RESUMO
Enzalutamide, a second-generation antiandrogen, is commonly prescribed for the therapy of advanced prostate cancer, but enzalutamide-resistant, lethal, or incurable disease invariably develops. To understand the molecular mechanism(s) behind enzalutamide resistance, here, we comprehensively analyzed a range of prostate tumors and clinically relevant models by gene expression array, immunohistochemistry, and Western blot, which revealed that enzalutamide-resistant prostate cancer cells and tumors overexpress the pseudokinase, Tribbles 2 (TRIB2). Inhibition of TRIB2 decreases the viability of enzalutamide-resistant prostate cancer cells, suggesting a critical role of TRIB2 in these cells. Moreover, the overexpression of TRIB2 confers resistance in prostate cancer cells to clinically relevant doses of enzalutamide, and this resistance is lost upon inhibition of TRIB2. Interestingly, we found that TRIB2 downregulates the luminal markers androgen receptor and cytokeratin 8 in prostate cancer cells but upregulates the neuronal transcription factor BRN2 (Brain-2) and the stemness factor SOX2 (SRY-box 2) to induce neuroendocrine characteristics. Finally, we show that inhibition of either TRIB2 or its downstream targets, BRN2 or SOX2, resensitizes resistant prostate cancer cells to enzalutamide. Thus, TRIB2 emerges as a potential new regulator of transdifferentiation that confers enzalutamide resistance in prostate cancer cells via a mechanism involving increased cellular plasticity and lineage switching.
Assuntos
Benzamidas , Proteínas Quinases Dependentes de Cálcio-Calmodulina , Nitrilas , Feniltioidantoína , Neoplasias da Próstata , Benzamidas/farmacologia , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Linhagem Celular Tumoral , Linhagem da Célula , Plasticidade Celular , Resistencia a Medicamentos Antineoplásicos , Humanos , Masculino , Nitrilas/farmacologia , Feniltioidantoína/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismoRESUMO
The etiology of many complex diseases involves both environmental exposures and inherited genetic predisposition as well as interactions between them. Gene-environment-wide interaction studies (GEWIS) provide a means to identify the interactions between genetic variation and environmental exposures that underlie disease risk. However, current GEWIS methods lack the capability to adjust for the potentially complex correlations in studies with varying degrees of relationships (both known and unknown) among individuals in admixed populations. We developed novel generalized estimating equation (GEE) based methods-GEE-adaptive and GEE-joint-to account for phenotypic correlations due to kinship while accounting for covariates, including, measures of genome-wide ancestry. In simulation studies of admixed individuals, both methods controlled family-wise error rates, an advantage over the case-only approach. They demonstrated higher power than traditional case-control methods across a wide range of underlying alternative hypotheses, especially where both marginal and interaction effects were present. We applied the proposed method to conduct a GEWIS of a known sarcoidosis risk factor (insecticide exposure) and risk of sarcoidosis in African Americans and identified two novel loci with suggestive evidence of G × E interaction.
Assuntos
Família , Interação Gene-Ambiente , Estudo de Associação Genômica Ampla/métodos , Sarcoidose/genética , Negro ou Afro-Americano/genética , Alelos , Estudos de Casos e Controles , Simulação por Computador , Frequência do Gene , Predisposição Genética para Doença , Humanos , Modelos Genéticos , Linhagem , Polimorfismo de Nucleotídeo Único , Sarcoidose/etnologiaRESUMO
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/virologiaRESUMO
OBJECTIVES: Microbial infections and mucosal dysbiosis influence morbidity in patients with systemic lupus erythematosus (SLE). In the oral cavity, periodontal bacteria and subgingival plaque dysbiosis provide persistent inflammatory stimuli at the mucosal surface. This study was undertaken to evaluate whether exposure to periodontal bacteria influences disease parameters in SLE patients. METHODS: Circulating antibodies to specific periodontal bacteria have been used as surrogate markers to determine an ongoing bacterial burden, or as indicators of past exposure to the bacteria. Banked serum samples from SLE patients in the Oklahoma Lupus Cohort were used to measure antibody titres against periodontal pathogens (Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, and Treponema denticola) and commensals (Capnocytophaga ochracea, and Streptococcus gordonii) by ELISA. Correlations between anti-bacterial antibodies and different clinicalparameters of SLE including, autoantibodies (anti-dsDNA, anti-SmRNP, anti-SSA/Ro and anti-SSB/La), complement, and disease activity (SLEDAI and BILAG) were studied. RESULTS: SLE patients had varying amounts of antibodies to different oral bacteria. The antibody titres against A. actinomycetemcomitans, P. gingivalis, T. denticola, and C. ochracea were higher in patients positive for anti-dsDNA antibodies, and they showed significant correlations with anti-dsDNA titres and reduced levels of complement. Among the periodontal pathogens, only antibodies to A. actinomycetemcomitans were associated with higher disease activity. CONCLUSIONS: Our results suggest that exposure to specific pathogenic periodontal bacteria influences disease activity in SLE patients. These findings provide a rationale for assessing and improving periodontal health in SLE patients, as an adjunct to lupus therapies.
