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1.
Sci Rep ; 11(1): 4011, 2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33597588

RESUMO

Juvenile idiopathic arthritis (JIA) is one of the most common chronic diseases in children. While clinical outcomes for patients with juvenile JIA have improved, the underlying biology of the disease and mechanisms underlying therapeutic response/non-response are poorly understood. We have shown that active JIA is associated with distinct transcriptional abnormalities, and that the attainment of remission is associated with reorganization of transcriptional networks. In this study, we used a multi-omics approach to identify mechanisms driving the transcriptional abnormalities in peripheral blood CD4+ T cells of children with active JIA. We demonstrate that active JIA is associated with alterations in CD4+ T cell chromatin, as assessed by ATACseq studies. However, 3D chromatin architecture, assessed by HiChIP and simultaneous mapping of CTCF anchors of chromatin loops, reveals that normal 3D chromatin architecture is largely preserved. Overlapping CTCF binding, ATACseq, and RNAseq data with known JIA genetic risk loci demonstrated the presence of genetic influences on the observed transcriptional abnormalities and identified candidate target genes. These studies demonstrate the utility of multi-omics approaches for unraveling important questions regarding the pathobiology of autoimmune diseases.

2.
Genome Biol ; 21(1): 281, 2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33213505

RESUMO

BACKGROUND: Systemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease characterized by the development of anti-nuclear antibodies. Susceptibility to SLE is multifactorial, with a combination of genetic and environmental risk factors contributing to disease development. Like other polygenic diseases, a significant proportion of estimated SLE heritability is not accounted for by common disease alleles analyzed by SNP array-based GWASs. Death-associated protein 1 (DAP1) was implicated as a candidate gene in a previous familial linkage study of SLE and rheumatoid arthritis, but the association has not been explored further. RESULTS: We perform deep sequencing across the DAP1 genomic segment in 2032 SLE patients, and healthy controls, and discover a low-frequency functional haplotype strongly associated with SLE risk in multiple ethnicities. We find multiple cis-eQTLs embedded in a risk haplotype that progressively downregulates DAP1 transcription in immune cells. Decreased DAP1 transcription results in reduced DAP1 protein in peripheral blood mononuclear cells, monocytes, and lymphoblastoid cell lines, leading to enhanced autophagic flux in immune cells expressing the DAP1 risk haplotype. Patients with DAP1 risk allele exhibit significantly higher autoantibody titers and altered expression of the immune system, autophagy, and apoptosis pathway transcripts, indicating that the DAP1 risk allele mediates enhanced autophagy, leading to the survival of autoreactive lymphocytes and increased autoantibody. CONCLUSIONS: We demonstrate how targeted sequencing captures low-frequency functional risk alleles that are missed by SNP array-based studies. SLE patients with the DAP1 genotype have distinct autoantibody and transcription profiles, supporting the dissection of SLE heterogeneity by genetic analysis.

3.
Front Genet ; 11: 784, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32774345

RESUMO

Nearest-neighbor Projected-Distance Regression (NPDR) is a feature selection technique that uses nearest-neighbors in high dimensional data to detect complex multivariate effects including epistasis. NPDR uses a regression formalism that allows statistical significance testing and efficient control for multiple testing. In addition, the regression formalism provides a mechanism for NPDR to adjust for population structure, which we apply to a GWAS of systemic lupus erythematosus (SLE). We also test NPDR on benchmark simulated genetic variant data with epistatic effects, main effects, imbalanced data for case-control design and continuous outcomes. NPDR identifies potential interactions in an epistasis network that influences the SLE disorder.

