders.
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... aav71 88? url_ ver= Z39. 88-2003& rfr_ id= ori: rid: cross ref. org& rfr_ dat= cr_ pub% 20% 200pu bmed) 39 have identified ∼ 232 genetic loci to be associated with MS risk, limited studies have been conducted to identify those that predict future worsening of disability 25,[40][41][42][43] . Additionally, genetic decision rules that can be translated to aid existing clinical and environmental prognostic models in identifying MS subjects prone to future worsening of disability is not yet available. ...
Limited studies have been conducted to identify and validate multiple sclerosis (MS) genetic loci associated with disability progression. We aimed to identify MS genetic loci associated with worsening of disability over time, and to develop and validate ensemble genetic learning model(s) to identify people with MS (PwMS) at risk of future worsening. We examined associations of 208 previously established MS genetic loci with the risk of worsening of disability; we learned ensemble genetic decision rules and validated the predictions in an external dataset. We found 7 genetic loci (rs7731626: HR 0.92, P = 2.4 × 10–5; rs12211604: HR 1.16, P = 3.2 × 10–7; rs55858457: HR 0.93, P = 3.7 × 10–7; rs10271373: HR 0.90, P = 1.1 × 10–7; rs11256593: HR 1.13, P = 5.1 × 10–57; rs12588969: HR = 1.10, P = 2.1 × 10–10; rs1465697: HR 1.09, P = 1.7 × 10–128) associated with risk worsening of disability; most of which were located near or tagged to 13 genomic regions enriched in peptide hormones and steroids biosynthesis pathways by positional and eQTL mapping. The derived ensembles produced a set of genetic decision rules that can be translated to provide additional prognostic values to existing clinical predictions, with the additional benefit of incorporating relevant genetic information into clinical decision making for PwMS. The present study extends our knowledge of MS progression genetics and provides the basis of future studies regarding the functional significance of the identified loci.
... Several attempts have been made to determine the primary genetic factor contributing to MS progression and severity [29][30][31]. Although it was demonstrated that genetic effects on MS disease severity and susceptibility are polygenic with modest influence [30,31], more studies are needed to further understand the pharmacogenetics of MS disease and to define the molecular target of CBD in MS patients by performing the ex vivo/in vitro research in human immune cells as reported by Furgiuele et al. [31]. ...
Multiple sclerosis (MS) is known as an autoimmune disease that damages the neurons in the central nervous system. MS is characterized by its most common symptoms of spasticity, muscle spasms, neuropathic pain, tremors, bladder dysfunction, dysarthria, and some intellectual problems, including memory disturbances. Several clinical studies have been conducted to investigate the effects of cannabis on the relief of these symptoms in MS patients. The efficacy of Cannabis sativa (C. Sativa) in the management of MS outcomes such as spasticity, pain, tremors, ataxia, bladder functions, sleep, quality of life, and adverse effects were assessed in this review. Most clinical studies showed the positive effects of cannabinoids with their different routes of administration, such as oromucosal spray and oral form, in reducing most MS symptoms. The oromucosal spray Nabiximols demonstrated an improvement in reducing MS spasticity, pain, and quality of life with a tolerated adverse effect. Oral cannabinoids are significantly effective for treating MS pain and spasticity, while the other symptoms indicate slight improvement and the evidence is quite inconsistent. Oromucosal spray and oral cannabis are mainly used for treating patients with MS and have positive effects on treating the most common symptoms of MS, such as pain and spasticity, whereas the other MS symptoms indicated slight improvement, for which further studies are needed.
... Although the International MS Genetic Consortium (IMSGC) 3,4 have identi ed ∼ 233 genetic loci to be associated with MS risk, limited studies have been conducted to identify those that predict future worsening of disability. [5][6][7][8][9] Machine learning models have recently been applied in studies of MS disability progression, including classical random forest (RF) and gradient boosting machines (GBM). 5,10−19 Despite their continued use in predicting MS progression outcomes, past and recent studies 15,16 (not related to MS) have shown that these models have (1) limited clinical utility: as they rely strictly on a discrete-time evolution of disease processes; meanwhile in MS, disability progression is characterised by a continuous-time evolution of expanded disability status scores (EDSS) 1,9 ; (2) weak predictive power: as they do not account for correlated outcomes 20 e.g. ...
