scholarly journals IL-6, IL-12, and IL-23 STAT-Pathway Genetic Risk and Responsiveness of Lymphocytes in Patients with Multiple Sclerosis

Cells ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 285 ◽  
Author(s):  
Marina von Essen ◽  
Helle Søndergaard ◽  
Eva Petersen ◽  
Finn Sellebjerg
Keyword(s):  
Multiple Sclerosis ◽  
Th17 Cells ◽  
Demyelinating Disease ◽  
Association Studies ◽  
Cell Types ◽  
Genome Wide Association Studies ◽  
Risk Alleles ◽  
Risk Snps ◽  
Donor Variation ◽  
Stat Pathway

Multiple sclerosis (MS) is an immune-mediated demyelinating disease characterized by central nervous system (CNS) lymphocyte infiltration, abundant production of pro-inflammatory cytokines, and inappropriate activation of Th1 and Th17 cells, B cells, and innate immune cells. The etiology of MS is complex, and genetic factors contribute to disease susceptibility. Genome-wide association studies (GWAS) have revealed numerous MS-risk alleles in the IL-6/STAT3, IL-12/STAT4, and IL-23/STAT3-pathways implicated in the differentiation of Th1 and Th17 cells. In this study, we investigated the signaling properties of these pathways in T, B, and NK cells from patients with relapsing-remitting MS (RRMS) and healthy controls, and assessed the genetic contribution to the activity of the pathways. This revealed a great variability in the level of STAT-pathway molecules and STAT activation between the cell types investigated. We also found a strong donor variation in IL-6, IL-12, and IL-23 responsiveness of primed CD4+ T cells. This variation could not be explained by a single MS-risk variant in a pathway component, or by an accumulation of multiple STAT-pathway MS-risk SNPs. The data of this study suggests that other factors in cohesion with the genetic background contribute to the responsiveness of the IL-6/STAT3, IL-12/STAT4, and IL-23/STAT3-pathways.

scholarly journals An investigation of genetic polymorphisms in Heparan Sulfate Proteoglycan core proteins and key modification enzymes in an Australian Caucasian multiple sclerosis population

2020 ◽  
Author(s):  
Rachel K Okolicsanyi ◽  
Julia Bluhm ◽  
Cassandra Miller ◽  
Lyn R Griffiths ◽  
Larisa M Haupt
Keyword(s):  
Multiple Sclerosis ◽  
Cell Surface ◽  
Heparan Sulfate ◽  
Demyelinating Disease ◽  
Core Protein ◽  
Association Studies ◽  
International Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Core Proteins

Abstract Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease affecting the central nervous system in young adults. Heparan sulfate proteoglycans (HSPGs) are ubiquitous to the cell surface and the extracellular matrix. HSPG biosynthesis is a complex process involving enzymatic attachment of heparan sulfate (HS) chains to a core protein. HS side chains mediate specific ligand and growth factor interactions directing cellular processes including cell adhesion, migration and differentiation. Two main families of HSPGs exist, the syndecans (SDC1-4) and glypicans (GPC1-6). The SDCs are transmembrane proteins, while the GPC family are GPI-linked to the cell surface. SDC1 has well-documented interactions with numerous signalling pathways. Genome wide association studies (GWAS) have identified regions of the genome associated with MS including a region on chromosome 13 containing GPC5 and GPC6. International studies have revealed significant associations between this region and disease development. Exostosin-1 (EXT1) and sulfatase-1 (SULF1) are two enzymes responsible for the generation of HS chains. EXT1, with documented tumour suppressor properties, is involved in initiation and polymerisation of the growing HS chain. SULF1 removes 6- O -sulfate groups from HS chains, thereby affecting protein-ligand interactions and subsequent downstream signalling with HS modification potentially having significant effects on MS progression. In this study we identified significant associations between single nucleotide polymorphisms in SDC1, GPC5 and GPC6 and MS in an Australian Caucasian case control population. Further significant associations in these genes were identified when the population was stratified by sex and disease subtype. No association was found for EXT1 or SULF1.

scholarly journals Schizophrenia Risk Alleles Often Affect The Expression of Many Genes and Each Gene May Have a Different Effect On The Risk; A Mediation Analysis

