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1.
Postepy Biochem ; 65(3): 217-223, 2019 10 01.
Artigo em Polonês | MEDLINE | ID: mdl-31643169

RESUMO

Transposable elements (TEs) are the sequences that are able to "jump" across the genome. They are found in virtually all organisms including human. Although in human, the majority of TEs lost their ability to autonomous transposition, they make up almost half of our genome, and played important roles in genome evolution. Fast progress in deep sequencing and functional analysis has revealed the importance of domes­ticated copies of transposable elements, including their regulatory sequences, transcripts and proteins in normal cells functioning. However, a growing numer of evidence suggest the involvment of TEs in development and progression of autoimmune and neurodegenerative disaeses as well as in many types of cancer. In this review we summarize the current state of knowledge about the LTR retroelements: endogenous retroviruses (ERVs) and Ty3/Gypsy retrotransposons, and their role in human organism.


Assuntos
Genoma Humano/genética , Retroelementos/genética , Doenças Autoimunes/genética , Retrovirus Endógenos/genética , Evolução Molecular , Humanos , Neoplasias/genética , Doenças Neurodegenerativas/genética , Sequências Repetidas Terminais/genética
2.
Isr Med Assoc J ; 21(7): 487-490, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31507126

RESUMO

BACKGROUND: Recurrent pericarditis is a state of repetitive inflammation of the pericardium with intervals of remission. The etiology of recurrent pericarditis is still largely unknown, yet most causes are presumed to be immune mediated. Genetic factors, including human leukocyte antigen (HLA) haplotypes, can be involved in dysregulation of the immune system and as a predisposition to several autoimmune conditions, including recurrent pericarditis. Several diseases are frequently associated with such manifestations. They include systemic lupus erythematosus, familial Mediterranean fever, and tumor necrosis factor receptor-associated periodic syndrome. However, idiopathic recurrent pericarditis remains the most frequently observed clinical condition and the conundrum of this disease still needs to be solved.


Assuntos
Doenças Autoimunes/genética , Predisposição Genética para Doença , Pericardite/fisiopatologia , Febre Familiar do Mediterrâneo/genética , Febre Familiar do Mediterrâneo/imunologia , Antígenos HLA/genética , Haplótipos , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Pericardite/genética , Pericardite/imunologia , Recidiva
3.
Genet Epidemiol ; 43(7): 844-863, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31407831

RESUMO

Epidemiologic studies show an increased risk of non-Hodgkin lymphoma (NHL) in patients with autoimmune disease (AD), due to a combination of shared environmental factors and/or genetic factors, or a causative cascade: chronic inflammation/antigen-stimulation in one disease leads to another. Here we assess shared genetic risk in genome-wide-association-studies (GWAS). Secondary analysis of GWAS of NHL subtypes (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and marginal zone lymphoma) and ADs (rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis). Shared genetic risk was assessed by (a) description of regional genetic of overlap, (b) polygenic risk score (PRS), (c)"diseasome", (d)meta-analysis. Descriptive analysis revealed few shared genetic factors between each AD and each NHL subtype. The PRS of ADs were not increased in NHL patients (nor vice versa). In the diseasome, NHLs shared more genetic etiology with ADs than solid cancers (p = .0041). A meta-analysis (combing AD with NHL) implicated genes of apoptosis and telomere length. This GWAS-based analysis four NHL subtypes and three ADs revealed few weakly-associated shared loci, explaining little total risk. This suggests common genetic variation, as assessed by GWAS in these sample sizes, may not be the primary explanation for the link between these ADs and NHLs.


Assuntos
Doenças Autoimunes/genética , Predisposição Genética para Doença , Linfoma não Hodgkin/genética , Alelos , Feminino , Antígenos HLA/genética , Humanos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
4.
Nat Commun ; 10(1): 2377, 2019 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-31147550

RESUMO

Glycans from microbial pathogens are well known pathogen-associated molecular patterns that are recognized by the host immunity; however, little is known about whether and how mammalian self-glycans activate the host immune response, especially in the context of autoimmune disease. Using biochemical fractionation and two-dimensional HPLC, we identify an abundant and bioactive free glycan, the Manß1-4GlcNAc disaccharide in TREX1-associated autoimmune diseases. We report that both monosaccharide residues and the ß1-4 linkage are critical for bioactivity of this disaccharide. We also show that Manß1-4GlcNAc is produced by oligosaccharyltransferase hydrolysis of lipid-linked oligosaccharides in the ER lumen, followed by ENGase and mannosidase processing in the cytosol and lysosomes. Furthermore, synthetic Manß1-4GlcNAc disaccharide stimulates a broad immune response in vitro, which is in part dependent on the STING-TBK1 pathway, and enhances antibody response in vivo. Together, our data identify Manß1-4GlcNAc as a novel innate immune modulator associated with chronic autoimmune diseases.