4.
Transl Psychiatry ; 10(1): 282, 2020 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-32788574

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

5.
Arthritis Rheumatol ; 72(5): 780-790, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31804013

RESUMO

OBJECTIVE: Genetic variants in the region of tumor necrosis factor-induced protein 3-interacting protein 1 (TNIP1) are associated with autoimmune disease and reduced TNIP1 gene expression. The aim of this study was to define the functional genetic mechanisms driving TNIP1 hypomorphic expression imparted by the systemic lupus erythematosus-associated TNIP1 H1 risk haplotype. METHODS: Dual luciferase expression and electrophoretic mobility shift assays were used to evaluate the allelic effects of 11 risk variants on enhancer function and nuclear protein binding in immune cell line models (Epstein-Barr virus [EBV]-transformed human B cells, Jurkat cells, and THP-1 cells), left in a resting state or stimulated with phorbol 12-myristate 13-acetate/ionomycin. HiChIP was used to define the regulatory 3-dimensional (3-D) chromatin network of the TNIP1 haplotype by detecting in situ long-range DNA contacts associated with H3K27ac-marked chromatin in EBV B cells. Then, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to determine the expression of genes within the 3-D chromatin network. RESULTS: Bioinformatics analyses of 50 single-nucleotide polymorphisms on the TNIP1 H1 risk haplotype identified 11 non-protein-coding variants with a high likelihood of influencing TNIP1 gene expression. Eight variants in EBV B cells, 5 in THP-1 cells, and 2 in Jurkat cells exhibited various allelic effects on enhancer activation, resulting in a cumulative suppressive effect on TNIP1 expression (net effect of risk variants -7.14 fold, -6.80 fold, and -2.44 fold, respectively; n > 3). Specifically, in EBV B cells, only 2 variants (rs10057690 and rs13180950) exhibited allele-specific loss of both enhancer activity and nuclear protein binding (each P < 0.01 relative to nonrisk alleles). In contrast, the rs10036748 risk allele reduced binding affinities of the transcriptional repressors basic helix-loop-helix family member 40/differentially expressed in chondrocytes 1 (bHLHe40/DEC1) (P < 0.05 relative to nonrisk alleles) and CREB-1 (P not significant) in EBV B cells, resulting in a gain of enhancer activity (P < 0.05). HiChIP and qRT-PCR analyses revealed that overall transcriptional repression of the TNIP1 haplotype extended to the neighboring genes DCTN4 and GMA2, both of which also showed decreased expression in the presence of the TNIP1 risk haplotype (P < 0.001 and P < 0.01, respectively, relative to the nonrisk haplotype); notably, it was found that these genes share a 3-D chromatin network. CONCLUSION: Hypomorphic TNIP1 expression results from the combined concordant and opposing effects of multiple risk variants carried on the TNIP1 risk haplotype, with the strongest regulatory effect in B lymphoid lineage cells. Furthermore, the TNIP1 risk haplotype effect extends to neighboring genes within a shared chromatin network.


Assuntos
Proteínas de Ligação a DNA/genética , Lúpus Eritematoso Sistêmico/genética , Linfócitos B , Cromatina , Expressão Gênica , Haplótipos , Humanos , Medição de Risco
6.
Ann Rheum Dis ; 78(9): 1235-1241, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31217170

RESUMO

OBJECTIVE: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with unknown aetiology. Epstein-Barr virus (EBV) is an environmental factor associated with SLE. EBV maintains latency in B cells with frequent reactivation measured by antibodies against viral capsid antigen (VCA) and early antigen (EA). In this study, we determined whether EBV reactivation and single nucleotide polymorphisms (SNPs) in EBV-associated host genes are associated with SLE transition. METHODS: SLE patient relatives (n=436) who did not have SLE at baseline were recontacted after 6.3 (±3.9) years and evaluated for interim transitioning to SLE (≥4 cumulative American College of Rheumatology criteria); 56 (13%) transitioned to SLE prior to the follow-up visit. At both visits, detailed demographic, environmental, clinical information and blood samples were obtained. Antibodies against viral antigens were measured by ELISA. SNPs in IL10, CR2, TNFAIP3 and CD40 genes were typed by ImmunoChip. Generalised estimating equations were used to test associations between viral antibody levels and transitioning to SLE. RESULTS: Mean baseline VCA IgG (4.879±1.797 vs 3.866±1.795, p=0.0003) and EA IgG (1.192±1.113 vs 0.7774±0.8484, p=0.0236) levels were higher in transitioned compared with autoantibody negative non-transitioned relatives. Increased VCA IgG and EA IgG were associated with transitioning to SLE (OR 1.28 95% CI 1.07 to 1.53, p=0.007, OR 1.43 95% CI 1.06 to 1.93, p=0.02, respectively). Significant interactions were observed between CD40 variant rs48100485 and VCA IgG levels and IL10 variant rs3024493 and VCA IgA levels in transitioning to SLE. CONCLUSION: Heightened serologic reactivation of EBV increases the probability of transitioning to SLE in unaffected SLE relatives.