Assuntos
Anticorpos Antibacterianos/sangue , Lúpus Eritematoso Discoide , Lúpus Eritematoso Sistêmico , Periodontite/imunologia , Autoanticorpos , Estudos de Coortes , Humanos , Porphyromonas gingivalis/imunologia , Treponema denticola/imunologiaRESUMO
Innate lymphoid cells (ILCs) are important regulators in various immune responses. The current paradigm states that all newly made ILCs originate from common lymphoid progenitors in the bone marrow. Id2, an inhibitor of E protein transcription factors, is indispensable for ILC differentiation. Unexpectedly, we found that ectopically expressing Id1 or deleting two E protein genes in the thymus drastically increased ILC2 counts in the thymus and other organs where ILC2 normally reside. Further evidence suggests a thymic origin of these mutant ILC2s. The mutant mice exhibit augmented spontaneous infiltration of eosinophils and heightened responses to papain in the lung and increased ability to expulse the helminth parasite, Nippostrongylus brasiliensis These results prompt the questions of whether the thymus naturally has the capacity to produce ILC2s and whether E proteins restrain such a potential. The abundance of ILC2s in Id1 transgenic mice also offers a unique opportunity for testing the biological functions of ILC2s.
Assuntos
Diferenciação Celular/imunologia , Imunidade Inata/imunologia , Linfócitos/imunologia , Células Progenitoras Linfoides/imunologia , Timo/imunologia , Animais , Linhagem da Célula/imunologia , Separação Celular , Regulação para Baixo , Citometria de Fluxo , Proteína 1 Inibidora de Diferenciação/imunologia , Linfócitos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Camundongos Transgênicos , Timo/citologiaRESUMO
BACKGROUND: Hirschsprung disease (HSCR) is a heterogeneous genetic disorder characterized by absence of ganglion cells along the intestines resulting in functional bowel obstruction. Mutations in neuregulin 1 (NRG1) gene have been implicated in some cases of intestinal aganglionosis. This study aims to investigate the contribution of the NRG1 gene to HSCR development in an Indonesian population. METHODS: We analyzed the entire coding region of the NRG1 gene in 54 histopathologically diagnosed HSCR patients. RESULTS: All patients were sporadic non-syndromic HSCR with 53/54 (98%) short-segment and 1/54 (2%) long-segment patients. NRG1 gene analysis identified one rare variant, c.397G > C (p.V133 L), and three common variants, rs7834206, rs3735774, and rs75155858. The p.V133 L variant was predicted to reside within a region of high mammalian conservation, overlapping with the promoter and enhancer histone marks of relevant tissues such as digestive and smooth muscle tissues and potentially altering the AP-4_2, BDP1_disc3, Egr-1_known1, Egr-1_known4, HEN1_2 transcription factor binding motifs. This p.V133 L variant was absent in 92 non-HSCR controls. Furthermore, the rs7834206 polymorphism was associated with HSCR by case-control analysis (p = 0.037). CONCLUSIONS: This study is the first report of a NRG1 rare variant associated with HSCR patients of South-East Asian ancestry and provides further insights into the contribution of NRG1 in the molecular genetic pathogenesis of HSCR.