Assuntos
Doenças Autoimunes/imunologia , Autoimunidade/imunologia , Dissacarídeos/imunologia , Imunidade Inata/imunologia , Proteínas de Membrana/imunologia , Proteínas Serina-Treonina Quinases/imunologia , Animais , Doenças Autoimunes/genética , Modelos Animais de Doenças , Retículo Endoplasmático , Exodesoxirribonucleases/genética , Fibroblastos , Camundongos , Fosfoproteínas/genética , Células RAW 264.7
5.
Orv Hetil ; 160(15): 563-572, 2019 Apr.
Artigo em Húngaro | MEDLINE | ID: mdl-30957538

RESUMO

MicroRNAs (miRNAs) are 18-25 nucleotide long, single stranded, endogenous, non-coding small RNAs playing an important role in regulating gene expression at posttranscriptional level. miRNAs control approximately 90% of protein-coding genes, and play a central role in various biological processes including immune cell lineage commitment, differentiation, proliferation, apoptosis and maintenance of immune homeostasis. Changes in the expression of certain miRNAs may lead to the development of many diseases, including systemic autoimmune diseases. In this study, we summarize the biogenesis of miRNAs, their role in regulation of the immune system, and review the latest research findings in systemic lupus erythematosus, primary Sjögren's syndrome, rheumatoid arthritis and systemic sclerosis. In the future, miRNAs may help not only in establishing diagnosis and prognosis but potentially serve as targets for modern therapeutic approaches in autoimmune diseases. Orv Hetil. 2019; 160(15): 563-572.


Assuntos
Artrite Reumatoide/genética , Doenças Autoimunes/genética , Lúpus Eritematoso Sistêmico/genética , MicroRNAs/genética , Escleroderma Sistêmico/genética , Síndrome de Sjogren/genética , Artrite Reumatoide/patologia , Doenças Autoimunes/etiologia , Doenças Autoimunes/imunologia , Regulação da Expressão Gênica , Humanos , Lúpus Eritematoso Sistêmico/patologia , MicroRNAs/imunologia , Escleroderma Sistêmico/patologia , Síndrome de Sjogren/patologia
6.
Immunity ; 50(4): 832-850, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995502

RESUMO

The common cytokine receptor γ chain, γc, is a component of the receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21. Mutation of the gene encoding γc results in X-linked severe combined immunodeficiency in humans, and γc family cytokines collectively regulate development, proliferation, survival, and differentiation of immune cells. Here, we review the basic biology of these cytokines, highlighting mechanisms of signaling and gene regulation that have provided insights for immunodeficiency, autoimmunity, allergic diseases, and cancer. Moreover, we discuss how studies of this family stimulated the development of JAK3 inhibitors and present an overview of current strategies targeting these pathways in the clinic, including novel antibodies, antagonists, and partial agonists. The diverse roles of these cytokines on a range of immune cells have important therapeutic implications.


Assuntos
Citocinas/classificação , Subunidade gama Comum de Receptores de Interleucina/genética , Família Multigênica/imunologia , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Citocinas/genética , Citocinas/imunologia , Evolução Molecular , Regulação da Expressão Gênica , Terapia Genética , Humanos , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/terapia , Janus Quinase 3/antagonistas & inibidores , Janus Quinases/antagonistas & inibidores , Janus Quinases/fisiologia , Subpopulações de Linfócitos/imunologia , Camundongos , Terapia de Alvo Molecular , Família Multigênica/genética , Neoplasias/genética , Neoplasias/imunologia , Subunidades Proteicas , Fatores de Transcrição STAT/fisiologia , Transdução de Sinais , Pesquisa Médica Translacional , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/imunologia , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/terapia
7.
Cancer Immunol Immunother ; 68(6): 897-905, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30863922