Assuntos
Anticorpos Antivirais/imunologia , Antígenos Virais/imunologia , Autoimunidade , Infecções por Herpesviridae/imunologia , Herpesvirus Humano 4/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Infecções por Herpesviridae/virologia , Humanos , Lúpus Eritematoso Sistêmico/virologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco
7.
EBioMedicine ; 42: 76-85, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30952617

RESUMO

BACKGROUND: Autoimmune disease prevention requires tools to assess an individual's risk of developing a specific disease. One tool is disease-associated autoantibodies, which accumulate in an asymptomatic preclinical period. However, patients sometimes exhibit autoantibodies associated with a different disease classification. When and how these alternative autoantibodies first appear remain unknown. This cross-sectional study characterizes alternative autoimmunity, and associated genetic and environmental factors, in unaffected first-degree relatives (FDRs) of patients, who exhibit increased future risk for the same disease. METHODS: Samples (n = 1321) from disease-specific autoantibody-positive (aAb+) systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and type 1 diabetes (T1D) patients; and unaffected aAb+ and autoantibody-negative (aAb-) SLE and RA FDRs were tested for SLE, RA, and T1D aAbs, as well as anti-tissue transglutaminase, anti-cardiolipin and anti-thyroperoxidase. FDR SLE and RA genetic risk scores (GRS) were calculated. FINDINGS: Alternative autoimmunity occurred in SLE patients (56%) and FDRs (57·4%), RA patients (32·6%) and FDRs (34·8%), and T1D patients (43%). Expanded autoimmunity, defined as autoantibodies spanning at least two other diseases, occurred in 18·5% of SLE patients, 16·4% of SLE FDRs, 7·8% of RA patients, 5·3% of RA FDRs, and 10·8% of T1D patients. SLE FDRs were more likely to have alternative (odds ratio [OR] 2·44) and expanded (OR 3·27) autoimmunity than RA FDRs. Alternative and expanded autoimmunity were associated with several environmental exposures. Alternative autoimmunity was associated with a higher RA GRS in RA FDRs (OR 1·41), and a higher SLE GRS in aAb+ RA FDRs (OR 1·87), but not in SLE FDRs. INTERPRETATION: Autoimmunity commonly crosses disease-specific boundaries in systemic (RA, SLE) and organ-specific (T1D) autoimmune diseases. Alternative autoimmunity is more common in SLE FDRs than RA FDRs, and is influenced by genetic and environmental factors. These findings have substantial implications for preclinical disease pathogenesis and autoimmune disease prevention studies. FUND: NIH U01AI101981, R01AR051394, U19AI082714, P30AR053483, P30GM103510, U54GM104938, U01AI101934, R01AI024717, U01AI130830, I01BX001834, & U01HG008666.


Assuntos
Artrite Reumatoide/etiologia , Autoimunidade/genética , Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/etiologia , Núcleo Familiar , Adulto , Idoso , Alelos , Artrite Reumatoide/diagnóstico , Autoanticorpos/imunologia , Meio Ambiente , Feminino , Frequência do Gene , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Masculino , Pessoa de Meia-Idade , Especificidade de Órgãos/imunologia , Polimorfismo de Nucleotídeo Único , Fatores de Risco
8.
Genes Immun ; 20(4): 281-292, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-29904099

RESUMO

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus triggered by immune hypersensitivity to food. Herein, we tested whether genetic risk factors for known, non-allergic, immune-mediated diseases, particularly those involving autoimmunity, were associated with EoE risk. We used the high-density Immunochip platform, encoding 200,000 genetic variants for major auto-immune disease. Accordingly, 1214 subjects with EoE of European ancestry and 3734 population controls were genotyped and assessed using data directly generated or imputed from the previously published GWAS. We found lack of association of EoE with the genetic variants in the major histocompatibility complex (MHC) class I, II, and III genes and nearly all other loci using a highly powered study design with dense genotyping throughout the locus. Importantly, we identified an EoE risk locus at 16p13 with genome-wide significance (Pcombined=2.05 × 10-9, odds ratio = 0.76-0.81). This region is known to encode for the genes CLEC16A, DEXI, and CIITI, which are expressed in immune cells and esophageal epithelial cells. Suggestive EoE risk were also seen 5q23 (intergenic) and 7p15 (JAZF1). Overall, we have identified an additional EoE risk locus at 16p13 and highlight a shared and unique genetic etiology of EoE with a spectrum of immune-associated diseases.


Assuntos
Cromossomos Humanos Par 16/genética , Esofagite Eosinofílica/genética , Loci Gênicos , Polimorfismo Genético , Proteínas de Ligação a DNA/genética , Humanos , Lectinas Tipo C/genética , Proteínas de Membrana/genética , Proteínas de Transporte de Monossacarídeos/genética , Proteínas Nucleares/genética , Transativadores/genética
9.
Arthritis Res Ther ; 20(1): 216, 2018 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-30268153

RESUMO

Genome-wide association studies (GWAS) and fine mapping studies in autoimmune diseases have identified thousands of genetic variants, the majority of which are located in non-protein-coding enhancer regions. Enhancers function within the context of the three-dimensional (3D) genome to form long-range DNA looping events with target gene promoters that spatially and temporally regulate gene expression. Investigating the functional significance of GWAS variants in the context of the 3D genome is essential for mechanistic understanding of these variants and how they influence disease pathology by altering DNA looping between enhancers and the target gene promoters they regulate. In this review, we discuss the functional complexity of the 3D genome and the technological approaches used to characterize DNA looping events. We then highlight examples from the literature that illustrate how functional mapping of the 3D genome can assist in defining mechanisms that influence pathogenic gene expression. We conclude by highlighting future advances necessary to fully integrate 3D genome analyses into the functional workup of GWAS variants in the continuing effort to improve the health of patients with autoimmune diseases.


