No evidence for association between rs10191329 severity locus and longitudinal disease severity in 1813 relapse-onset multiple sclerosis patients from the MSBase registry.

Background: The International Multiple Sclerosis Genetics Consortium and MultipleMS Consortium recently reported a genetic variant associated with multiple sclerosis (MS) severity. However, it remains unclear if these variants remain associated with more robust, longitudinal measures of disease severity.

Methods: We examined the top variant, rs10191329, from Harroud et al.

Not all roads lead to the immune system: the genetic basis of multiple sclerosis severity.

Multiple sclerosis is a leading cause of neurological disability in adults. Heterogeneity in multiple sclerosis 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 multiple sclerosis registry, MSBase.

How to Choose a Shunt for Patients with Normal Pressure Hydrocephalus: A Short Guide to Selecting the Best Shunt Assembly.

Most patients with hydrocephalus are still managed with the implantation of a cerebrospinal fluid (CSF) shunt in which the CSF flow is regulated by a differential-pressure valve (DPV). Our aim in this review is to discuss some basic concepts in fluid mechanics that are frequently ignored but that should be understood by neurosurgeons to enable them to choose the most adequate shunt for each patient. We will present data, some of which is not provided by manufacturers, which may help neurosurgeons in selecting the most appropriate shunt.

Considerations in the Use of Gravitational Valves in the Management of Hydrocephalus. Some Lessons Learned with the Dual-Switch Valve.

In the past decade, there has been a clear trend towards better outcomes in patients with hydrocephalus, especially those with normal pressure hydrocephalus (NPH). This is partly due to the availability of more sophisticated hardware and a better understanding of implants. However, there is little evidence to show the superiority of a specific type of valve over another.

Targeted resequencing reveals rare variants enrichment in multiple sclerosis susceptibility genes.

Although genome-wide association studies have identified a number of common variants associated with multiple sclerosis (MS) susceptibility, little is known about the relevance of rare variants. Here, we aimed to explore the role of rare variants in 14 MS risk genes (FCRL1, RGS1, TIMMDC1, HHEX, CXCR5, LTBR, TSFM, GALC, TRAF3, STAT3, TNFSF14, IFI30, CD40, and CYP24A1) by targeted resequencing in an Iberian population of 524 MS cases and 546 healthy controls. Four rare variants-enriched regions within CYP24A1, FCRL1, RGS1, and TRAF3 were identified as significantly associated with MS.

A New Risk Variant for Multiple Sclerosis at 11q23.3 Is Associated with Expansion of Circulating Regulatory T Cells.

Genome-wide association studies and meta-analysis have contributed to the identification of more than 200 associated with multiple sclerosis (MS). However, a proportion of MS heritability remains unknown. We aimed to uncover new genetic variants associated with MS and determine their functional effects.

Splice-site variant in ACSL5: a marker promoting opposing effect on cell viability and protein expression.

Long-chain Acyl-CoA synthetases (ACSLs) activate fatty acids (FAs) by thioesterification with Coenzyme A (CoA), generating FA-CoAs. These products are essential for lipid metabolism and carcinogenesis. In previous study, we identified an intronic variant rs2256368:A>G, whose G allele promotes exon 20 skipping in up to 43% of ACSL5 transcripts but its functional relevance is unclear.

SP140 regulates the expression of immune-related genes associated with multiple sclerosis and other autoimmune diseases by NF-κB inhibition.

SP140 locus has been associated with multiple sclerosis (MS) as well as other autoimmune diseases by genome-wide association studies (GWAS). The causal variant of these associations (rs28445040-T) alters the splicing of the SP140 gene transcripts reducing the protein expression. We aimed to understand why the reduction of SP140 expression produced by the risk variant can increase the susceptibility to MS.

Analysis of Plasminogen Genetic Variants in Multiple Sclerosis Patients.

Multiple sclerosis (MS) is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p.G420D) in plasminogen (PLG) as a putative genetic risk factor for MS.

A splice variant in the ACSL5 gene relates migraine with fatty acid activation in mitochondria.

Genome-wide association studies (GWAS) in migraine are providing the molecular basis of this heterogeneous disease, but the understanding of its aetiology is still incomplete. Although some biomarkers have currently been accepted for migraine, large amount of studies for identifying new ones is needed. The migraine-associated variant rs12355831:A>G (P=2 × 10), described in a GWAS of the International Headache Genetic Consortium, is localized in a non-coding sequence with unknown function.

A comparison of genomic profiles of complex diseases under different models.

Background: Various approaches are being used to predict individual risk to polygenic diseases from data provided by genome-wide association studies. As there are substantial differences between the diseases investigated, the data sets used and the way they are tested, it is difficult to assess which models are more suitable for this task.

Results: We compared different approaches for seven complex diseases provided by the Wellcome Trust Case Control Consortium (WTCCC) under a within-study validation approach.

Genome-wide significant association with seven novel multiple sclerosis risk loci.

Objective: A recent large-scale study in multiple sclerosis (MS) using the ImmunoChip platform reported on 11 loci that showed suggestive genetic association with MS. Additional data in sufficiently sized and independent data sets are needed to assess whether these loci represent genuine MS risk factors.

Methods: The lead SNPs of all 11 loci were genotyped in 10 796 MS cases and 10 793 controls from Germany, Spain, France, the Netherlands, Austria and Russia, that were independent from the previously reported cohorts.

The multiple sclerosis-associated regulatory variant rs10877013 affects expression of CYP27B1 and VDR under inflammatory or vitamin D stimuli.

Background: Vitamin D deficit is considered an important risk factor for many inflammatory and autoimmune diseases.

