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Multiple sclerosis (MS) is a chronic autoimmune inflammatory and neurodegenerative disease of the central nervous system, which is characterized by significant clinical heterogeneity. Primary progressive MS (PPMS) develops in 10-15% of patients. Unlike the most common relapsing-remitting form of MS, PPMS involves steady progress of neurodegeneration and, as a consequence, a persistent gradual increase in neurological symptoms. The peculiarities of epigenetic regulation of gene expression may be one of the reasons for the differences in the pathogenesis of the two MS forms. DNA methylation is one of the key epigenetic mechanisms, which remains almost unexplored in different cell populations of PPMS patients. The goal of this work was to identify differential methylation profiles of the CpG sites in the CD14+ monocyte DNA, which characterize PPMS. A genome-wide analysis of DNA methylation in PPMS patients and healthy individuals has identified 169 differentially methylated positions (DMPs), 90.5% of which were hypermethylated in PPMS patients. More than half of all DMPs are located in/near known genes and within CpG islands and their neighboring regions, which indicates their high functional significance. We have found six differentially methylated regions (DMRs) in the OR2L13, CAT, LCLAT1, HOXA5, RNF39, and CRTAC1 genes involved in inflammation and neurodegeneration, which indicates active epigenetic regulation of their expression.
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Esclerosis Múltiple Crónica Progresiva , Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Enfermedades Neurodegenerativas , Humanos , Esclerosis Múltiple/genética , Esclerosis Múltiple Crónica Progresiva/genética , Esclerosis Múltiple Recurrente-Remitente/genética , Epigénesis Genética , Metilación de ADN , Monocitos , Enfermedades Neurodegenerativas/genética , Proteínas de Unión al Calcio/genéticaRESUMEN
OBJECTIVE: To study the whole-genome DNA methylation profiles of peripheral blood mononuclear blood cells (PBMCs) of patients with relapsing-remitting multiple sclerosis (RRMS) in remission and relapse in order to assess the contribution of this epigenetic mechanism of gene expression regulation to the activity of the pathological process. MATERIAL AND METHODS: Eight patients with RRMS in remission and 6 patients in relapse were included in the study. Methylation levels of DNA CpG sites in PBMCs were analyzed using Infinium HumanMethylation450 BeadChip DNA microarrays. RESULTS: Seven differentially methylated positions (DMPs) were identified, of which 3 were hypermethylated (cg02981003, cg18486102, cg19533582) and 4 were hypomethylated (cg16814680, cg1964802, cg18584440, cg08291996) during RRMS relapse. Five DMPs are located in protein-coding genes (GPR123, FAIM2, BTNL2, ZNF8, ASAP2), one in microRNA gene (MIR548N), and one in an intergenic region. For all identified DMPs, we observed a change in DNA methylation levels of more than 20% (range 20.2-57.5%). Hierarchical clustering of DNA samples on the heatmap shows their clear aggregation into separate clusters corresponding to RRMS patients in the stages of relapse and remission. CONCLUSION: For the first time it was shown that during relapse and remission of RRMS there are differences in the DNA methylation profile that allow discrimination between these clinical stages. These data indicate the involvement of the epigenetic mechanism of DNA methylation in the activation of the pathological process in RRMS.