Assuntos
Predisposição Genética para Doença , Variação Genética , Doença de Hirschsprung/genética , Neuregulina-1/genética , Adulto , Povo Asiático/genética , Estudos de Casos e Controles , Feminino , Humanos , Indonésia , Masculino , Reação em Cadeia da Polimerase , Ligação Proteica , Análise de Sequência de DNA , Fatores de Transcrição/genéticaRESUMO
RATIONALE: Sarcoidosis is a multisystem disease of unknown cause. Löfgren's syndrome (LS) is a characteristic subgroup of sarcoidosis that is associated with a good prognosis in sarcoidosis. However, little is known about its genetic architecture or its broader phenotype, non-LS sarcoidosis. OBJECTIVES: To address the genetic architecture of sarcoidosis phenotypes, LS and non-LS. METHODS: An association study in a white Swedish cohort of 384 LS, 664 non-LS, and 2,086 control subjects, totaling 3,134 subjects using a fine-mapping genotyping platform was conducted. Replication was performed in four independent cohorts, three of white European descent (Germany, n = 4,975; the Netherlands, n = 613; and Czech Republic, n = 521), and one of black African descent (United States, n = 1,657), totaling 7,766 subjects. MEASUREMENTS AND MAIN RESULTS: A total of 727 LS-associated variants expanding throughout the extended major histocompatibility complex (MHC) region and 68 non-LS-associated variants located in the MHC class II region were identified and confirmed. A shared overlap between LS and non-LS defined by 17 variants located in the MHC class II region was found. Outside the MHC region, two LS-associated loci, in ADCY3 and between CSMD1 and MCPH1, were observed and replicated. CONCLUSIONS: Comprehensive and integrative analyses of genetics, transcription, and pathway modeling on LS and non-LS indicates that these sarcoidosis phenotypes have different genetic susceptibility, genomic distributions, and cellular activities, suggesting distinct molecular mechanisms in pathways related to immune response with a common region.
Assuntos
Predisposição Genética para Doença/genética , Genômica/métodos , Genótipo , Fenótipo , Sarcoidose Pulmonar/genética , República Tcheca , Feminino , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Suécia , Estados UnidosRESUMO
BACKGROUND: Adapter trimming and removal of duplicate reads are common practices in next-generation sequencing pipelines. Sequencing reads ambiguously mapped to repetitive and low complexity regions can also be problematic for accurate assessment of the biological signal, yet their impact on sequencing data has not received much attention. We investigate how trimming the adapters, removing duplicates, and filtering out reads overlapping low complexity regions influence the significance of biological signal in RNA- and ChIP-seq experiments. METHODS: We assessed the effect of data processing steps on the alignment statistics and the functional enrichment analysis results of RNA- and ChIP-seq data. We compared differentially processed RNA-seq data with matching microarray data on the same patient samples to determine whether changes in pre-processing improved correlation between the two. We have developed a simple tool to remove low complexity regions, RepeatSoaker, available at https://github.com/mdozmorov/RepeatSoaker, and tested its effect on the alignment statistics and the results of the enrichment analyses. RESULTS: Both adapter trimming and duplicate removal moderately improved the strength of biological signals in RNA-seq and ChIP-seq data. Aggressive filtering of reads overlapping with low complexity regions, as defined by RepeatMasker, further improved the strength of biological signals, and the correlation between RNA-seq and microarray gene expression data. CONCLUSIONS: Adapter trimming and duplicates removal, coupled with filtering out reads overlapping low complexity regions, is shown to increase the quality and reliability of detecting biological signals in RNA-seq and ChIP-seq data.
Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , RNA/genética , Análise de Sequência de RNA/métodos , HumanosRESUMO
HLA-DRB1 is a sarcoidosis risk gene, and the *03:01 allele is strongly associated with disease resolution in European sarcoidosis cases. Whereas the HLA-DRB1 variation is associated with sarcoidosis susceptibility in African Americans, DRB1 risk alleles are not as well defined, and associations with disease resolution have not been studied. Associations between genotyped and imputed HLA-DRB1 alleles and disease susceptibility/resolution were evaluated in a sample of 1,277 African-American patients with sarcoidosis and 1,467 control subjects. In silico binding assays were performed to assess the functional significance of the associated alleles. Increased disease susceptibility was associated with the HLA-DRB1 alleles *12:01 (odds ratio [OR], 2.11; 95% confidence interval [CI], 1.65-2.69; P = 3.2 × 10(-9)) and *11:01 (OR, 1.69; 95% CI, 1.42-2.01; P = 3.0 × 10(-9)). The strongest protective association was found with *03:01 (OR, 0.56; 95% CI, 0.44-0.73; P = 1.0 × 10(-5)). The African-derived allele *03:02 was associated with decreased risk of persistent radiographic disease (OR, 0.52; 95% CI, 0.37-0.72; P = 1.3 × 10(-4)), a finding consistent across the three component studies comprising the analytic sample. The DRB1*03:01 association with disease persistence was dependent upon local ancestry, with carriers of at least one European allele at DRB1 at a decreased risk of persistent disease (OR, 0.36; 95% CI, 0.14-0.94; P = 0.037). Results of in silico binding analyses showed that DRB1*03:01 consistently demonstrated the highest binding affinities for six bacterial peptides previously found in sarcoidosis granulomas, whereas *12:01 displayed the lowest binding affinities. This study has identified DRB1*03:01 and *03:02 as novel alleles associated with disease susceptibility and course in African Americans. Further investigation of DRB1*03 alleles may uncover immunologic factors that favor sarcoidosis protection and resolution among African Americans.
Assuntos
Cadeias HLA-DRB1/genética , Sarcoidose Pulmonar/genética , Negro ou Afro-Americano/genética , Estudos de Casos e Controles , Progressão da Doença , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Sarcoidose Pulmonar/etnologia , Sarcoidose Pulmonar/patologiaRESUMO
Genome-wide association studies (GWAS) that draw samples from multiple studies with a mixture of relationship structures are becoming more common. Analytical methods exist for using mixed-sample data, but few methods have been proposed for the analysis of genotype-by-environment (G×E) interactions. Using GWAS data from a study of sarcoidosis susceptibility genes in related and unrelated African Americans, we explored the current analytic options for genotype association testing in studies using both unrelated and family-based designs. We propose a novel method-generalized least squares (GLX)-to estimate both SNP and G×E interaction effects for categorical environmental covariates and compared this method to generalized estimating equations (GEE), logistic regression, the Cochran-Armitage trend test, and the WQLS and MQLS methods. We used simulation to demonstrate that the GLX method reduces type I error under a variety of pedigree structures. We also demonstrate its superior power to detect SNP effects while offering computational advantages and comparable power to detect G×E interactions versus GEE. Using this method, we found two novel SNPs that demonstrate a significant genome-wide interaction with insecticide exposure-rs10499003 and rs7745248, located in the intronic and 3' UTR regions of the FUT9 gene on chromosome 6q16.1.
Assuntos
Negro ou Afro-Americano/genética , Família , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Sarcoidose/genética , Meio Ambiente , Genótipo , Humanos , Análise dos Mínimos Quadrados , Modelos Logísticos , Modelos Genéticos , Linhagem , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Systemic lupus erythematosus (SLE) is a chronic heterogeneous autoimmune disorder characterized by the loss of tolerance to self-antigens and dysregulated interferon responses. The etiology of SLE is complex, involving both heritable and environmental factors. Candidate-gene studies and genome-wide association (GWA) scans have been successful in identifying new loci that contribute to disease susceptibility; however, much of the heritable risk has yet to be identified. In this study, we sought to replicate 1,580 variants showing suggestive association with SLE in a previously published GWA scan of European Americans; we tested a multiethnic population consisting of 7,998 SLE cases and 7,492 controls of European, African American, Asian, Hispanic, Gullah, and Amerindian ancestry to find association with the disease. Several genes relevant to immunological pathways showed association with SLE. Three loci exceeded the genome-wide significance threshold: interferon regulatory factor 8 (IRF8; rs11644034; p(meta-Euro) = 2.08 × 10(-10)), transmembrane protein 39A (TMEM39A; rs1132200; p(meta-all) = 8.62 × 10(-9)), and 17q21 (rs1453560; p(meta-all) = 3.48 × 10(-10)) between IKAROS family of zinc finger 3 (AIOLOS; IKZF3) and zona pellucida binding protein 2 (ZPBP2). Fine mapping, resequencing, imputation, and haplotype analysis of IRF8 indicated that three independent effects tagged by rs8046526, rs450443, and rs4843869, respectively, were required for risk in individuals of European ancestry. Eleven additional replicated effects (5 × 10(-8) < p(meta-Euro) < 9.99 × 10(-5)) were observed with CFHR1, CADM2, LOC730109/IL12A, LPP, LOC63920, SLU7, ADAMTSL1, C10orf64, OR8D4, FAM19A2, and STXBP6. The results of this study increase the number of confirmed SLE risk loci and identify others warranting further investigation.