Objective: To investigate the influence of the multiple sclerosis (MS)-associated regulatory variant rs10877013 on the expression of genes involved in vitamin D activation (CYP27B1), vitamin D receptor (VDR), and vitamin D degradation (CYP24A1) under inflammatory environment or vitamin D.

Methods: We used lipopolysaccharide and interferon-gamma (LPS+IFNγ) activated monocytes from 119 individuals and vitamin D-stimulated lymphoblastoid cell lines (LCLs, n = 109) of 1000 genomes to quantify the mRNA expression of vitamin D genes by quantitative reverse transcription polymerase chain reaction (RT-qPCR).

Influence of the LILRA3 Deletion on Multiple Sclerosis Risk: Original Data and Meta-Analysis.

Background: Multiple sclerosis (MS) is a neurodegenerative, autoimmune disease of the central nervous system. Genome-wide association studies (GWAS) have identified over hundred polymorphisms with modest individual effects in MS susceptibility and they have confirmed the main individual effect of the Major Histocompatibility Complex. Additional risk loci with immunologically relevant genes were found significantly overrepresented.

A functional variant that affects exon-skipping and protein expression of SP140 as genetic mechanism predisposing to multiple sclerosis.

Several variants in strong linkage disequilibrium (LD) at the SP140 locus have been associated with multiple sclerosis (MS), Crohn's disease (CD) and chronic lymphocytic leukemia (CLL). To determine the causal polymorphism, we have integrated high-density data sets of expression quantitative trait loci (eQTL), using GEUVADIS RNA sequences and 1000 Genomes genotypes, with MS-risk variants of the high-density Immunochip array performed by the International Multiple Sclerosis Genetic Consortium (IMSGC). The variants most associated with MS were also correlated with a decreased expression of the full-length RNA isoform of SP140 and an increase of an isoform lacking exon 7.

A new risk variant for multiple sclerosis at the immunoglobulin heavy chain locus associates with intrathecal IgG, IgM index and oligoclonal bands.

Background: Recent findings have shown a correlation between the intrathecal IgG index and variants at the immunoglobulin heavy chain (IGHC) locus in patients with multiple sclerosis (MS).

Objectives: The objective of this paper is to analyse the association of the locus with MS susceptibility and its relationship with intrathecal immunoglobulin (Ig) parameters.

Methods: We genotyped the rs11621145 variant, located at the IGHC locus, in 2726 patients with MS and 2133 healthy controls.

Human endogenous retrovirus HERV-Fc1 association with multiple sclerosis susceptibility: a meta-analysis.

Background: Human endogenous retroviruses (HERVs) are repetitive sequences derived from ancestral germ-line infections by exogenous retroviruses and different HERV families have been integrated in the genome. HERV-Fc1 in chromosome X has been previously associated with multiple sclerosis (MS) in Northern European populations. Additionally, HERV-Fc1 RNA levels of expression have been found increased in plasma of MS patients with active disease.

HERV-W polymorphism in chromosome X is associated with multiple sclerosis risk and with differential expression of MSRV.

Background: Multiple Sclerosis (MS) is an autoimmune demyelinating disease that occurs more frequently in women than in men. Multiple Sclerosis Associated Retrovirus (MSRV) is a member of HERV-W, a multicopy human endogenous retroviral family repeatedly implicated in MS pathogenesis. MSRV envelope protein is elevated in the serum of MS patients and induces inflammation and demyelination but, in spite of this pathogenic potential, its exact genomic origin and mechanism of generation are unknown.

MANBA, CXCR5, SOX8, RPS6KB1 and ZBTB46 are genetic risk loci for multiple sclerosis.

A recent genome-wide association study reported five loci for which there was strong, but sub-genome-wide significant evidence for association with multiple sclerosis risk. The aim of this study was to evaluate the role of these potential risk loci in a large and independent data set of ≈ 20,000 subjects. We tested five single nucleotide polymorphisms rs228614 (MANBA), rs630923 (CXCR5), rs2744148 (SOX8), rs180515 (RPS6KB1), and rs6062314 (ZBTB46) for association with multiple sclerosis risk in a total of 8499 cases with multiple sclerosis, 8765 unrelated control subjects and 958 trios of European descent.

Fine mapping and functional analysis of the multiple sclerosis risk gene CD6.

CD6 has recently been identified and validated as risk gene for multiple sclerosis (MS), based on the association of a single nucleotide polymorphism (SNP), rs17824933, located in intron 1. CD6 is a cell surface scavenger receptor involved in T-cell activation and proliferation, as well as in thymocyte differentiation. In this study, we performed a haptag SNP screen of the CD6 gene locus using a total of thirteen tagging SNPs, of which three were non-synonymous SNPs, and replicated the recently reported GWAS SNP rs650258 in a Spanish-Basque collection of 814 controls and 823 cases.

Role of the small GTPase Rab27a during herpes simplex virus infection of oligodendrocytic cells.

Background: The morphogenesis of herpes simplex virus type 1 (HSV-1) comprises several events, of which some are not completely understood. It has been shown that HSV-1 glycoproteins accumulate in the trans-Golgi network (TGN) and in TGN-derived vesicles. It is also accepted that HSV-1 acquires its final morphology through a secondary envelopment by budding into TGN-derived vesicles coated with viral glycoproteins and tegument proteins.

Identification of a functional variant in the KIF5A-CYP27B1-METTL1-FAM119B locus associated with multiple sclerosis.

Background And Aim: Several studies have highlighted the association of the 12q13.3-12q14.1 region with coeliac disease, type 1 diabetes, rheumatoid arthritis and multiple sclerosis (MS); however, the causal variants underlying diseases are still unclear.