RESUMO

Immune-checkpoint inhibition (ICI) treatments improve outcomes for metastatic melanoma; however, > 60% of treated patients do not respond to ICI. Current biomarkers do not reliably explain ICI resistance. Given the link between ICI and autoimmunity, we investigated if genetic susceptibility to autoimmunity modulates ICI efficacy. In 436 patients with metastatic melanoma receiving single line ICI or combination treatment, we tested 25 SNPs, associated with > 2 autoimmune diseases in recent genome-wide association studies, for modulation of ICI efficacy. We found that rs17388568-a risk variant for allergy, colitis and type 1 diabetes-was associated with increased anti-PD-1 response, with significance surpassing multiple testing adjustments (OR 0.26; 95% CI 0.12-0.53; p = 0.0002). This variant maps to a locus of established immune-related genes: IL2 and IL21. Our study provides first evidence that autoimmune genetic susceptibility may modulate ICI efficacy, suggesting that systematic testing of autoimmune risk loci could reveal personalized biomarkers of ICI response.


Assuntos
Doenças Autoimunes/terapia , Biomarcadores Tumorais/genética , Predisposição Genética para Doença/genética , Imunoterapia/métodos , Melanoma/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Biomarcadores Tumorais/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Feminino , Células Germinativas/imunologia , Células Germinativas/metabolismo , Humanos , Interleucina-2/genética , Interleucinas/genética , Masculino , Melanoma/genética , Melanoma/imunologia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Polimorfismo de Nucleotídeo Único/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Fatores de Risco
8.
Hum Immunol ; 80(5): 296-301, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30849449

RESUMO

ERAP1 is an aminopeptidase involved in trimming long peptides to the lengths required for presentation by MHC class I. ERAP1 substrate preference is for peptides with hydrophobic or aliphatic N-terminal amino acids, with lower efficacy with charged and small hydrophilic amino acids and almost complete inefficiency with proline. Since ERAP1 efficiently trims peptides to eight amino acids or even shorter, and many MHC-I allotypes can only bind peptides that are eight or nine amino acids or longer, ERAP1 both produces and destroys potential ligands of these alleles. The observation that ERAP1 modulates the levels of presentation for only a subset of the immunopeptidome conflicts with the common assumption that most MHC-I peptides are derived from longer peptides that are produced by the proteasome, transported into the endoplasmic reticulum (ER) by the Transporter Associated Peptide Presentation (TAP) and then trimmed by ERAP1. A more likely mechanism is that cellular protein degradation produces surplus amounts of peptides that fit perfectly and are rapidly loaded onto the MHC, with only a minority of peptides requiring trimming within the ER before loading. Alternatively, ERAP1 may not be present in all ER compartments or vesicles where peptide processing and loading take place and thus affects just a subset of the immunopeptidome.


Assuntos
Aminopeptidases/metabolismo , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos de Histocompatibilidade Menor/metabolismo , Peptídeos/imunologia , Peptídeos/metabolismo , Alelos , Aminopeptidases/genética , Animais , Apresentação do Antígeno , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Autoimunidade , Ativação Enzimática , Haplótipos , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Ligantes , Antígenos de Histocompatibilidade Menor/genética , Ligação Proteica , Proteólise , Relação Estrutura-Atividade
9.
PLoS One ; 14(3): e0213179, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30845238

RESUMO

Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by the accumulation of pulmonary surfactant in alveolar macrophages and alveoli, resulting in respiratory impairment and an increased risk of opportunistic infections. Autoimmune PAP is an autoimmune lung disease that is caused by autoantibodies directed against granulocyte-macrophage colony-stimulating factor (GM-CSF). A shared feature among many autoimmune diseases is a distinct genetic association to HLA alleles. In the present study, we HLA-typed patients with autoimmune PAP to determine if this disease had any HLA association. We analyzed amino acid and allele associations for HLA-A, B, C, DRB1, DQB1, DPB1, DRB3, DRB4 and DRB5 in 41 autoimmune PAP patients compared to 1000 ethnic-matched controls and did not find any HLA association with autoimmune PAP. Collectively, these data may suggest the absence of a genetic association to the HLA in the development of autoimmune PAP.