Assuntos
Cromatina/química , Cromatina/genética , Predisposição Genética para Doença/genética , Genoma Humano/genética , Estudo de Associação Genômica Ampla/métodos , Conformação Molecular , Humanos , Regiões Promotoras Genéticas/genética
10.
Transl Psychiatry ; 8(1): 180, 2018 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-30185774

RESUMO

Genomic variation underlying major depressive disorder (MDD) likely involves the interaction and regulation of multiple genes in a network. Data-driven co-expression network module inference has the potential to account for variation within regulatory networks, reduce the dimensionality of RNA-Seq data, and detect significant gene-expression modules associated with depression severity. We performed an RNA-Seq gene co-expression network analysis of mRNA data obtained from the peripheral blood mononuclear cells of unmedicated MDD (n = 78) and healthy control (n = 79) subjects. Across the combined MDD and HC groups, we assigned genes into modules using hierarchical clustering with a dynamic tree cut method and projected the expression data onto a lower-dimensional module space by computing the single-sample gene set enrichment score of each module. We tested the single-sample scores of each module for association with levels of depression severity measured by the Montgomery-Åsberg Depression Scale (MADRS). Independent of MDD status, we identified 23 gene modules from the co-expression network. Two modules were significantly associated with the MADRS score after multiple comparison adjustment (adjusted p = 0.009, 0.028 at 0.05 FDR threshold), and one of these modules replicated in a previous RNA-Seq study of MDD (p = 0.03). The two MADRS-associated modules contain genes previously implicated in mood disorders and show enrichment of apoptosis and B cell receptor signaling. The genes in these modules show a correlation between network centrality and univariate association with depression, suggesting that intramodular hub genes are more likely to be related to MDD compared to other genes in a module.


Assuntos
Transtorno Depressivo Maior/genética , Redes Reguladoras de Genes , RNA Mensageiro/análise , Adulto , Sequência de Bases , Estudos de Casos e Controles , Análise por Conglomerados , Feminino , Variação Genética , Humanos , Leucócitos Mononucleares , Modelos Logísticos , Masculino , Escalas de Graduação Psiquiátrica , Índice de Gravidade de Doença , Adulto Jovem
11.
Hum Mol Genet ; 27(21): 3813-3824, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30085094

RESUMO

Genetic variation within the major histocompatibility complex (MHC) contributes substantial risk for systemic lupus erythematosus, but high gene density, extreme polymorphism and extensive linkage disequilibrium (LD) have made fine mapping challenging. To address the problem, we compared two association techniques in two ancestrally diverse populations, African Americans (AAs) and Europeans (EURs). We observed a greater number of Human Leucocyte Antigen (HLA) alleles in AA consistent with the elevated level of recombination in this population. In EUR we observed 50 different A-C-B-DRB1-DQA-DQB multilocus haplotype sequences per hundred individuals; in the AA sample, these multilocus haplotypes were twice as common compared to Europeans. We also observed a strong narrow class II signal in AA as opposed to the long-range LD observed in EUR that includes class I alleles. We performed a Bayesian model choice of the classical HLA alleles and a frequentist analysis that combined both single nucleotide polymorphisms (SNPs) and classical HLA alleles. Both analyses converged on a similar subset of risk HLA alleles: in EUR HLA- B*08:01 + B*18:01 + (DRB1*15:01 frequentist only) + DQA*01:02 + DQB*02:01 + DRB3*02 and in AA HLA-C*17:01 + B*08:01 + DRB1*15:03 + (DQA*01:02 frequentist only) + DQA*02:01 + DQA*05:01+ DQA*05:05 + DQB*03:19 + DQB*02:02. We observed two additional independent SNP associations in both populations: EUR rs146903072 and rs501480; AA rs389883 and rs114118665. The DR2 serotype was best explained by DRB1*15:03 + DQA*01:02 in AA and by DRB1*15:01 + DQA*01:02 in EUR. The DR3 serotype was best explained by DQA*05:01 in AA and by DQB*02:01 in EUR. Despite some differences in underlying HLA allele risk models in EUR and AA, SNP signals across the extended MHC showed remarkable similarity and significant concordance in direction of effect for risk-associated variants.