Assuntos
Proteínas do Ovo/genética , Predisposição Genética para Doença , Fator de Transcrição Ikaros/genética , Fatores Reguladores de Interferon/genética , Lúpus Eritematoso Sistêmico/genética , Proteínas de Membrana/genética , Povo Asiático/genética , População Negra/genética , Mapeamento Cromossômico , Feminino , Haplótipos/genética , Hispânico ou Latino/genética , Humanos , Indígenas Norte-Americanos/genética , Lúpus Eritematoso Sistêmico/etnologia , Masculino , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de DNA , População Branca/genéticaRESUMO
Systemic lupus erythematosus (SLE) is considered to be the prototypic autoimmune disease, with a complex genetic architecture influenced by environmental factors. We sought to replicate a putative association at 11p13 not yet exceeding genome-wide significance (p < 5 × 10(-8)) identified in a genome-wide association study (GWAS). Our GWA scan identified two intergenic SNPs located between PDHX and CD44 showing suggestive evidence of association with SLE in cases of European descent (rs2732552, p = 0.004, odds ratio [OR] = 0.78; rs387619, p = 0.003, OR = 0.78). The replication cohort consisted of >15,000 subjects, including 3562 SLE cases and 3491 controls of European ancestry, 1527 cases and 1811 controls of African American (AA) descent, and 1265 cases and 1260 controls of Asian origin. We observed robust association at both rs2732552 (p = 9.03 × 10(-8), OR = 0.83) and rs387619 (p = 7.7 × 10(-7), OR = 0.83) in the European samples with p(meta) = 1.82 × 10(-9) for rs2732552. The AA and Asian SLE cases also demonstrated association at rs2732552 (p = 5 × 10(-3), OR = 0.81 and p = 4.3 × 10(-4), OR = 0.80, respectively). A meta-analysis of rs2732552 for all racial and ethnic groups studied produced p(meta) = 2.36 × 10(-13). This locus contains multiple regulatory sites that could potentially affect expression and functions of CD44, a cell-surface glycoprotein influencing immunologic, inflammatory, and oncologic phenotypes, or PDHX, a subunit of the pyruvate dehydrogenase complex.
Assuntos
Cromossomos Humanos Par 11/genética , Loci Gênicos , Predisposição Genética para Doença , Receptores de Hialuronatos/genética , Lúpus Eritematoso Sistêmico/genética , Complexo Piruvato Desidrogenase/genética , Negro ou Afro-Americano/genética , Indígena Americano ou Nativo do Alasca/genética , Povo Asiático/genética , Estudos de Coortes , Feminino , Haplótipos , Hispânico ou Latino/genética , Humanos , Desequilíbrio de Ligação , Lúpus Eritematoso Sistêmico/etnologia , Masculino , Polimorfismo de Nucleotídeo Único , População Branca/genéticaRESUMO
BACKGROUND: The expense of human leukocyte antigen (HLA) allele genotyping has motivated the development of imputation methods that use dense single nucleotide polymorphism (SNP) genotype data and the region's haplotype structure, but the performance of these methods in admixed populations (such as African Americans) has not been adequately evaluated. We compared genotype-based-derived from both genome-wide genotyping and targeted sequencing-imputation results to existing allele data for HLA-DRB1, -DQB1, and -DPB1. RESULTS: In European Americans, the newly-developed HLA Genotype Imputation with Attribute Bagging (HIBAG) method outperformed HLA*IMP:02. In African Americans, HLA*IMP:02 performed marginally better than HIBAG pre-built models, but HIBAG models constructed using a portion of our African American sample with both SNP genotyping and four-digit HLA class II allele typing had consistently higher accuracy than HLA*IMP:02. However, HIBAG was significantly less accurate in individuals heterozygous for local ancestry (p ≤0.04). Accuracy improved in models with equal numbers of African and European chromosomes. Variants added by targeted sequencing and SNP imputation further improved both imputation accuracy and the proportion of high quality calls. CONCLUSION: Combining the HIBAG approach with local ancestry and dense variant data can produce highly-accurate HLA class II allele imputation in African Americans.