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Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Humanos , Esclerosis Múltiple/genética , Metilación de ADN , Leucocitos Mononucleares/patología , Esclerosis Múltiple Recurrente-Remitente/genética , Enfermedad Crónica , ADN , Recurrencia , Butirofilinas/genética , Proteínas Activadoras de GTPasa/genética , Factores de Transcripción de Tipo Kruppel/genéticaRESUMEN
The pathogenesis of multiple sclerosis (MS), a chronic disease of the CNS, includes autoimmune and neurodegenerative components. In most cases, patients develop relapsing-remitting MS (RRMS), while 10-15% of patients develop primary progressive MS (PPMS), which differs from RRMS in the mechanisms of the pathological process, some demographic, and some clinical characteristics. These differences may be explained by the epigenetic regulation of gene expression in PPMS including DNA methylation as one of the key epigenetic processes. The features of DNA methylation in various cell populations in PPMS patients remain understudied. The goal of this study is to identify differentially methylated CpG sites (DMSs) of the genome of CD4+ T lymphocytes, which characterize PPMS. The study included eight treatment-naive PPMS patients and eight healthy controls. Genome-wide analysis of DNA methylation of CD4+ T lymphocytes was performed using high-density DNA microarrays. We have identified 108 DMSs, which distinguish PPMS patients from healthy controls. In PPMS patients 81% of the DMSs are hypermethylated. More than a half of the identified DMSs are located in known genes in CpG islands and adjacent regions, which indicates a high functional significance of these DMSs in PPMS development. Analysis of the overrepresentation of DMS-containing genes in the main biological processes demonstrates their involvement in the regulation of cell adhesion to the extracellular matrix and the development of the immune response, i.e., antigen processing and presentation, and development of the immune system. Genome-wide analysis of DNA methylation in CD4+ T lymphocytes of PPMS patients indicates the involvement of this epigenetic process in the immunopathogenesis of the disease. These results may help better understand the pathogenesis of this severe form of MS.
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Esclerosis Múltiple Crónica Progresiva , Esclerosis Múltiple , Linfocitos T CD4-Positivos/metabolismo , Metilación de ADN , Epigénesis Genética , Humanos , Esclerosis Múltiple/genética , Esclerosis Múltiple Crónica Progresiva/genéticaRESUMEN
There is increasing evidence that the interaction of the mitochondrial and nuclear genomes substantially affects the risk of neurodegenerative diseases. The role of mitonuclear interactions in the development of multiple sclerosis, a severe chronic neurodegenerative disease of a polygenic nature, is poorly understood. In this work, we analyzed the association of multiple sclerosis with two-component mitonuclear combinations that include each of seven polymorphic variants of the nuclear genome localized in the region of the UCP2, and KIF1B genes and in the PVT1 locus (MYC, PVT1, and MIR1208 genes) and each often polymorphisms of the mitochondrial genome, as well as individual genetic variants that make up these combinations. Association of the individual components of these combinations with multiple sclerosis was also evaluated. 507 patients with multiple sclerosis and 321 healthy individuals were enrolled in the study, all participants were ethnic Russians. Two mitonuclear combinations associated with multiple sclerosis were identified: the UCP2 (rs660339)*A + MT-ATP6 (rs193303045)*G combination was characterized by p-value = 0.015 and OR= 1.39 [95% CI 1.05-1.87], and the PVT1 (rs2114358)*G + MT-ND1 (rs1599988)*С combination - by p-value = 0.012 and OR = 1.77 [95% CI 1.10-2.84]. Only one of the individual components of these combinations, allele rs660339*A of the nuclear gene UCP2 encoding uncoupling protein 2 of the mitochondrial anion carrier family, was independently associated with multiple sclerosis (p = 0.028; OR = 1.36 [95% CI 1.01-1.84]). This study expands the current understanding of the role of mitonuclear interactions and variance of nuclear genes, whose products function in mitochondria, and in risk of MS.
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Genoma Mitocondrial , Esclerosis Múltiple , Enfermedades Neurodegenerativas , Núcleo Celular/genética , ADN Mitocondrial , Humanos , Esclerosis Múltiple/genética , Polimorfismo de Nucleótido SimpleRESUMEN
The epigenetic mechanisms of gene expression regulation are a group of the key cellular and molecular pathways that lead to inherited alterations in genes' activity without changing their coding sequence. DNA methylation at the C5 position of cytosine in CpG dinucleotides is amongst the central epigenetic mechanisms. Currently, the number of studies that are devoted to the identification of methylation patterns specific to multiple sclerosis (MS), a severe chronic autoimmune disease of the central nervous system, is on a rapid rise. However, the issue of the contribution of DNA methylation to the development of the different clinical phenotypes of this highly heterogeneous disease has only begun to attract the attention of researchers. This review summarizes the data on the molecular mechanisms underlying DNA methylation and the MS risk factors that can affect the DNA methylation profile and, thereby, modulate the expression of the genes involved in the disease's pathogenesis. The focus of our attention is centered on the analysis of the published data on the differential methylation of DNA from various biological samples of MS patients obtained using both the candidate gene approach and high-throughput methods.