Assuntos
Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Complexo Principal de Histocompatibilidade/genética , Polimorfismo de Nucleotídeo Único , Afro-Americanos/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudos de Associação Genética , Haplótipos , Humanos , Masculino , Modelos Genéticos
12.
JCI Insight ; 3(14)2018 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-30046013

RESUMO

Site-1 protease (S1P), encoded by MBTPS1, is a serine protease in the Golgi. S1P regulates lipogenesis, endoplasmic reticulum (ER) function, and lysosome biogenesis in mice and in cultured cells. However, how S1P differentially regulates these diverse functions in humans has been unclear. In addition, no human disease with S1P deficiency has been identified. Here, we report a pediatric patient with an amorphic and a severely hypomorphic mutation in MBTPS1. The unique combination of these mutations results in a frequency of functional MBTPS1 transcripts of approximately 1%, a finding that is associated with skeletal dysplasia and elevated blood lysosomal enzymes. We found that the residually expressed S1P is sufficient for lipid homeostasis but not for ER and lysosomal functions, especially in chondrocytes. The defective S1P function specifically impairs activation of the ER stress transducer BBF2H7, leading to ER retention of collagen in chondrocytes. S1P deficiency also causes abnormal secretion of lysosomal enzymes due to partial impairment of mannose-6-phosphate-dependent delivery to lysosomes. Collectively, these abnormalities lead to apoptosis of chondrocytes and lysosomal enzyme-mediated degradation of the bone matrix. Correction of an MBTPS1 variant or reduction of ER stress mitigated collagen-trafficking defects. These results define a new congenital human skeletal disorder and, more importantly, reveal that S1P is particularly required for skeletal development in humans. Our findings may also lead to new therapies for other genetic skeletal diseases, as ER dysfunction is common in these disorders.


Assuntos
Doenças do Desenvolvimento Ósseo/genética , Doenças do Desenvolvimento Ósseo/metabolismo , Pró-Proteína Convertases/genética , Pró-Proteína Convertases/metabolismo , Transporte Proteico , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Apoptose , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Doenças do Desenvolvimento Ósseo/fisiopatologia , Técnicas de Cultura de Células , Pré-Escolar , Condrócitos/metabolismo , Colágeno/metabolismo , Retículo Endoplasmático/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Doenças Genéticas Inatas , Complexo de Golgi/metabolismo , Homeostase , Humanos , Lipogênese , Lisossomos/metabolismo , Manosefosfatos , Mutação
13.
Nat Commun ; 9(1): 2905, 2018 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-30046115

RESUMO

Genetic variants can confer risk to complex genetic diseases by modulating gene expression through changes to the epigenome. To assess the degree to which genetic variants influence epigenome activity, we integrate epigenetic and genotypic data from lupus patient lymphoblastoid cell lines to identify variants that induce allelic imbalance in the magnitude of histone post-translational modifications, referred to herein as histone quantitative trait loci (hQTLs). We demonstrate that enhancer hQTLs are enriched on autoimmune disease risk haplotypes and disproportionately influence gene expression variability compared with non-hQTL variants in strong linkage disequilibrium. We show that the epigenome regulates HLA class II genes differently in individuals who carry HLA-DR3 or HLA-DR15 haplotypes, resulting in differential 3D chromatin conformation and gene expression. Finally, we identify significant expression QTL (eQTL) x hQTL interactions that reveal substructure within eQTL gene expression, suggesting potential implications for functional genomic studies that leverage eQTL data for subject selection and stratification.


Assuntos
Cromatina/genética , Haplótipos/genética , Desequilíbrio de Ligação/genética , Locos de Características Quantitativas/genética , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino
14.
Am J Hum Genet ; 102(6): 1158-1168, 2018 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-29861105

RESUMO

ßIV spectrin links ankyrinG (AnkG) and clustered ion channels at axon initial segments (AISs) and nodes of Ranvier to the axonal cytoskeleton. Here, we report bi-allelic pathogenic SPTBN4 variants (three homozygous and two compound heterozygous) that cause a severe neurological syndrome that includes congenital hypotonia, intellectual disability, and motor axonal and auditory neuropathy. We introduced these variants into ßIV spectrin, expressed these in neurons, and found that 5/7 were loss-of-function variants disrupting AIS localization or abolishing phosphoinositide binding. Nerve biopsies from an individual with a loss-of-function variant had reduced nodal Na+ channels and no nodal KCNQ2 K+ channels. Modeling the disease in mice revealed that although ankyrinR (AnkR) and ßI spectrin can cluster Na+ channels and partially compensate for the loss of AnkG and ßIV spectrin at nodes of Ranvier, AnkR and ßI spectrin cannot cluster KCNQ2- and KCNQ3-subunit-containing K+ channels. Our findings define a class of spectrinopathies and reveal the molecular pathologies causing nervous-system dysfunction.