Assuntos
Doenças Autoimunes/patologia , Antígenos HLA/genética , Proteinose Alveolar Pulmonar/patologia , Adulto , Alelos , Autoanticorpos/sangue , Doenças Autoimunes/genética , Feminino , Frequência do Gene , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Teste de Histocompatibilidade , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Proteinose Alveolar Pulmonar/genética
10.
Nat Commun ; 10(1): 1183, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30862784

RESUMO

T regulatory (Treg) cells maintain immunological tolerance and organ homeostasis. Activated Treg cells differentiate into effector Treg subsets that acquire tissue-specific functions. Ca2+ influx via Ca2+ release-activated Ca2+ (CRAC) channels formed by STIM and ORAI proteins is required for the thymic development of Treg cells, but its function in mature Treg cells remains unclear. Here we show that deletion of Stim1 and Stim2 genes in mature Treg cells abolishes Ca2+ signaling and prevents their differentiation into follicular Treg and tissue-resident Treg cells. Transcriptional profiling of STIM1/STIM2-deficient Treg cells reveals that Ca2+ signaling regulates transcription factors and signaling pathways that control the identity and effector differentiation of Treg cells. In the absence of STIM1/STIM2 in Treg cells, mice develop a broad spectrum of autoantibodies and fatal multiorgan inflammation. Our findings establish a critical role of CRAC channels in controlling lineage identity and effector functions of Treg cells.


Assuntos
Doenças Autoimunes/imunologia , Canais de Cálcio Ativados pela Liberação de Cálcio/fisiologia , Cálcio/metabolismo , Diferenciação Celular/imunologia , Linfócitos T Reguladores/fisiologia , Animais , Autoanticorpos/imunologia , Doenças Autoimunes/genética , Transplante de Medula Óssea , Cátions Bivalentes/metabolismo , Modelos Animais de Doenças , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Molécula 1 de Interação Estromal/genética , Molécula 1 de Interação Estromal/metabolismo , Molécula 2 de Interação Estromal/genética , Molécula 2 de Interação Estromal/metabolismo , Quimeras de Transplante
11.
Drug Metab Pers Ther ; 34(1)2019 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-30840585

RESUMO

Background The thiopurine S-methyltransferase (TPMT)/azathioprine (AZA) gene-drug pair is one of the most well-known pharmacogenetic markers. Despite this, few studies investigated the implementation of TPMT testing and the combined evaluation of genotype and phenotype in multidisciplinary clinical settings where patients are undergoing chronic therapy with AZA. Methods A total of 356 AZA-treated patients for chronic autoimmune diseases were enrolled. DNA was isolated from whole blood and the samples were analyzed for the c.460G>A and c.719A>G variants by the restriction fragment length polymorphism (RFLP) technique and sequenced for the c.238G>C variant. The TPMT enzyme activity was determined in erythrocytes by a high-performance liquid chromatography (HPLC) assay. Results All the patients enrolled were genotyped while the TPMT enzyme activity was assessed in 41 patients. Clinical information was available on 181 patients. We found no significant difference in the odds of having adverse drug reactions (ADRs) in wild-type patients and variant allele carriers, but the latter had an extra risk of experiencing hematologically adverse events. The enzyme activity was significantly associated to genotype. Conclusions TPMT variant allele carriers have an extra risk of experiencing hematologically adverse events compared to wild-type patients. Interestingly, only two out of 30 (6.6%) patients had discordant results between genotype, phenotype and onset of ADRs.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Azatioprina/efeitos adversos , Azatioprina/uso terapêutico , Genótipo , Metiltransferases/genética , Fenótipo , Doenças Autoimunes/enzimologia , Doenças Autoimunes/genética , Cromatografia Líquida de Alta Pressão , Doença Crônica , Eritrócitos/efeitos dos fármacos , Feminino , Humanos , Itália , Masculino , Metiltransferases/metabolismo
12.
Front Biosci (Landmark Ed) ; 24: 870-889, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30844719