Assuntos
Negro ou Afro-Americano/genética , Técnicas de Genotipagem/métodos , Cadeias beta de HLA-DP/genética , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Alelos , Humanos , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA , População Branca/genéticaRESUMO
The genetic factors underlying the pathogenesis of lupus nephritis associated with systemic lupus erythematosus are largely unknown, although animal studies indicate that nuclear factor (NF)-κB is involved. We reported previously that a knockin mouse expressing an inactive form of ABIN1 (ABIN1[D485N]) develops lupus-like autoimmune disease and demonstrates enhanced activation of NF-κB and mitogen-activated protein kinases in immune cells after toll-like receptor stimulation. In the current study, we show that ABIN1[D485N] mice develop progressive GN similar to class III and IV lupus nephritis in humans. To investigate the clinical relevance of ABIN1 dysfunction, we genotyped five single-nucleotide polymorphisms in the gene encoding ABIN1, TNIP1, in samples from European-American, African American, Asian, Gullah, and Hispanic participants in the Large Lupus Association Study 2. Comparing cases of systemic lupus erythematosus with nephritis and cases of systemic lupus erythematosus without nephritis revealed strong associations with lupus nephritis at rs7708392 in European Americans and rs4958881 in African Americans. Comparing cases of systemic lupus erythematosus with nephritis and healthy controls revealed a stronger association at rs7708392 in European Americans but not at rs4958881 in African Americans. Our data suggest that variants in the TNIP1 gene are associated with the risk for lupus nephritis and could be mechanistically involved in disease development via aberrant regulation of NF-κB and mitogen-activated protein kinase activity.
Assuntos
Proteínas de Ligação a DNA/fisiologia , Nefrite Lúpica/genética , Animais , Proteínas de Ligação a DNA/genética , Imunofluorescência , Humanos , Rim/patologia , Rim/fisiopatologia , Nefrite Lúpica/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/fisiologia , Polimorfismo de Nucleotídeo ÚnicoRESUMO
OBJECTIVE: The objective of this study is to assess the effects of social determinants of health (SDOH) and race-ethnicity on readmission and to investigate the potential for geospatial clustering of patients with a greater burden of SDOH that could lead to a higher risk of readmission. DESIGN: A retrospective study of inpatients at five hospitals within Henry Ford Health (HFH) in Detroit, Michigan from November 2015 to December 2018 was conducted. SETTING: This study used an adult inpatient registry created based on HFH electronic health record data as the data source. A subset of the data elements in the registry was collected for data analyses that included readmission index, race-ethnicity, six SDOH variables and demographics and clinical-related variables. PARTICIPANTS: The cohort was composed of 248 810 admission patient encounters with 156 353 unique adult patients between the study time period. Encounters were excluded if they did not qualify as an index admission for all payors based on the Centers for Medicare and Medicaid Service definition. MAIN OUTCOME MEASURE: The primary outcome was 30-day all-cause readmission. This binary index was identified based on HFH internal data supplemented by external validated readmission data from the Michigan Health Information Network. RESULTS: Race-ethnicity and all SDOH were significantly associated with readmission. The effect of depression on readmission was dependent on race-ethnicity, with Hispanic patients having the strongest effect in comparison to either African Americans or non-Hispanic whites. Spatial analysis identified ZIP codes in the City of Detroit, Michigan, as over-represented for individuals with multiple SDOH. CONCLUSIONS: There is a complex relationship between SDOH and race-ethnicity that must be taken into consideration when providing healthcare services. Insights from this study, which pinpoint the most vulnerable patients, could be leveraged to further improve existing models to predict risk of 30-day readmission for individuals in future work.