Assuntos
Axônios/patologia , Deficiência Intelectual/genética , Doença dos Neurônios Motores/genética , Hipotonia Muscular/congênito , Hipotonia Muscular/genética , Proteínas do Tecido Nervoso/genética , Espectrina/genética , Alelos , Animais , Axônios/metabolismo , Células COS , Criança , Pré-Escolar , Chlorocebus aethiops , Feminino , Células HEK293 , Humanos , Lactente , Deficiência Intelectual/complicações , Deficiência Intelectual/fisiopatologia , Lipídeos , Masculino , Camundongos Knockout , Doença dos Neurônios Motores/complicações , Doença dos Neurônios Motores/fisiopatologia , Hipotonia Muscular/complicações , Hipotonia Muscular/fisiopatologia , Proteínas Mutantes/metabolismo , Mutação/genética , Ratos Sprague-Dawley
15.
PeerJ ; 5: e3863, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29043109

RESUMO

BACKGROUND: Species of the scyphozoan family Pelagiidae (e.g., Pelagia noctiluca, Chrysaora quinquecirrha) are well-known for impacting fisheries, aquaculture, and tourism, especially for the painful sting they can inflict on swimmers. However, historical taxonomic uncertainty at the genus (e.g., new genus Mawia) and species levels hinders progress in studying their biology and evolutionary adaptations that make them nuisance species, as well as ability to understand and/or mitigate their ecological and economic impacts. METHODS: We collected nuclear (28S rDNA) and mitochondrial (cytochrome c oxidase I and 16S rDNA) sequence data from individuals of all four pelagiid genera, including 11 of 13 currently recognized species of Chrysaora. To examine species boundaries in the U.S. Atlantic sea nettle Chrysaora quinquecirrha, specimens were included from its entire range along the U.S. Atlantic and Gulf of Mexico coasts, with representatives also examined morphologically (macromorphology and cnidome). RESULTS: Phylogenetic analyses show that the genus Chrysaora is paraphyletic with respect to other pelagiid genera. In combined analyses, Mawia, sampled from the coast of Senegal, is most closely related to Sanderia malayensis, and Pelagia forms a close relationship to a clade of Pacific Chrysaora species (Chrysaora achlyos, Chrysaora colorata, Chrysaora fuscescens, and Chrysaora melanaster). Chrysaora quinquecirrha is polyphyletic, with one clade from the U.S. coastal Atlantic and another in U.S. Atlantic estuaries and Gulf of Mexico. These genetic differences are reflected in morphology, e.g., tentacle and lappet number, oral arm length, and nematocyst dimensions. Caribbean sea nettles (Jamaica and Panama) are genetically similar to the U.S. Atlantic estuaries and Gulf of Mexico clade of Chrysaora quinquecirrha. DISCUSSION: Our phylogenetic hypothesis for Pelagiidae contradicts current generic definitions, revealing major disagreements between DNA-based and morphology-based phylogenies. A paraphyletic Chrysaora raises systematic questions at the genus level for Pelagiidae; accepting the validity of the recently erected genus Mawia, as well as past genera, will require the creation of additional pelagiid genera. Historical review of the species-delineating genetic and morphological differences indicates that Chrysaora quinquecirrha Desor 1848 applies to the U.S. Coastal Atlantic Chrysaora species (U.S. Atlantic sea nettle), while the name C. chesapeakei Papenfuss 1936 applies to the U.S. Atlantic estuarine and Gulf of Mexico Chrysaora species (Atlantic bay nettle). We provide a detailed redescription, with designation of a neotype for Chrysaora chesapeakei, and clarify the description of Chrysaora quinquecirrha. Since Caribbean Chrysaora are genetically similar to Chrysaora chesapeakei, we provisionally term them Chrysaora c.f. chesapeakei. The presence of Mawia benovici off the coast of Western Africa provides a potential source region for jellyfish introduced into the Adriatic Sea in 2013.