RESUMO

Congenital and genetic disorders cause many diseases in Arab countries due to large family sizes and high levels of inbreeding. Saudi Arabia (SA) has the highest consanguinity rates among Middle Eastern countries (~60% of all marriages) and is burdened by the highest number of genetic diseases. Genetic diseases can be life-threatening, often manifesting early in life. Approximately 8% of births in SA are affected, and more common genetic diseases, such as metabolic disease and cancer, manifest later in life in up to 20% of the population. This represents a massive healthcare burden to SA hospitals. The number of genetic disorders in the human population ranges from 7000 to 8000, over 3000 of which are caused by unknown mutations. In 2013, SA initiated the Saudi Human Genome Program (SHGP), which aims to sequence over 100,000 human genomes, with the goal of identifying strategies to discover, prevent, diagnose and treat genetic disorders through precision therapy. High-technology genomics and informatic-based centers that exploit next-generation sequencing (NGS) have now identified mutations underlying many unexplained diseases.


Assuntos
Genoma Humano , Medicina de Precisão/métodos , Análise de Sequência de DNA/métodos , Doenças Autoimunes/genética , Doenças do Sistema Nervoso Central/genética , Anormalidades Congênitas/genética , Consanguinidade , Feminino , Genômica , Humanos , Deficiência Intelectual/genética , Nefropatias/genética , Deformidades Congênitas dos Membros/genética , Masculino , Mutação , Síndromes Neoplásicas Hereditárias/genética , Arábia Saudita
13.
Gene ; 700: 17-22, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-30890477

RESUMO

The weaker expression of the two main proteins adhering melanocytes to the epidermis basal layer, Epithelial Cadherin (E-cadherin) and Discoidin Domain Receptor Tyrosine kinase 1 (DDR1), has been implicated as one of the aggravating factors in the loss of melanocytes in vitiligo. The present study was designed to assess the association between single nucleotide polymorphisms (SNP) in the genes encoding these proteins, CDH1 and DDR1, and the risk of developing vitiligo. The independent case-control study was conducted on the sample including152 patients with vitiligo and 152 matched controls. A questionnaire was completed for recording demographic and clinical characteristics of vitiligo patients. Venous blood samples were taken from all the subjects. Genotype frequencies were determined for CDHI C/T (rs 10431924) and DDRI A/C (rs 2267641) genes polymorphisms using polymerase chain reaction (PCR) amplification method and Restriction Fragment Length Polymorphism (RFLP) analysis. The CDH1 CC genotype was found to be significantly associated with the risk of developing vitiligo. The results of stratified analysis revealed a correlation between CDH1 CC genotype and late age of onset, clinical type of vitiligo, the absence of autoimmune comorbidities and family history of autoimmune disorders. However, the expression level of CDH1 TT genotype increased significantly in patients with autoimmune comorbidities. There was also a significant relationship between the DDR1 CC genotype and the risk of developing vitiligo. The results of stratified analysis revealed a correlation between DDR1 CC genotype and early age of onset, clinical type of vitiligo and absence of family history of autoimmune disorders. The findings of the study confirm the conjecture previously made in the literature regarding the melanocytes' adhesion deficit as an initial step for pigment loss in vitiligo and emphasize the substantial role of friction and koebner phenomenon in the pathogenesis of vitiligo. Moreover, a probable association can be proposed between the adhesion deficit involved in vitiligo and autoimmune disorders.


Assuntos
Antígenos CD/genética , Doenças Autoimunes/genética , Caderinas/genética , Receptor com Domínio Discoidina 1/genética , Polimorfismo de Nucleotídeo Único , Vitiligo/genética , Adulto , Idade de Início , Estudos de Casos e Controles , Comorbidade , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Adulto Jovem
14.
Biomed Pharmacother ; 112: 108583, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30780103

RESUMO

MicroRNAs (miRNAs) are a class of small noncoding RNAs that are only 21-25 nt long. Many studies have shown that miRNA dysfunction is closely related to the occurrence and development of diseases. By combining with the 3' noncoding region of target gene mRNA, miRNAs can mediate the degradation or translation inhibition of mRNA and exert a powerful regulation effect on gene expression at the posttranscriptional level, mainly inhibiting the translation or degradation of targets. Therefore, they are a class of molecules that play a negative regulatory role. Current studies have found that miR-16 is closely related to the occurrence of several autoimmune diseases. Studies have reported that miR-16 participates in the occurrence and development of rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, inflammatory bowel disease, autoimmune thyroid disease, juvenile idiopathic arthritis, primary Sjogren's syndrome and other autoimmune diseases by regulating the expression of cytokines such as TNF-α, IL-8, IL-6, and IL-4; regulating activin A receptor (ACVR), growth differentiation factor-5 (GDF-5) and adenosine A2a receptor (A2AR) expression; affecting the proliferation, differentiation of Th17 cells and Treg cells; and regulating the balance between the cells. In this review, emphasis will be placed on the recent progress in characterizing the roles of miR-16 in these autoimmune diseases.