2020 ◽  
Author(s):  
Xi Peng ◽  
Joel S. Bader ◽  
Dimitrios Avramopoulos
Keyword(s):  
Gene Expression ◽  
Mediation Analysis ◽  
Target Genes ◽  
Risk Allele ◽  
Association Studies ◽  
Cell Types ◽  
Developmental Time ◽  
Genome Wide Association Studies ◽  
Expression Change ◽  
Risk Alleles

ABSTRACTVariants identified by genome-wide association studies (GWAS) are often expression quantitative trait loci (eQTLs), suggesting they are proxies or are themselves regulatory. Across many datasets analyses show that variants often affect multiple genes. Lacking data on many tissue types, developmental time points and homogeneous cell types, the extent of this one-to-many relationship is underestimated. This raises questions on whether a disease eQTL target gene explains the genetic association or is a by-stander and puts into question the direction of expression effect of on the risk, since the many variant - regulated genes may have opposing effects, imperfectly balancing each other. We used two brain gene expression datasets (CommonMind and BrainSeq) for mediation analysis of schizophrenia-associated variants. We confirm that eQTL target genes often mediate risk but the direction in which expression affects risk is often different from that in which the risk allele changes expression. Of 38 mediator genes significant in both datasets 33 showed consistent mediation direction (Chi2 test P=6*10−6). One might expect that the expression would correlate with the risk allele in the same direction it correlates with disease. For 15 of these 33 (45%), however, the expression change associated with the risk allele was protective, suggesting the likely presence of other target genes with overriding effects. Our results identify specific risk mediating genes and suggest caution in interpreting the biological consequences of targeted modifications of gene expression, as not all eQTL targets may be relevant to disease while those that are, might have different than expected directions.

scholarly journals Mapping genomic loci prioritises genes and implicates synaptic biology in schizophrenia

2020 ◽  
Author(s):  
◽  
Stephan Ripke ◽  
James TR Walters ◽  
Michael C O'Donovan
Keyword(s):  
Developmental Disorder ◽  
Association Studies ◽  
Cell Types ◽  
Genome Wide Association Studies ◽  
Biological Processes ◽  
Neuronal Function ◽  
Protein Coding ◽  
Risk Alleles ◽  
Genome Wide ◽  
Coding Variants

Schizophrenia is a psychiatric disorder whose pathophysiology is largely unknown. It has a heritability of 60-80%, much of which is attributable to common risk alleles, suggesting genome-wide association studies can inform our understanding of aetiology. Here, in 69,369 people with schizophrenia and 236,642 controls, we report common variant associations at 270 distinct loci. Using fine-mapping and functional genomic data, we prioritise 19 genes based on protein-coding or UTR variation, and 130 genes in total as likely to explain these associations. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in autism and developmental disorder. Associations were concentrated in genes expressed in CNS neurons, both excitatory and inhibitory, but not other tissues or cell types, and implicated fundamental processes related to neuronal function, particularly synaptic organisation, differentiation and transmission. We identify biological processes of pathophysiological relevance to schizophrenia, show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders, and provide a rich resource of priority genes and variants to advance mechanistic studies.

scholarly journals An investigation of genetic polymorphisms in Heparan Sulfate Proteoglycan core proteins and key modification enzymes in an Australian Caucasian multiple sclerosis population

2020 ◽  
Author(s):  
Rachel K Okolicsanyi ◽  
Julia Bluhm ◽  
Cassandra Miller ◽  
Lyn R Griffiths ◽  
Larisa M Haupt
Keyword(s):  
Multiple Sclerosis ◽  
Cell Surface ◽  
Heparan Sulfate ◽  
Demyelinating Disease ◽  
Core Protein ◽  
Association Studies ◽  
International Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Core Proteins