16.
Am J Pathol ; 187(12): 2799-2810, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28935578

RESUMO

Transcription factor NF-κB regulates expression of numerous genes that control inflammation and is activated in glomerular cells in glomerulonephritis (GN). We previously identified genetic variants for a NF-κB regulatory, ubiquitin-binding protein ABIN1 as risk factors for GN in systemic autoimmunity. The goal was to define glomerular inflammatory events controlled by ABIN1 function in GN. Nephrotoxic serum nephritis was induced in wild-type (WT) and ubiquitin-binding deficient ABIN1[D485N] mice, and renal pathophysiology and glomerular inflammatory phenotypes were assessed. Proteinuria was also measured in ABIN1[D485N] mice transplanted with WT mouse bone marrow. Inflammatory activation of ABIN1[D472N] (D485N homolog) cultured human-derived podocytes, and interaction with primary human neutrophils were also assessed. Disruption of ABIN1 function exacerbated proteinuria, podocyte injury, glomerular NF-κB activity, glomerular expression of inflammatory mediators, and glomerular recruitment and retention of neutrophils in antibody-mediated nephritis. Transplantation of WT bone marrow did not prevent the increased proteinuria in ABIN1[D845N] mice. Tumor necrosis factor-stimulated enhanced expression and secretion of NF-κB-targeted proinflammatory mediators in ABIN1[D472N] cultured podocytes compared with WT cells. Supernatants from ABIN1[D472N] podocytes accelerated chemotaxis of human neutrophils, and ABIN1[D472N] podocytes displayed a greater susceptibility to injurious morphologic findings induced by neutrophil granule contents. These studies define a novel role for ABIN1 dysfunction and NF-κB in mediating GN through proinflammatory activation of podocytes.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Glomerulonefrite/patologia , NF-kappa B/metabolismo , Podócitos/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Glomerulonefrite/metabolismo , Humanos , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Camundongos Mutantes
17.
PLoS Genet ; 13(6): e1006820, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28640813

RESUMO

Sjögren's syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN) pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performed cis-expression quantitative trait locus (eQTL) analyses focusing on differentially expressed type I IFN-inducible transcripts identified through a transcriptome profiling study. Multiple cis-eQTLs were associated with transcript levels of 2'-5'-oligoadenylate synthetase 1 (OAS1) peaking at rs10774671 (PeQTL = 6.05 × 10-14). Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (Pmeta = 2.59 × 10-9; odds ratio = 0.75; 95% confidence interval = 0.66-0.86). The risk allele of rs10774671 shifts splicing of OAS1 from production of the p46 isoform to multiple alternative transcripts, including p42, p48, and p44. We found that the isoforms were differentially expressed within each genotype in controls and patients with and without autoantibodies. Furthermore, our results showed that the three alternatively spliced isoforms lacked translational response to type I IFN stimulation. The p48 and p44 isoforms also had impaired protein expression governed by the 3' end of the transcripts. The SS risk allele of rs10774671 has been shown by others to be associated with reduced OAS1 enzymatic activity and ability to clear viral infections, as well as reduced responsiveness to IFN treatment. Our results establish OAS1 as a risk locus for SS and support a potential role for defective viral clearance due to altered IFN response as a genetic pathophysiological basis of this complex autoimmune disease.


Assuntos
2',5'-Oligoadenilato Sintetase/genética , Interferon Tipo I/genética , Locos de Características Quantitativas/genética , Síndrome de Sjogren/genética , 2',5'-Oligoadenilato Sintetase/biossíntese , Alelos , Processamento Alternativo/genética , Feminino , Regulação da Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Interferon Tipo I/metabolismo , Masculino , Síndrome de Sjogren/metabolismo , Síndrome de Sjogren/patologia , Viroses/genética , Viroses/virologia
18.
PLoS One ; 12(2): e0171193, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28234905

RESUMO

Antiviral defenses are inappropriately activated in systemic lupus erythematosus (SLE) and association between SLE and the antiviral helicase gene, IFIH1, is well established. We sought to extend the previously reported association of pathogenic soluble mediators and autoantibodies with mouse Mda5 to its human ortholog, IFIH1. To better understand the role this gene plays in human lupus, we assessed association of IFIH1 variants with soluble mediators and autoantibodies in 357 European-American SLE patients, first-degree relatives, and unrelated, unaffected healthy controls. Association between each of 135 genotyped SNPs in IFIH1 and four lupus-associated plasma mediators, IL-6, TNF-α, IFN-ß, and IP-10, were investigated via linear regression. No significant associations were found to SNPs orthologous to those identified in exon 13 of the mouse. However, outside of this region there were significant associations between IL-6 and rs76162067 (p = 0.008), as well as IP-10 and rs79711023 (p = 0.003), located in a region of IFIH1 previously shown to directly influence MDA-5 mediated IP-10 and IL-6 secretion. SLE patients and FDRs carrying the minor allele for rs79711023 demonstrated lower levels of IP-10, while only FDRs carrying the minor allele for rs76162067 demonstrated an increased level of IL-6. This would suggest that the change in IP-10 is genotypically driven, while the change in IL-6 may be reflective of SLE transition status. These data suggest that IFIH1 may contribute to SLE pathogenesis via altered inflammatory mechanisms.