Assuntos
Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , MicroRNAs/fisiologia , Animais , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Doenças Autoimunes/genética , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Síndrome de Sjogren/genética , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th17/imunologia , Células Th17/metabolismo
16.
Nat Commun ; 10(1): 391, 2019 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-30674883

RESUMO

Vitiligo is an autoimmune disease in which melanocyte destruction causes skin depigmentation, with 49 loci known from previous GWAS. Aiming to define vitiligo subtypes, we discovered that age-of-onset is bimodal; one-third of cases have early onset (mean 10.3 years) and two-thirds later onset (mean 34.0 years). In the early-onset subgroup we found novel association with MHC class II region indel rs145954018, and independent association with the principal MHC class II locus from previous GWAS, represented by rs9271597; greatest association was with rs145954018del-rs9271597A haplotype (P = 2.40 × 10-86, OR = 8.10). Both rs145954018 and rs9271597 are located within lymphoid-specific enhancers, and the rs145954018del-rs9271597A haplotype is specifically associated with increased expression of HLA-DQB1 mRNA and HLA-DQ protein by monocytes and dendritic cells. Thus, for vitiligo, MHC regulatory variation confers extreme risk, more important than HLA coding variation. MHC regulatory variation may represent a significant component of genetic risk for other autoimmune diseases.


Assuntos
Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Genes MHC da Classe II/imunologia , Predisposição Genética para Doença , Haplótipos/imunologia , Vitiligo/genética , Vitiligo/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Células Dendríticas , Feminino , Regulação da Expressão Gênica/genética , Genes MHC da Classe II/genética , Loci Gênicos , Genótipo , Antígenos HLA-DQ/metabolismo , Cadeias beta de HLA-DQ/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Monócitos , Fenótipo , RNA Mensageiro/metabolismo , Regulação para Cima , Adulto Jovem
17.
Genes (Basel) ; 10(2)2019 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-30678091

RESUMO

Genome-wide association studies (GWASes) revealed several single-nucleotide polymorphisms (SNPs) in the human 17q12-21 locus associated with autoimmune diseases. However, follow-up studies are still needed to identify causative SNPs directly mediating autoimmune risk in the locus. We have chosen six SNPs in high linkage disequilibrium with the GWAS hits that showed the strongest evidence of causality according to association pattern and epigenetic data and assessed their functionality in a local genomic context using luciferase reporter system. We found that rs12946510, rs4795397, rs12709365, and rs8067378 influenced the reporter expression level in leukocytic cell lines. The strongest effect visible in three distinct cell types was observed for rs12946510 that is predicted to alter MEF2A/C and FOXO1 binding sites.


Assuntos
Doenças Autoimunes/genética , Cromossomos Humanos Par 17/genética , Polimorfismo de Nucleotídeo Único , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Humanos , Células Jurkat , Desequilíbrio de Ligação , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/metabolismo , Locos de Características Quantitativas
18.
Am J Hum Genet ; 104(1): 55-64, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30598166