Abstract Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease affecting the central nervous system in young adults. Heparan sulfate proteoglycans (HSPGs) are ubiquitous to the cell surface and the extracellular matrix. HSPG biosynthesis is a complex process involving enzymatic attachment of heparan sulfate (HS) chains to a core protein. HS side chains mediate specific ligand and growth factor interactions directing cellular processes including cell adhesion, migration and differentiation. Two main families of HSPGs exist, the syndecans (SDC1-4) and glypicans (GPC1-6). The SDCs are transmembrane proteins, while the GPC family are GPI-linked to the cell surface. SDC1 has well-documented interactions with numerous signalling pathways. Genome wide association studies (GWAS) have identified regions of the genome associated with MS including a region on chromosome 13 containing GPC5 and GPC6. International studies have revealed significant associations between this region and disease development. The exostosin-1 (EXT1) and sulfatase-1 (SULF1) are key enzymes contributing to the generation of HS chains. EXT1, with documented tumour suppressor properties, is involved in initiation and polymerisation of the growing HS chain. SULF1 removes 6- O -sulfate groups from HS chains, affecting protein-ligand interactions and subsequent downstream signalling with HS modification potentially having significant effects on MS progression. In this study we identified significant associations between single nucleotide polymorphisms in SDC1, GPC5 and GPC6 and MS in an Australian Caucasian case control population. Further significant associations in these genes were identified when the population was stratified by sex and disease subtype. No association was found for EXT1 or SULF1.

scholarly journals Host Genetics and Gut Microbiome: Perspectives for Multiple Sclerosis

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1181
Author(s):  
Alessandro Maglione ◽  
Miriam Zuccalà ◽  
Martina Tosi ◽  
Marinella Clerico ◽  
Simona Rolla
Keyword(s):  
Multiple Sclerosis ◽  
Environmental Factors ◽  
Lupus Erythematosus ◽  
Gut Microbiome ◽  
Complex Disease ◽  
Current Knowledge ◽  
Association Studies ◽  
Future Research ◽  
Genome Wide Association Studies ◽  
Host Genetics

As a complex disease, Multiple Sclerosis (MS)’s etiology is determined by both genetic and environmental factors. In the last decade, the gut microbiome has emerged as an important environmental factor, but its interaction with host genetics is still unknown. In this review, we focus on these dual aspects of MS pathogenesis: we describe the current knowledge on genetic factors related to MS, based on genome-wide association studies, and then illustrate the interactions between the immune system, gut microbiome and central nervous system in MS, summarizing the evidence available from Experimental Autoimmune Encephalomyelitis mouse models and studies in patients. Finally, as the understanding of influence of host genetics on the gut microbiome composition in MS is in its infancy, we explore this issue based on the evidence currently available from other autoimmune diseases that share with MS the interplay of genetic with environmental factors (Inflammatory Bowel Disease, Rheumatoid Arthritis and Systemic Lupus Erythematosus), and discuss avenues for future research.

scholarly journals Involvement of astrocyte and oligodendrocyte gene sets in migraine

Cephalalgia ◽  
2015 ◽  
Vol 36 (7) ◽  
pp. 640-647 ◽  
Author(s):  
Else Eising ◽  
Christiaan de Leeuw ◽  
Josine L Min ◽  
Verneri Anttila ◽  
Mark HG Verheijen ◽  
...  
Keyword(s):  
Migraine With Aura ◽  
Genetic Background ◽  
Migraine Without Aura ◽  
Protein Modification ◽  
Association Studies ◽  
Cell Types ◽  
Familial Hemiplegic Migraine ◽  
Genome Wide Association Studies ◽  
Brain Disorder ◽  
Gene Sets

Background Migraine is a common episodic brain disorder characterized by recurrent attacks of severe unilateral headache and additional neurological symptoms. Two main migraine types can be distinguished based on the presence of aura symptoms that can accompany the headache: migraine with aura and migraine without aura. Multiple genetic and environmental factors confer disease susceptibility. Recent genome-wide association studies (GWAS) indicate that migraine susceptibility genes are involved in various pathways, including neurotransmission, which have already been implicated in genetic studies of monogenic familial hemiplegic migraine, a subtype of migraine with aura. Methods To further explore the genetic background of migraine, we performed a gene set analysis of migraine GWAS data of 4954 clinic-based patients with migraine, as well as 13,390 controls. Curated sets of synaptic genes and sets of genes predominantly expressed in three glial cell types (astrocytes, microglia and oligodendrocytes) were investigated. Discussion Our results show that gene sets containing astrocyte- and oligodendrocyte-related genes are associated with migraine, which is especially true for gene sets involved in protein modification and signal transduction. Observed differences between migraine with aura and migraine without aura indicate that both migraine types, at least in part, seem to have a different genetic background.

scholarly journals Atrial fibrillation associated common risk variants in SYNE2 lead to lower expression of nesprin-2α1 and increased nuclear stiffness