Assuntos
Quimiocina CXCL10/genética , Helicase IFIH1 Induzida por Interferon/genética , Interleucina-6/genética , Lúpus Eritematoso Sistêmico/genética , Adulto , Idoso , Animais , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Mediadores da Inflamação/metabolismo , Interferon beta/genética , Camundongos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fator de Necrose Tumoral alfa/genética
19.
Nat Genet ; 49(3): 433-437, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28135245

RESUMO

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a strong genetic component characterized by autoantibody production and a type I interferon signature. Here we report a missense variant (g.74779296G>A; p.Arg90His) in NCF1, encoding the p47phox subunit of the phagocyte NADPH oxidase (NOX2), as the putative underlying causal variant that drives a strong SLE-associated signal detected by the Immunochip in the GTF2IRD1-GTF2I region at 7q11.23 with a complex genomic structure. We show that the p.Arg90His substitution, which is reported to cause reduced reactive oxygen species (ROS) production, predisposes to SLE (odds ratio (OR) = 3.47 in Asians (Pmeta = 3.1 × 10-104), OR = 2.61 in European Americans, OR = 2.02 in African Americans) and other autoimmune diseases, including primary Sjögren's syndrome (OR = 2.45 in Chinese, OR = 2.35 in European Americans) and rheumatoid arthritis (OR = 1.65 in Koreans). Additionally, decreased and increased copy numbers of NCF1 predispose to and protect against SLE, respectively. Our data highlight the pathogenic role of reduced NOX2-derived ROS levels in autoimmune diseases.


Assuntos
Doenças Autoimunes/genética , Predisposição Genética para Doença/genética , NADPH Oxidases/genética , Polimorfismo de Nucleotídeo Único/genética , Afro-Americanos/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Humanos , Lúpus Eritematoso Sistêmico/genética , Masculino , Espécies Reativas de Oxigênio/metabolismo , Síndrome de Sjogren/genética
20.
Ann Rheum Dis ; 76(1): 153-158, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27283331

RESUMO

OBJECTIVE: We examined whether measures of vitamin D were associated with transitioning to systemic lupus erythematosus (SLE) in individuals at risk for SLE. METHODS: 436 individuals who reported having a relative with SLE but who did not have SLE themselves were evaluated at baseline and again an average of 6.3 (±3.9) years later. Fifty-six individuals transitioned to SLE (≥4 cumulative American College of Rheumatology criteria). 25-Hydroxyvitamin D (25[OH]D) levels were measured by ELISA. Six single-nucleotide polymorphisms in four vitamin D genes were genotyped. Generalised estimating equations, adjusting for correlation within families, were used to test associations between the vitamin D variables and the outcome of transitioning to SLE. RESULTS: Mean baseline 25[OH]D levels (p=0.42) and vitamin D supplementation (p=0.65) were not different between those who did and did not transition to SLE. Vitamin D deficiency (25[OH]D <20 ng/mL) was greater in those who transitioned compared with those who did not transition to SLE (46% vs 33%, p=0.05). The association between 25[OH]D and SLE was modified by CYP24A1 rs4809959, where for each additional minor allele increased 25[OH]D was associated with decreased SLE risk: zero minor alleles (adjusted OR: 1.03, CI 0.98 to 1.09), one minor allele (adjusted OR: 1.01, CI 0.97 to 1.05) and two minor alleles (adjusted OR: 0.91, CI 0.84 to 0.98). Similarly, vitamin D deficiency significantly increased the risk of transitioning to SLE in those with two minor alleles at rs4809959 (adjusted OR: 4.90, CI 1.33 to 18.04). CONCLUSIONS: Vitamin D status and CYP24A1 may have a combined role in the transition to SLE in individuals at increased genetic risk for SLE.


Assuntos
Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/genética , Deficiência de Vitamina D/sangue , Vitamina D3 24-Hidroxilase/genética , Vitamina D/análogos & derivados , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Adulto , Idoso , Alelos , Feminino , Predisposição Genética para Doença , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptores de Calcitriol/genética , Fatores de Risco , Vitamina D/sangue , Proteína de Ligação a Vitamina D/genética
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