RESUMO

Phenome-wide association studies (PheWASs) have been a useful tool for testing associations between genetic variations and multiple complex traits or diagnoses. Linking PheWAS-based associations between phenotypes and a variant or a genomic region into a network provides a new way to investigate cross-phenotype associations, and it might broaden the understanding of genetic architecture that exists between diagnoses, genes, and pleiotropy. We created a network of associations from one of the largest PheWASs on electronic health record (EHR)-derived phenotypes across 38,682 unrelated samples from the Geisinger's biobank; the samples were genotyped through the DiscovEHR project. We computed associations between 632,574 common variants and 541 diagnosis codes. Using these associations, we constructed a "disease-disease" network (DDN) wherein pairs of diseases were connected on the basis of shared associations with a given genetic variant. The DDN provides a landscape of intra-connections within the same disease classes, as well as inter-connections across disease classes. We identified clusters of diseases with known biological connections, such as autoimmune disorders (type 1 diabetes, rheumatoid arthritis, and multiple sclerosis) and cardiovascular disorders. Previously unreported relationships between multiple diseases were identified on the basis of genetic associations as well. The network approach applied in this study can be used to uncover interactions between diseases as a result of their shared, potentially pleiotropic SNPs. Additionally, this approach might advance clinical research and even clinical practice by accelerating our understanding of disease mechanisms on the basis of similar underlying genetic associations.


Assuntos
Doença/genética , Registros Eletrônicos de Saúde , Estudos de Associação Genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Doenças Autoimunes/genética , Doenças Cardiovasculares/genética , Epigenômica , Humanos
19.
Hum Mol Genet ; 28(8): 1369-1380, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30541027

RESUMO

The role of somatic variants in diseases beyond cancer is increasingly being recognized, with potential roles in autoinflammatory and autoimmune diseases. However, as mutation rates and allele fractions are lower, studies in these diseases are substantially less tolerant of false positives, and bio-informatics algorithms require high replication rates. We developed a pipeline combining two variant callers, MuTect2 and VarScan2, with technical filtering and prioritization. Our pipeline detects somatic variants with allele fractions as low as 0.5% and achieves a replication rate of >55%. Validation in an independent data set demonstrates excellent performance (sensitivity > 57%, specificity > 98%, replication rate > 80%). We applied this pipeline to the autoimmune disease multiple sclerosis (MS) as a proof-of-principle. We demonstrate that 60% of MS patients carry 2-10 exonic somatic variants in their peripheral blood T and B cells, with the vast majority (80%) occurring in T cells and variants persisting over time. Synonymous variants significantly co-occur with non-synonymous variants. Systematic characterization indicates somatic variants are enriched for being novel or very rare in public databases of germline variants and trend towards being more damaging and conserved, as reflected by higher phred-scaled combined annotation-dependent depletion (CADD) and genomic evolutionary rate profiling (GERP) scores. Our pipeline and proof-of-principle now warrant further investigation of common somatic genetic variation on top of inherited genetic variation in the context of autoimmune disease, where it may offer subtle survival advantages to immune cells and contribute to the capacity of these cells to participate in the autoimmune reaction.


Assuntos
Doenças Autoimunes/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Análise de Sequência de DNA/métodos , Imunidade Adaptativa/genética , Adulto , Algoritmos , Alelos , Biologia Computacional/métodos , Análise Mutacional de DNA , Feminino , Variação Genética/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único/genética , Reprodutibilidade dos Testes , Software
20.
Cancer Lett ; 443: 108-114, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30529154

RESUMO

MicroRNAs (miRNAs) are essential factors of an extensively conserved post-transcriptional process to regulate gene expression. MiRNAs play a pivotal role in immunity, including controlling the differentiation of various immune cells as well as their immunological functions. The miR-183 cluster, which is comprised of miR-183, -96 and -182, is a miRNA family with sequence homology. These miRNAs are usually transcribed together as a polycistronic miRNA cluster during development and are required for maturation of sensory organs. In comparison to defined sensory-specific role of these miRNAs in normal development, they are frequently over-expressed in several non-sensory diseases, including autoimmune diseases and cancers. Because individual miRNAs of miR-183 cluster have both common and unique targets within functionally interrelated pathways, they can show cooperative or opposing effects on biological processes, implying the complexity of this miR cluster-mediated gene regulation. Therefore, a better understanding of the molecular regulation of miR-183 cluster expression and its downstream networks is important for the therapeutic applications. In this review, we will discuss the characteristics of miR-183 cluster and a wide variety of evidence on its function in immune system. Newer knowledge summarized here will help readers understand the versatile role of miR-183 cluster in this field.


Assuntos
Imunidade , MicroRNAs/genética , Animais , Doenças Autoimunes/genética , Regulação da Expressão Gênica no Desenvolvimento , Redes Reguladoras de Genes , Humanos , Família Multigênica , Neoplasias/genética , Neoplasias/imunologia
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