2019 ◽  
Author(s):  
Nana Liu ◽  
Jeffrey Hsu ◽  
Gautam Mahajan ◽  
Han Sun ◽  
John Barnard ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Association Studies ◽  
Dominant Negative ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Gene Encoding ◽  
Enhancer Activity ◽  
Risk Alleles ◽  
Risk Variants ◽  
Lower Expression

ABSTRACTRationaleAtrial fibrillation (AF) genome-wide association studies (GWAS) identified significant associations for rs1152591 and linked variants in the SYNE2 gene encoding the nesprin-2 protein that connects the nuclear membrane with the cytoskeletonObjectiveDetermine the effects of the AF-associated rs1152591 and rs1152595, two linked intronic single nucleotide polymorphisms (SNPs), on SYNE2 expression and investigate the mechanisms for their association with AF.Methods and ResultsRNA sequencing of human left atrial appendage (LAA) tissues indicated that rs1152591 and rs1152595 were significantly associated with the expressions of SYNE2α1, a short mRNA isoform, without an effect on the expression of the full-length SYNE2 mRNA. SYNE2α1 mRNA uses an alternative transcription start site and encodes an N-terminal deleted 62 kDa nesprin-2α1 isoform, which can act as a dominant-negative on nuclear-cytoskeleton connectivity. Western blot and qPCR assays confirmed that AF risk alleles of both SNPs were associated with lower expression of nesprin-2α1 in human LAA tissues. Reporter gene transfections demonstrated that the risk vs. reference alleles of rs1152591 and rs1152595 had decreased enhancer activity. SYNE2 siRNA knockdown (KD) or nesprin-2α1 overexpression studies in human stem cell-derived induced cardiomyocytes (iCMs) resulted in ~12.5 % increases in the nuclear area compared to controls (p<0.001). Atomic force microscopy demonstrated that SYNE2 KD or nesprin-2α1 overexpression led to 57.5% or 33.2% decreases, respectively, in nuclear stiffness compared to controls (p< 0.0001).ConclusionsAF-associated SNPs rs1152591 and rs1152595 downregulate the expression of SYNE2α1, increasing nuclear-cytoskeletal connectivity and nuclear stiffness. The resulting increase in mechanical stress may play a role in the development of AF.

scholarly journals Genetic and Real-World Clinical Data, Combined with Empirical Validation, Nominate Jak-Stat Signaling as a Target for Alzheimer’s Disease Therapeutic Development

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 425 ◽  
Author(s):  
Alejo J. Nevado-Holgado ◽  
Elena Ribe ◽  
Laura Thei ◽  
Laura Furlong ◽  
Miguel-Angel Mayer ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Data ◽  
Real World ◽  
Association Studies ◽  
Rna Expression ◽  
Genome Wide Association Studies ◽  
Rodent Models ◽  
Therapeutic Development ◽  
Stat Pathway

As genome-wide association studies (GWAS) have grown in size, the number of genetic variants that have been associated per disease has correspondingly increased. Despite this increase in the number of single-nucleotide polymorphisms (SNPs) identified per disease, their biological interpretation has in many cases remained elusive. To address this, we have combined GWAS results with orthogonal sources of evidence, namely the current knowledge of molecular pathways; real-world clinical data from six million patients; RNA expression across tissues from Alzheimer’s disease (AD) patients, and purpose-built rodent models for experimental validation. In more detail, first we show that when examined at a pathway level, analysis of all GWAS studies groups AD in a cluster with disorders of immunity and inflammation. Using clinical data, we show that the degree of comorbidity of these diseases with AD correlates with the strength of their genetic association with molecular participants in the Janus kinases/signal transducer and activator of transcription (JAK-STAT) pathway. Using four independent RNA expression datasets we then find evidence for the altered regulation of JAK-STAT pathway genes in AD. Finally, we use both in vitro and in vivo rodent models to demonstrate that Aβ induces gene expression of the key drivers of this pathway, providing experimental evidence to validate these data-driven observations. These results therefore nominate JAK-STAT anomalies as a prominent aetiopathological event in AD and hence a potential target for therapeutic development, and moreover demonstrate a de novo multi-modal approach to derive information from rapidly increasing genomic datasets.

scholarly journals Analysis of putative cis-regulatory elements regulating blood pressure variation