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Recently, it has been shown that dysfunction of mitochondria is an important component of the molecular mechanisms of the development of many neurodegenerative diseases. These include multiple sclerosis, a chronic autoimmune and neurodegenerative disease of the central nervous system, which is characterized by clinical heterogeneity. The role of genetic variability of mitochondrial DNA in the development of various clinical forms of multiple sclerosis is poorly understood. The aim of present study was to analyze the association often mitochondrial DNA single nucleotide polymorphisms and the nine most common European mitochondrial haplogroups (H, J, K, U, T, I, V, W and X) with a severe and relatively rare multiple sclerosis disease form-primary progressive multiple sclerosis. 110 patients with primary progressive multiple sclerosis and 406 healthy controls were enrolled in the study, all ethnic Russians. For the first time association of the m.12308*G (rs2853498) variant (P = 0.024) and haplogroup U (P = 0.0004, passes the adjustment for multiple comparisons: Pcorr = 0.0076) with primary progressive multiple sclerosis was shown. Comparison of these data with the results of our previous study [1], that was focused on the role of mitochondrial genome variability in susceptibility to the most common form of multiple sclerosis, relapsing-remitting multiple sclerosis, leads to the conclusion that two different mitochondrial haplogroups, U and J, are involved in the development of two different clinical forms of multiple sclerosis. The results may contribute to the identification of new targets for the treatment of primary progressive multiple sclerosis, for which there is no effective pathogenetic treatment at the moment.
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ADN Mitocondrial/genética , Genoma Mitocondrial , Esclerosis Múltiple , Enfermedades Neurodegenerativas , Estudios de Casos y Controles , Haplotipos , Humanos , Esclerosis Múltiple/genética , Enfermedades Neurodegenerativas/genética , Polimorfismo de Nucleótido Simple , Federación de RusiaRESUMEN
Increased sensitivity and availability of magnetic resonance imaging (MRI) in neurological routine practice led to the fact that more and more experts began to encounter changes typical for multiple sclerosis (MS) according to MRI in the absence of anamnestic and clinical indications of damage to the central nervous system (CNS). This nosological form has been defined as a radiologically isolated syndrome (RIS). More and more RIS cases convert to MS (up to 30% in the first 5 years after RIS diagnosis). At the moment, there are no biological markers that allow combining RIS and MS into one pathological process and early treatment with disease-modifying drugs (DMT). Prospective studies are actively being conducted to identify demographic, clinical, neuroimaging and biochemical conversion predictors. The identification of the molecular biological RIS features, combining these changes with MS, is an urgent scientific task and will allow timely initiation of therapy of the pathological process already at the subclinical stage.
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Enfermedades Desmielinizantes , Esclerosis Múltiple , Humanos , Imagen por Resonancia Magnética , Pronóstico , Estudios ProspectivosRESUMEN
The review discusses the role of mitochondria in multiple sclerosis (MS). Previously, damage to the mitochondria was regarded as a manifestation of secondary damage to axons and neurons, i.e. as a marker of neurodenegation. Recently, the role of mitochondria in the early stages of MS development, when they could participate in the activation of innate immunity and trigger activation of autoimmune responses of acquired immunity, has been increasingly discussed. The role of polymorphism mitochondrial DNA changes in MS is discussed.
