100 research outputs found
Analysis of Plasminogen Genetic Variants in Multiple Sclerosis Patients
Dessa Sadovnick, A.; Alcina, Antonio; Fedetz, MarĂa; Matesanz, F.; Vilariño-GĂŒell, Carles; Dessa Sadovnick, A. et. al.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. Genotyping of PLG p.G420D (rs139071351) in 2160 MS patients, and 886 controls from Canada, identified 10 additional probands, two sporadic patients and one control with the variant. Segregation in families harboring the rs139071351 variant, identified p.G420D in 26 out of 30 family members diagnosed with MS, 14 unaffected parents, and 12 out of 30 family members not diagnosed with disease. Despite considerably reduced penetrance, linkage analysis supports cosegregation of PLG p.G420D and disease. Genotyping of PLG p.G420D in 14446 patients, and 8797 controls from Canada, France, Spain, Germany, Belgium, and Austria failed to identify significant association with disease (P = 0.117), despite an overall higher prevalence in patients (OR = 1.32; 95% CI = 0.93â1.87). To assess whether additional rare variants have an effect on MS risk, we sequenced PLG in 293 probands, and genotyped all rare variants in cases and controls. This analysis identified nine rare missense variants, and although three of them were exclusively observed in MS patients, segregation does not support pathogenicity. PLG is a plausible biological candidate for MS owing to its involvement in immune system response, blood-brain barrier permeability, and myelin degradation. Moreover, components of its activation cascade have been shown to present increased activity or expression in MS patients compared to controls; further studies are needed to clarify whether PLG is involved in MS susceptibility.We
also thank GĂ©nĂ©thon, LâAssociation Française contre les Myopathies
(AFM), la Fondation pour lâAide Ă la Recherche sur la SclĂ©rose en
Plaques (ARSEP), and the Biological Resources Centre (BRC) of The
French Multiple Sclerosis Genetics Group (CRB-REFGENSEP). This
research was undertaken thanks to funding from the Canada Research
Chair [950-228408] and Canada Excellence Research Chair programs
[214444], Canadian Institutes of Health Research [MOP-137051],
Vancouver Coastal Health Research Institute, the Milan & Maureen
Ilich Foundation [11-32095000], and the Vancouver Foundation
[ADV14-1597]. Replication studies received funding from the program
âInvestissements dâavenirâ ANR-10-IAIHU-06. Fondo de InvestigaciĂłn
Sanitaria (FIS)-Instituto de Salud Carlos III (ISCIII)-Fondos
Europeos de Desarrollo Regional (FEDER), UniĂłn Europea [grant numbers
P12/00555, PI13/01527, PI13/01466 and PI13/0879 to F.M., A.A.
and G.I.] and Junta de AndalucĂa -FEDER [grant number CTS2704
to F.M.]. B.D. is a Clinical Investigator of the Research Foundation
Flanders (FWO-Vlaanderen). A.G. and B.D. are supported by the
Research Fund KU Leuven (OT/11/087 and CREA/14/023) and the
Research Foundation Flanders (G073415N). A.L.T. reports personal
fees from Biogen Idec, Chugai, Medimmune, Teva Innovation, and
EMD Serono, and grants and personal fees from Genzyme Sanofi
and Roche.Peer reviewe
The Inheritance of Resistance Alleles in Multiple Sclerosis
Multiple sclerosis (MS) is a complex trait in which alleles at or near the class II loci HLA-DRB1 and HLA-DQB1 contribute significantly to genetic risk. HLA-DRB1*15 and HLA-DRB1*17-bearing haplotypes and interactions at the HLA-DRB1 locus increase risk of MS but it has taken large samples to identify resistance HLA-DRB1 alleles. In this investigation of 7,093 individuals from 1,432 MS families, we have assessed the validity, mode of inheritance, associated genotypes, and the interactions of HLA-DRB1 resistance alleles. HLA-DRB1*14-, HLA-DRB1*11-, HLA-DRB1*01-, and HLA-DRB1*10-bearing haplotypes are protective overall but they appear to operate by different mechanisms. The first type of resistance allele is characterised by HLA-DRB1*14 and HLA-DRB1*11. Each shows a multiplicative mode of inheritance indicating a broadly acting suppression of risk, but a different degree of protection. In contrast, a second type is exemplified by HLA-DRB1*10 and HLA-DRB1*01. These alleles are significantly protective when they interact specifically in trans with HLA-DRB1*15-bearing haplotypes. HLA-DRB1*01 and HLA-DRB1*10 do not interact with HLA-DRB1*17, implying that several mechanisms may be operative in major histocompatibility complexâassociated MS susceptibility, perhaps analogous to the resistance alleles. There are major practical implications for risk and for the exploration of mechanisms in animal models. Restriction of antigen presentation by HLA-DRB1*15 seems an improbably simple mechanism of major histocompatibility complexâassociated susceptibility
An Extremes of outcome strategy provides evidence that multiple sclerosis severity is determined by alleles at the <i>HLA-DRB1</i> locus
Multiple sclerosis (MS) is a common inflammatory disease of the
central nervous system unsurpassed for variability in disease outcome.