Limited studies have been conducted to identify and validate multiple sclerosis (MS) genetic loci associated with disability progression. We aimed to identify MS genetic loci associated with worsening of disability over time, and to develop and validate ensemble genetic learning model(s) to identify people with MS (PwMS) at risk of future worsening. We examined associations of 208 previously established MS genetic loci with the risk of worsening of disability; we learned ensemble genetic decision rules and validated the predictions in an external dataset. We found 7 genetic loci ( rs7731626: HR = 0.92, P = 2.4x10 − 5 ; rs12211604: HR = 1.16, P = 3.2x10 − 7 ; rs55858457: HR = 0.93, P = 3.7x10 − 7 ; rs10271373: HR = 0.90, P = 1.1x10 − 7 ; rs11256593: HR = 1.13, P = 5.1x10 − 57 ; rs12588969: HR = 1.10, P = 2.1x10 − 10 ; rs1465697: HR = 1.09, P = 1.7x10 − 128 ) associated with worsening of disability; most of which are located near or tagged to 13 genomic regions enriched in peptide hormones and steroids biosynthesis pathways by positional and eQTL mapping. The derived ensembles provided a set of genetic decision rules that can be translated to provide additional prognostic values to existing clinical predictions, with the additional benefit of incorporating relevant genetic information into clinical decision making for PwMS. The present study extends our knowledge of MS progression genetics and provides the basis of future studies regarding the functional significance of the identified loci.
... 5,6 Further, there is strong evidence to suggest that currently known risk variants, aside from HLA-DRB1*15:01, play no major role in determining MS severity. [7][8][9] A genetic influence on MS outcome is, however, plausible, in particular relating to the severity of secondary inflammation (e.g. development of slowly expanding, or chronic rim-active lesions), resilience to neuroaxonal injury, or remyelination capacity. ...
Multiple sclerosis (MS) is a leading cause of neurological disability in adults. Heterogeneity in MS clinical presentation has posed a major challenge for identifying genetic variants associated with disease outcomes. To overcome this challenge, we used prospectively ascertained clinical outcomes data from the largest international MS Registry, MSBase. We assembled a cohort of deeply phenotyped individuals with relapse-onset MS. We used unbiased genome-wide association study and machine learning approaches to assess the genetic contribution to longitudinally defined MS severity phenotypes in 1,813 individuals. Our results did not identify any variants of moderate to large effect sizes that met genome-wide significance thresholds. However, we demonstrate that clinical outcomes in relapse-onset MS are associated with multiple genetic loci of small effect sizes. Using a machine learning approach incorporating over 62,000 variants and demographic variables available at MS disease onset, we could predict severity with an area under the receiver operator curve (AUROC) of 0.87 (95% CI 0.83 - 0.91). This approach, if externally validated, could quickly prove useful for clinical stratification at MS onset. Further, we find evidence to support central nervous system and mitochondrial involvement in determining MS severity.
... This and the low number of participants included in our study may explain the lack of association with this genetic variant. The lack of associations with the two HLA variants may be explained by the fact that one is known as a susceptibility variant and the other as a protective variant of MS not known to be involved in disease attenuating or ameliorating effects (Jensen et al., 2010). ...
Background
: Smoking, cardiovascular risk factors, and genetic factors can have adverse effects in MS.
Objective
: To determine if smoking after disease onset, cardiovascular risk factors, and genetic variants influence primary progressive MS (PPMS).
Method
: In this cross-sectional study, smoking habits, Framingham Risk Score (FRS), genetic variants, including the low-density lipoprotein receptor-related protein 2 (LRP2) SNP rs12988804 and MRI were collected in 60 PPMS trial participants. Disability and cognition were assessed with the Age-Related Multiple Sclerosis Severity (ARMSS) score, the Progressive-Onset MS Multiple Sclerosis Severity Score, and the Brief International Cognitive Assessment for MS.
Results
: Smoking after PPMS onset was significantly associated with higher ARMSS (95% CI 0.8–2.4, p = 0.00016) statistically significant after Bonferroni correction. Lower magnetization transfer ratio in lesions was also significantly associated with smoking after onset of PPMS (95% CI -0.9–-4.4, p = 0.0035; significant after Bonferroni correction). Pack-years in people who smoked after onset was likewise significantly associated with higher ARMSS score (b = 0.06 95% CI 0.02–0.09, p = 0.0021) as well as lower Symbol Digit Modalities Test scores (b = -0.40; 95% CI -0.66–-0.13, p = 0.0037), both statistically significant after Bonferroni correction. The LRP2 risk allele was associated with decreased performance on the California Verbal Learning Test 2 (CC vs. CT+TT 95% CI -14.2–-3.4, p = 0.0018; significant after Bonferroni correction).
Conclusion
: If validated, these findings suggest that intervention regarding smoking may be beneficial in PPMS. If confirmed, assessment of the LRP2 gene variant may aid in the understanding of underlying pathological mechanisms in PPMS.
... First of all, candidate gene studies have assessed the role of genes implicated in MS susceptibility in determining disease course, failing to identify any significant association (Jensen et al., 2010) except for the HLA-DRB1 * 1501 allele (Hauser et al., 2000;Barcellos et al., 2003). Interestingly enough, a subsequent GWAS (Baranzini et al., 2009) also failed to identify an enrichment of associated genes implicated in immunological functions. ...