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Mitocondrias , Esclerosis Múltiple , Axones , Humanos , Inmunidad Innata , NeuronasRESUMEN
Pharmacogenetics (PG) investigates the inherited variants of the human genome that underlie individual differences in drug metabolic transformation, delivery, and mechanism of action. Not only the contributions of individual genes, but also their cumulative effect should be considered in the case of polygenic diseases, which include the majority of human diseases. Multiple sclerosis (MS) is a severe autoimmune neurodegenerative disorder of the central nervous system (CNS) and is polygenic in nature. Understanding the role that the immune system plays in the pathogenesis of MS helped to design drugs for its pathogenetic therapy. These drugs are known as the disease-modifying treatments (DMTs). Among these are interferon ß (IFN-ß) and glatiramer acetate (GA), whose treatment efficacy and long-term safety have been proven in many clinical trials. However their efficacy on MS course varies from highly effective to lack of response. Prognostic genetic biomarkers of treatment efficacy can help to identify the MS patient groups where a particular drug is preferential or even strictly indicated to use. The review summarizes the findings from pharmacogenetic studies evaluating the efficacy of IFN-ß and GA in MS patients, including the author's original data.
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Herencia Multifactorial/genética , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/genética , Farmacogenética , Medicina de Precisión , Marcadores Genéticos , Acetato de Glatiramer/uso terapéutico , Humanos , Interferón beta/uso terapéuticoRESUMEN
Genetic analysis of thousands of patients with multiple sclerosis (MS) and healthy Russian donors showed that the carriage of groups of HLA-DRB1*15 and HLA-DRB1*03 alleles is associated with the risk of MS, whereas the carriage of groups of HLA-DRB1*01 and HLA-DRB1*11 alleles is protective. Recombinant HLA-DRB1*01:01 with a high affinity can recognize the fragments of myelin basic protein (MBP), one of the autoantigens in MS. However, the comparison of the kinetic parameters of the load of MBP and viral HA peptides on HLA-DRB1*01:01, which is catalyzed by HLA-DM, showed a significantly lower rate of exchange of CLIP for MBP peptides. We assume that the observed protective properties of the group of HLA-DRB1*01 alleles may be directly associated with the ability of HLA-DRB1*01:01 to kinetically distinguish peptides of exogenous and endogenous nature.
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Autoantígenos/metabolismo , Cadenas HLA-DRB1/metabolismo , Esclerosis Múltiple/metabolismo , Proteína Básica de Mielina/metabolismo , Péptidos/metabolismo , Autoantígenos/química , Autoantígenos/genética , Femenino , Cadenas HLA-DRB1/química , Cadenas HLA-DRB1/genética , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/genética , Proteína Básica de Mielina/química , Proteína Básica de Mielina/genética , Péptidos/química , Péptidos/genéticaRESUMEN
Multiple sclerosis is a chronic disease of the central nervous system, combining in its pathogenesis both autoimmune and neurodegenerative components, and is characterized by a highly heterogeneous clinical phenotype. Genetic susceptibility to the development of the most common relapsing-remitting course of the disease is extensively studied, while the genetic architecture of the aggressive primary progressive course of multiple sclerosis remains poorly understood. We analyzed the association of polymorphic variants in miRNA genes MIR146A, MIR196A2, and MIR499A with the risk of primary progressive multiple sclerosis one by one and in biallelic combinations with variants of immune-related genes; the analysis was performed in comparison with healthy individuals and with relapsing-remitting multiple sclerosis patients. The allele MIR196A2*C was useful in discriminating between two main courses of multiple sclerosis, one by one and in combination with alleles of the IFNAR2, IL7RA, IL6, PVT1, CD86, CCL5, and PSMB9 genes. The data presented in the current work may be used for the construction of a biomarker panel, to differentiate primary progressive and relapsing-remitting courses of multiple sclerosis on the initial stages of the disease.