2020 ◽  
Vol 29 (11) ◽  
pp. 1922-1932
Author(s):  
Priyanka Nandakumar ◽  
Dongwon Lee ◽  
Thomas J Hoffmann ◽  
Georg B Ehret ◽  
Dan Arking ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Association Studies ◽  
Specific Effect ◽  
Cell Types ◽  
Regulatory Elements ◽  
Open Chromatin ◽  
Genome Wide Association Studies ◽  
Cell Type ◽  
Functional Scores ◽  
Cell Type Specific

Abstract Hundreds of loci have been associated with blood pressure (BP) traits from many genome-wide association studies. We identified an enrichment of these loci in aorta and tibial artery expression quantitative trait loci in our previous work in ~100 000 Genetic Epidemiology Research on Aging study participants. In the present study, we sought to fine-map known loci and identify novel genes by determining putative regulatory regions for these and other tissues relevant to BP. We constructed maps of putative cis-regulatory elements (CREs) using publicly available open chromatin data for the heart, aorta and tibial arteries, and multiple kidney cell types. Variants within these regions may be evaluated quantitatively for their tissue- or cell-type-specific regulatory impact using deltaSVM functional scores, as described in our previous work. We aggregate variants within these putative CREs within 50 Kb of the start or end of ‘expressed’ genes in these tissues or cell types using public expression data and use deltaSVM scores as weights in the group-wise sequence kernel association test to identify candidates. We test for association with both BP traits and expression within these tissues or cell types of interest and identify the candidates MTHFR, C10orf32, CSK, NOV, ULK4, SDCCAG8, SCAMP5, RPP25, HDGFRP3, VPS37B and PPCDC. Additionally, we examined two known QT interval genes, SCN5A and NOS1AP, in the Atherosclerosis Risk in Communities Study, as a positive control, and observed the expected heart-specific effect. Thus, our method identifies variants and genes for further functional testing using tissue- or cell-type-specific putative regulatory information.

scholarly journals An Intergenic rs9275596 Polymorphism on Chr. 6p21 Is Associated with Multiple Sclerosis in Latvians

Medicina ◽  
2020 ◽  
Vol 56 (4) ◽  
pp. 154 ◽  
Author(s):  
Natalia Paramonova ◽  
Ilva Trapina ◽  
Kristine Dokane ◽  
Jolanta Kalnina ◽  
Tatjana Sjakste ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Autoimmune Diseases ◽  
Functional Significance ◽  
Structural Changes ◽  
Association Studies ◽  
Cumulative Effect ◽  
Chronic Inflammatory Disease ◽  
Genome Wide Association Studies ◽  
Rare Alleles ◽  
Mental Symptoms

Background and objectives: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system, leading to demyelination of neurons and potentially debilitating physical and mental symptoms. The disease is more prevalent in women than in men. The major histocompatibility complex (MHC) region has been identified as a major genetic determinant for autoimmune diseases, and its role in some neurological disorders including MS was evaluated. An intergenic single-nucleotide polymorphism (SNP), rs9275596, located between the HLA-DQB1 and HLA-DQA2 genes, is in significant association with various autoimmune diseases according to genome-wide association studies (GWASs). A cumulative effect of this SNP with other polymorphisms from this region was revealed. The aim of the study was to verify the data on rs9275596 association in multiple sclerosis in a case/control study of the Latvian population and to evaluate eventual functional significance of allele substitutions. Materials and Methods: rs9275596 (chr6:32713854; GRCh38.p12) was genotyped in 273 MS patients and 208 controls on main and sex-specific associations. Eventual functional significance of allele substitutions was evaluated in silico using publicly available tools. Results: The rs9275596 rare alleles were identified as a disease susceptibility factor in association with the MS main group and in affected females (p < 0.001 and p < 0.01, respectively). Risk factor genotypes with rare alleles included were associated with the MS common cohort (p < 0.002) and female cohort (odds ratio, OR = 2.24) and were identified as disease susceptible in males (OR = 2.41). It was shown that structural changes of rs9275596 affect the secondary structure of DNA. Functional significance of allele substitutions was evaluated on the eventual sequence affinity to transcription factors (TFs) and splicing signals similarity. A possible impact of the particular polymorphisms on the transcription and splicing efficiency is discussed. Conclusions: Our results suggest susceptibility of rs9275596 to multiple sclerosis in Latvians.

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