A cohort of sporadic MS cases (n=63), taken from opposite
extremes of the distribution of long-term outcome, was used to
determine the role of the HLA-DRB1 locus on MS disease severity.
Genotyping sets of benign and malignant MS patients showed that
HLA-DRB1*01 was significantly underrepresented in malignant
compared with benign cases. This allele appears to attenuate the
progressive disability that characterizes MS in the long term. The
observation was doubly replicated in (i) Sardinian benign and
malignant patients and (ii) a cohort of affected sibling pairs
discordant for HLA-DRB1*01. Among the latter, mean disability
progression indices were significantly lower in those carrying the
HLA-DRB1*01 allele compared with their disease-concordant siblings
who did not. The findings were additionally supported by
similar transmission distortion of HLA-DRB1*04 subtypes closely
related to HLA-DRB1*01. The protective effect of HLA-DRB1*01 in
sibling pairs may result from a specific epistatic interaction with the
susceptibility allele HLA-DRB1*1501. A high-density (>700) SNP
examination of the MHC region in the benign and malignant
patients could not identify variants differing significantly between
the two groups, suggesting that HLA-DRB1 may itself be the
disease-modifying locus. We conclude that HLA-DRB1*01, previously
implicated in disease resistance, acts as an independent
modifier of disease progression. These results closely link susceptibility
to long-term outcome in MS, suggesting that shared quantitative
MHC-based mechanisms are common to both, emphasizing
the central role of this region in pathogenesis
An extension to a statistical approach for family based association studies provides insights into genetic risk factors for multiple sclerosis in the HLA-DRB1 gene
Background: Multiple sclerosis (MS) is a complex trait in which genes in the MHC class II region exert the single strongest effect on genetic susceptibility. The principal MHC class II haplotype that increases MS risk in individuals of Northern European descent are those that bear HLA-DRB1*15. However, several other HLA-DRB1 alleles have been positively and negatively associated with MS and each of the main allelotypes is composed of many sub-allelotypes with slightly different sequence composition. Given the role of this locus in antigen presentation it has been suggested that variations in the peptide binding site of the allele may underlie allelic variation in disease risk. Methods: In an investigation of 7,333 individuals from 1,352 MS families, we assessed the nucleotide sequence of HLA-DRB1 for any effects on disease susceptibility extending a recently published method of statistical analysis for family-based association studies to the particular challenges of hyper-variable genetic regions. Results: We found that amino acid 60 of the HLA-DRB1 peptide sequence, which had previously been postulated based on structural features, is unlikely to play a major role. Instead, empirical evidence based on sequence information suggests that MS susceptibility arises primarily from amino acid 13. Conclusion: Identifying a single amino acid as a major risk factor provides major practical implications for risk and for the exploration of mechanisms, although the mechanism of amino acid 13 in the HLA-DRB1 sequence's involvement in MS as well as the identity of additional variants on MHC haplotypes that influence risk need to be uncovered
Methylation of class II transactivator gene promoter IV is not associated with susceptibility to Multiple Sclerosis
<p>Abstract</p> <p>Background</p> <p>Multiple sclerosis (MS) is a complex trait in which alleles at or near the class II loci <it>HLA-DRB1 </it>and <it>HLA-DQB1 </it>contribute significantly to genetic risk. The MHC class II transactivator (<it>MHC2TA</it>) is the master controller of expression of class II genes, and methylation of the promoter of this gene has been previously been shown to alter its function. In this study we sought to assess whether or not methylation of the <it>MHC2TA </it>promoter pIV could contribute to MS disease aetiology.</p> <p>Methods</p> <p>In DNA from peripheral blood mononuclear cells from a sample of 50 monozygotic disease discordant MS twins the <it>MHC2TA </it>promoter IV was sequenced and analysed by methylation specific PCR.</p> <p>Results</p> <p>No methylation or sequence variation of the <it>MHC2TA </it>promoter pIV was found.</p> <p>Conclusion</p> <p>The results of this study cannot support the notion that methylation of the pIV promoter of <it>MHC2TA </it>contributes to MS disease risk, although tissue and timing specific epigenetic modifications cannot be ruled out.</p
NLRX1 inhibits the early stages of CNS inflammation and prevents the onset of spontaneous autoimmunity