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Predisposición Genética a la Enfermedad , MicroARNs/genética , Esclerosis Múltiple Crónica Progresiva/genética , Polimorfismo Genético , Alelos , Humanos , Factores de RiesgoRESUMEN
Functional disruption and neuronal loss followed by progressive dysfunction of the nervous system underlies the pathogenesis of numerous disorders defined as "neurodegenerative diseases". Multiple sclerosis, a chronic inflammatory demyelinating disease of the central nervous system resulting in serious neurological dysfunctions and disability, is one of the most common neurodegenerative diseases. Recent studies suggest that disturbances in mitochondrial functioning are key factors leading to neurodegeneration. In this review, we consider data on mitochondrial dysfunctions in multiple sclerosis, which were obtained both with patients and with animal models. The contemporary data indicate that the axonal degeneration in multiple sclerosis largely results from the activation of Ca2+-dependent proteases and from misbalance of ion homeostasis caused by energy deficiency. The genetic studies analyzing association of mitochondrial DNA polymorphic variants in multiple sclerosis suggest the participation of mitochondrial genome variability in the development of this disease, although questions of the involvement of individual genomic variants are far from being resolved.
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Mitocondrias/patología , Esclerosis Múltiple/patología , Animales , Genoma Mitocondrial/genética , Humanos , Mitocondrias/genética , Esclerosis Múltiple/genética , Neuronas/patologíaRESUMEN
For the first time in the history of ethnic Russians, an association analysis the development of multiple sclerosis (MS) was performed for the mitochondrial haplogroups H, J, K, and U, as well as for the individual mitochondrial DNA (mtDNA) polymorphisms discriminating these haplogroups (m.1719G > A, m. 7028C > T, m.9055G > A, m.10398A > G, m.12308A > G). A total of 283 unrelated patients with the relapsing-remitting form of MS and 290 healthy controls were enrolled in the study. Association of haplogroup J with MS was observed (P = 0.0055, OR = 2.00 [95% CI 1.21-3.41]). After gender stratification, the association remained significant in women (P = 0.0083, OR = 2.20 [95% CI 1.19-4.03]). A multilocus analysis of the association between combinations of mtDNA haplogroups with variants of 38 nuclear immune-related genes and MS risk was carried out. MS-associated biallelic combinations of haplogroup J with the alleles CCL5 rs2107538*A, PVT1 rs2114358*G, TNFSF14 rs1077667*C, and IL4 rs2243250*C, which were not associated with MS individually, were identified. For the combination of haplogroup J and the CCL5*A allele (P = 0.00043, OR = 5.47 [95% CI 1.85-16.15]), a epistatic (synergistic) interaction between the components was established using two statistical criteria: the PFLINT value in the Fisher-like interaction numeric test and the synergy factor, SF (PFLINT = 0.025, SF = 4.32 [95% CI 1.20-15.60]). The combination of haplogroup J and the PVT1*G allele is characterized by PFLINT = 0.084; SF = 3.05 [95% CI 1.00-9.31] and can also be epistatic. Thus, interaction between nuclear and mitochondrial genome components in the risk of developing MS was demonstrated for the first time.
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AIM: To analyze the involvement of immune response genes in the pathogenesis of primary progressive multiple sclerosis (PPMS). MATERIAL AND METHODS: This multicenter study included 111 patients with PPMS from the Russian ethnic group. The association of PPMS with genes of immune system was analyzed by the study of polymorphic variants of genes of cytokines and genes of antigen-presenting cells. RESULTS AND CONCLUSION: The genotypes of IL-4 (rs2243250)*C/C and CLEC16A (rs6498169)*G/G were associated with PPMS in Russians. The association between the HLA-DRB1*15 and PPMS found out in other populations was confirmed in Russians.