... However, several studies have found that this allele does not predict disease severity or brain atrophy in MS [12][13][14][15]. Other non-HLA susceptibility genes with small individual effects implicated in MS risk by genome-wide association studies (GWAS) have also not shown associations with disease severity [16,17]. The finding that the HLA DRB1*1501 allele is not detected in all patients with MS while some people never develop MS despite inheritance of this allele, supports the suggestion of distinct subtypes involving other genes and/or environmental triggers. ...
Background:
Multiple sclerosis is a disorder related to demyelination of axons. Iron is an essential cofactor in myelin synthesis. Previously, we described two children (males of mixed ancestry) with relapsing-remitting multiple sclerosis (RRMS) where long-term remission was achieved by regular iron supplementation. A genetic defect in iron metabolism was postulated, suggesting that more advanced genetic studies could shed new light on disease pathophysiology related to iron.
Methods:
Whole exome sequencing (WES) was performed to identify causal pathways. Blood tests were performed over a 10 year period to monitor the long-term effect of a supplementation regimen. Clinical wellbeing was assessed quarterly by a pediatric neurologist and regular feedback was obtained from the schoolteachers.
Results:
WES revealed gene variants involved in iron absorption and transport, in the transmembrane protease, serine 6 (TMPRSS6) and transferrin (TF) genes; multiple genetic variants in CUBN, which encodes cubilin (a receptor involved in the absorption of vitamin B12 as well as the reabsorption of transferrin-bound iron and vitamin D in the kidneys); SLC25A37 (involved in iron transport into mitochondria) and CD163 (a scavenger receptor involved in hemorrhage resolution). Variants were also found in COQ3, involved with synthesis of Coenzyme Q10 in mitochondria. Neither of the children had the HLA-DRB1*1501 allele associated with increased genetic risk for MS, suggesting that the genetic contribution of iron-related genetic variants may be instrumental in childhood MS. In both children the RRMS has remained stable without activity over the last 10 years since initiation of nutritional supplementation and maintenance of normal iron levels, confirming the role of iron deficiency in disease pathogenesis in these patients.
Conclusion:
Our findings highlight the potential value of WES to identify heritable risk factors that could affect the reabsorption of transferrin-bound iron in the kidneys causing sustained iron loss, together with inhibition of vitamin B12 absorption and vitamin D reabsorption (CUBN) and iron transport into mitochondria (SLC25A37) as the sole site of heme synthesis. This supports a model for RRMS in children with an apparent iron-deficient biochemical subtype of MS, with oligodendrocyte cell death and impaired myelination possibly caused by deficits of energy- and antioxidant capacity in mitochondria.
... Several studies have explored the genetic basis of clinical course, age of onset and severity, although no genome-wide significant associations have been discovered. 36,37,43,[74][75][76][77] Whether more detailed disease parameters are more prone to error measurement, systematic differences across centres or simply not heritable remains to be determined, but a recent study showing that clinical scores can be predictive across centres suggests that lack of heritability is not the issue. 78 Similarly, patient response to therapy is largely unpredictable; there is no evidence to date, for example, that different patients have slightly different pathologies and would thus respond to distinct modes of therapy targeting those specific pathways, although efforts to dissect this issue are underway. ...
Large-scale genetic studies of multiple sclerosis have identified over 230 risk effects across the human genome, making it a prototypical common disease with complex genetic architecture. Here, after a brief historical background on the discovery and definition of the disease, we summarise the last fifteen years of genetic discoveries and map out the challenges that remain to translate these findings into an aetiological framework and actionable clinical understanding. © 2018 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australasian Society for Immunology Inc.
... Although the discovery of MS susceptibility loci has been very successful, with more than 200 genome-wide so far, this success has not been translated into subphenotypes of the disease. No association was identified with primary progressive MS or the MS Severity Score (MSSS) in any of the published studies (Jensen et al. 2010;International Multiple Sclerosis Genetics Consortium 2011;George et al. 2016), whereas some reports exist for magnetic resonance imaging (MRI) measurements that need further replication to be considered robust Matsushita et al. 2015). On the contrary, studies on laboratory measurements have been successful. ...
The contribution of genetic inheritance in multiple sclerosis was established early on. Although multiple sclerosis is not a Mendelian disease, its incidence and prevalence is higher in family members of affected individuals compared with the general population. Throughout the last decade, several small studies failed to identify any robust genetic associations besides the classic associations in the major histocompatibility complex region. During the past few years, genome-wide association studies (GWAS) have revolutionized the genetics of multiple sclerosis, uncovering more than 200 implicated genetic loci. Here, we describe these main findings and discuss the new avenues that these discoveries lay open.