Nucleotide-binding, leucine-rich repeat containing X1 (NLRX1) is a mitochondria-located innate immune sensor that inhibits major pro-inflammatory pathways such as type I interferon and nuclear factor-ÎșB signaling. We generated a novel, spontaneous, and rapidly progressing mouse model of multiple sclerosis (MS) by crossing myelin-specific T-cell receptor (TCR) transgenic mice with Nlrx1â/â mice. About half of the resulting progeny developed spontaneous experimental autoimmune encephalomyelitis (spEAE), which was associated with severe demyelination and inflammation in the central nervous system (CNS). Using lymphocyte-deficient mice and a series of adoptive transfer experiments, we demonstrate that genetic susceptibility to EAE lies within the innate immune compartment. We show that NLRX1 inhibits the subclinical stages of microglial activation and prevents the generation of neurotoxic astrocytes that induce neuronal and oligodendrocyte death in vitro. Moreover, we discovered several mutations within NLRX1 that run in MS-affected families. In summary, our findings highlight the importance of NLRX1 in controlling the early stages of CNS inflammation and preventing the onset of spontaneous autoimmunity
PRKCA and multiple sclerosis : association in two independent populations
Multiple sclerosis (MS) is a chronic disease of the central nervous system responsible for a large portion of neurological disabilities in young adults. Similar to what occurs in numerous complex diseases, both unknown environmental factors and genetic predisposition are required to generate MS. We ascertained a set of 63 Finnish MS families, originating from a high-risk region of the country, to identify a susceptibility gene within the previously established 3.4-Mb region on 17q24. Initial single nucleotide polymorphism (SNP)-based association implicated PRKCA (protein kinase C alpha) gene, and this association was replicated in an independent set of 148 Finnish MS families (p = 0.0004; remaining significant after correction for multiple testing). Further, a dense set of 211 SNPs evenly covering the PRKCA gene and the flanking regions was selected from the dbSNP database and analyzed in two large, independent MS cohorts: in 211 Finnish and 554 Canadian MS families. A multipoint SNP analysis indicated linkage to PRKCA and its telomeric flanking region in both populations, and SNP haplotype and genotype combination analyses revealed an allelic variant of PRKCA, which covers the region between introns 3 and 8, to be over-represented in Finnish MS cases (odds ratio = 1.34, 95% confidence interval 1.07-1.68). A second allelic variant, covering the same region of the PRKCA gene, showed somewhat stronger evidence for association in the Canadian families (odds ratio = 1.64, 95% confidence interval 1.39-1.94). Initial functional relevance for disease predisposition was suggested by the expression analysis: The transcript levels of PRKCA showed correlation with the copy number of the Finnish and Canadian "risk" haplotypes in CD4-negative mononuclear cells of five Finnish multiplex families and in lymphoblast cell lines of 11 Centre d'Etude du Polymorphisme Humain (CEPH) individuals of European origin
Expression of the Multiple Sclerosis-Associated MHC Class II Allele HLA-DRB1*1501 Is Regulated by Vitamin D
Multiple sclerosis (MS) is a complex trait in which allelic variation in the MHC class II region exerts the single strongest effect on genetic risk. Epidemiological data in MS provide strong evidence that environmental factors act at a population level to influence the unusual geographical distribution of this disease. Growing evidence implicates sunlight or vitamin D as a key environmental factor in aetiology. We hypothesised that this environmental candidate might interact with inherited factors and sought responsive regulatory elements in the MHC class II region. Sequence analysis localised a single MHC vitamin D response element (VDRE) to the promoter region of HLA-DRB1. Sequencing of this promoter in greater than 1,000 chromosomes from HLA-DRB1 homozygotes showed absolute conservation of this putative VDRE on HLA-DRB1*15 haplotypes. In contrast, there was striking variation among nonâMS-associated haplotypes. Electrophoretic mobility shift assays showed specific recruitment of vitamin D receptor to the VDRE in the HLA-DRB1*15 promoter, confirmed by chromatin immunoprecipitation experiments using lymphoblastoid cells homozygous for HLA-DRB1*15. Transient transfection using a luciferase reporter assay showed a functional role for this VDRE. B cells transiently transfected with the HLA-DRB1*15 gene promoter showed increased expression on stimulation with 1,25-dihydroxyvitamin D3 (Pâ=â0.002) that was lost both on deletion of the VDRE or with the homologous âVDREâ sequence found in nonâMS-associated HLA-DRB1 haplotypes. Flow cytometric analysis showed a specific increase in the cell surface expression of HLA-DRB1 upon addition of vitamin D only in HLA-DRB1*15 bearing lymphoblastoid cells. This study further implicates vitamin D as a strong environmental candidate in MS by demonstrating direct functional interaction with the major locus determining genetic susceptibility. These findings support a connection between the main epidemiological and genetic features of this disease with major practical implications for studies of disease mechanism and prevention
- âŠ