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Interleucina-4 , Lectinas Tipo C , Proteínas de Transporte de Monosacáridos , Esclerosis Múltiple Crónica Progresiva , Genotipo , Humanos , Interleucina-4/genética , Lectinas Tipo C/genética , Proteínas de Transporte de Monosacáridos/genética , Esclerosis Múltiple Crónica Progresiva/genética , Esclerosis Múltiple Crónica Progresiva/inmunología , Factores de Riesgo , Federación de RusiaRESUMEN
In search of genetic markers of myocardial infarction (MI) risk, which have prognostic significance for Russians, we performed a replication study of MI association with genetic variants of PCSK9 (rs562556), APOE (epsilon polymorphism, rs7412 and rs429358), LPL (rs320), MTHFR (rs1801133), eNOS (rs2070744), and the 9p21 region (rs1333049) in 405 patients with MI and 198 controls. Significant MI association was observed with variants of the lipid metabolism genes (PCSK9, APOE and LPL), and of eNOS. The SNPs in the MTHFR gene and the 9p21 region were not significantly associated with MI one by one but were included in several different MI-associated allelic combinations identified by multilocus analysis. Since we have not revealed nonlinear epistatic interactions between the components of the identified combinations, we postulate that the cumulative effect of genes that form a combination arises from the summation of their small independent contributions. The prognostic significance of the additive composite model built from the PCSK9, APOE, LPL, and eNOS genes as genetic markers was assessed using ROC analysis. After we included these markers in the previously published composite model of individual genetic risk of MI, the prognostic efficacy in our sample reached AUC = 0.676. However, the results obtained in this study certainly need to be replicated in an independent sample of Russians.
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Multiple sclerosis (MS) is a severe neurodegenerative disease of polygenic etiology affecting the central nervous system. In addition to genetic factors, epigenetic mechanisms, primarily DNA methylation, which regulate gene expression, play an important role in MS development and progression. In this study, we have performed the first whole-genome DNA methylation profiling of peripheral blood mononuclear cells in relapsing-remitting MS (RRMS) and primary-progressive MS (PPMS) patients and compared them to those of healthy individuals in order to identify the differentially methylated CpG-sites (DMSs) associated with these common clinical disease courses. In addition, we have performed a pairwise comparison of DNA methylation profiles in RRMS and PPMS patients. All three pairwise comparisons showed significant differences in methylation profiles. Hierarchical clustering of the identified DMS methylation levels and principal component analysis for data visualization demonstrated a clearly defined aggregation of DNA samples of the compared groups into separate clusters. Compared with the control, more DMSs were identified in PPMS patients than in RRMS patients (67 and 30, respectively). More than half of DMSs are located in genes, exceeding the expected number for random distribution of DMSs between probes. RRMS patients mostly have hypomethylated DMSs, while in PPMS patients DMSs are mostly hypermethylated. CpG-islands and CpG-shores contain 60% of DMSs, identified by pairwise comparison of RRMS and control groups, and 79% of those identified by pairwise comparison of PPMS and control groups. Pairwise comparison of patients with two clinical MS courses revealed 51 DMSs, 82% of which are hypermethylated in PPMS. Overall, it was demonstrated that there are more changes in the DNA methylation profiles in PPMS than in RRMS. The data confirm the role of DNA methylation in MS development. We have shown, for the first time, that DNA methylation as an epigenetic mechanism is involved in the formation of two distinct clinical courses of MS: namely, RRMS and PPMS.
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MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression at the post-transcriptional level through base-pairing predominantly with a 3'-untranslated region of target mRNA, followed by mRNA degradation or translational repression. Totally, miRNAs change, through a complex regulatory network, the expression of more than 60% of human genes. MiRNAs are key regulators of the immune response that affect maturation, proliferation, differentiation, and activation of immune cells, as well as antibody secretion and release of inflammatory mediators. Disruption of this regulation may lead to the development of various pathological conditions, including autoimmune inflammation. This review summarizes the data on biogenesis and the mechanisms of miRNA action. We discuss the role of miRNAs in the development and the action of the immune system, as well as in the development of an autoimmune inflammatory response. Special attention is given to the role of miRNAs in the autoimmune inflammation in multiple sclerosis, which is a serious socially significant disease of the central nervous system. Currently, a lot of research is focused on this problem.
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AIM: To study the association of polymorphisms in the IL2RA and TNFRSF1A genes with severity and early clinical manifestations of remitted multiple sclerosis (MS). MATERIAL AND METHODS: Five hundred and eight patients of Russian ethnicity with bout-onset MS were genotyped for IL7RA (rs6897932), IL2RA (rs2104286) and TNFRSF1A (rs1800693) polymorphisms. Association analysis of the gene variants with disease severity, variants of MS manifestation, and first remission duration was performed. RESULTS AND CONCLUSION: Dividing the MS patients by disease severity, estimated with the MSSS, we found a significant increase in the TNFRSF1A*T/T genotype carriage in patients with milder MS course (MSSS≤3), and, respectively, in the TNFRSF1A*C allele carriage in patients with moderate to severe MS (MSSS> 3). Dividing the MS patients into two groups according to their MS manifestation variants, we revealed a significant increase in the TNFRSF1A*T allele carriage in patients with favorable variants of MS manifestation (optic neuritis or sensory disturbances), and of the TNFRSF1A*C/C genotype in patients with unfavorable variants (motor disorders, brain stem disorders, impaired coordination, pelvic disorders, mental disorders or polysymptomatic onset). No associations with first remission duration were observed. Multi-locus analysis to search for allelic combinations associated with the studied clinical features of MS was applied. In this analysis, a polymorphic variant of CTLA4 gene (rs231775), for which we have previously reported the association of the CTLA4*G allele with short first remission (less than 1 year), was also included. The carriage of biallelic combination (CTLA4*G + TNFRSF1A*C) was associated with short first remission more significantly than the carriage of CTLA4*G by itself. One more biallelic combination associated with short first remission (CTLA4*G/G + IL7RA*T), was identified. No other biallelic combinations significantly associated with the clinical features studied were observed.
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Subunidad alfa del Receptor de Interleucina-2/genética , Esclerosis Múltiple/genética , Polimorfismo Genético , Receptores de Interleucina-7/genética , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Alelos , Antígeno CTLA-4/genética , Etnicidad , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Polimorfismo de Nucleótido Simple , Federación de RusiaRESUMEN
Multiple sclerosis (MS) is a common complex neurodegenerative disease of the central nervous system. It develops with autoimmune inflammation and demyelination. Genome-wide association studies (GWASs) serve as a powerful tool for investigating the genetic architecture of MS and are generally used to identify the genetic factors of disease susceptibility, clinical phenotypes, and treatment response. This review considers the main achievements and challenges of using GWAS to identify the genes involved in MS. It also describes hypothesis-driven studies with extensive genome coverage of the selected regions, complementary to GWASs. To date, over 100 MS risk loci have been identified by the combination of both approaches; 40 of them were found in at least two GWASs and meet genome-wide significance threshold (p ≤ 5 × 10(-8)) in at least one GWAS, whereas the threshold for the rest of GWASs was set in our review at p < 1 × 10(-5). Yet, MS risk loci identified to date explain only a part of the total heritability, and the reasons of "missing heritability" are discussed. The functions of MS-associated genes are described briefly; the majority of them encode immune-response proteins involved in the main stages of MS pathogenesis.
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Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Esclerosis Múltiple/genética , Sitios Genéticos , Estudio de Asociación del Genoma Completo/estadística & datos numéricos , Humanos , Modelos Genéticos , Esclerosis Múltiple/epidemiología , Polimorfismo de Nucleótido SimpleRESUMEN
Multiple sclerosis (MS) is a chronic neuro-inflammatory disease of complex etiology. The results of GWAS, a high-throughput method to discover genetic architecture of MS, require replication in independent ethnic groups. We performed a replication study of nine GWAS-identified SNPs in immune response in Russians. Associations of CLEC16A and IL2RA with MS were validated. Besides, we observed the associations of CLEC16A and IRF8 in women, and IL7RA and CD58 in men. With multi-locus association analysis two protective biallelic combinations: (TNFRSF1A*T+CLEC16A*A) and (TNFRSF1A*T+IRF8*A) were identified in women. Associations of CLEC16A*G/G and both biallelic combinations in women with MS survived the permutation test.