Assuntos
Readmissão do Paciente , Determinantes Sociais da Saúde , Humanos , Readmissão do Paciente/estatística & dados numéricos , Estudos Retrospectivos , Masculino , Feminino , Determinantes Sociais da Saúde/etnologia , Pessoa de Meia-Idade , Michigan , Adulto , Idoso , Etnicidade/estatística & dados numéricos , Disparidades em Assistência à Saúde/etnologia , Disparidades em Assistência à Saúde/estatística & dados numéricos , Estados Unidos , Disparidades nos Níveis de SaúdeRESUMO
OBJECTIVE: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and altered type I interferon expression. Genetic surveys and genome-wide association studies have identified >30 SLE susceptibility genes. One of these genes, TNIP1, encodes the ABIN1 protein. ABIN1 functions in the immune system by restricting NF-κB signaling. The present study was undertaken to investigate the genetic factors that influence association with SLE in genes that regulate the NF-κB pathway. METHODS: We analyzed a dense set of genetic markers spanning TNIP1 and TAX1BP1, as well as the TNIP1 homolog TNIP2, in case-control populations of diverse ethnic origins. TNIP1, TNIP2, and TAX1BP1 were fine-mapped in a total of 8,372 SLE cases and 7,492 healthy controls from European-ancestry, African American, Hispanic, East Asian, and African American Gullah populations. Levels of TNIP1 messenger RNA (mRNA) and ABIN1 protein in Epstein-Barr virus-transformed human B cell lines were analyzed by quantitative reverse transcription-polymerase chain reaction and Western blotting, respectively. RESULTS: We found significant associations between SLE and genetic variants within TNIP1, but not in TNIP2 or TAX1BP1. After resequencing and imputation, we identified 2 independent risk haplotypes within TNIP1 in individuals of European ancestry that were also present in African American and Hispanic populations. Levels of TNIP1 mRNA and ABIN1 protein were reduced among subjects with these haplotypes, suggesting that they harbor hypomorphic functional variants that influence susceptibility to SLE by restricting ABIN1 expression. CONCLUSION: Our results confirm the association signals between SLE and TNIP1 variants in multiple populations and provide new insight into the mechanism by which TNIP1 variants may contribute to SLE pathogenesis.
Assuntos
Proteínas de Ligação a DNA/genética , Haplótipos/genética , Lúpus Eritematoso Sistêmico/etnologia , Lúpus Eritematoso Sistêmico/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Negro ou Afro-Americano/genética , Negro ou Afro-Americano/estatística & dados numéricos , Asiático/genética , Asiático/estatística & dados numéricos , Linfócitos B/citologia , Linhagem Celular Transformada , Feminino , Marcadores Genéticos/genética , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genética , Hispânico ou Latino/genética , Hispânico ou Latino/estatística & dados numéricos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Estados Unidos/epidemiologia , População Branca/genética , População Branca/estatística & dados numéricosRESUMO
Large scale meta-analyses of genomics and genetics have spurred research in a number of fields, such as cancer, genetics and immunology. Publicly available 'omics databases provide valuable hypothesis generating and validation tools. To date, no such initiative has been undertaken for Hidradenitis Suppurativa (HS), an inflammatory skin disease of unknown etiology. We present here, a longitudinal initiative seeking to aggregate publicly available 'omics data to enhance research efforts in HS. In its first iteration, we include bulk and single-cell RNA sequencing data from untreated HS patients. Our data, aggregated from publicly available GEO datasets provides a tool to profile gene expression in specific tissue types (i.e. lesional, perilesional, nonlesional and healthy skin) as well as map cell-specific gene expression on single-cell data from HS lesions.
RESUMO
Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition that can manifest with abscesses, sinus tracts, and scarring in the intertriginous areas of the body. HS is characterized by immune dysregulation, featuring elevated levels of myeloid cells, T helper (Th) cells, and pro-inflammatory cytokines, particularly those involved in Th1- and Th17-mediated immunity. In most epidemiological studies, HS shows a strong female sex bias, with reported female-to-male ratios estimated at roughly 3:1, suggesting that sex-related factors contribute to HS pathophysiology. In this article, we review the role of intrinsic and extrinsic factors that contribute to immunological differences between the sexes and postulate their role in the female sex bias observed in HS. We discuss the effects of hormones, X chromosome dosage, genetics, the microbiome, and smoking on sex-related differences in immunity to postulate potential immunological mechanisms in HS pathophysiology. Future studies are required to better characterize sex-biased factors that contribute to HS disease presentations.
Assuntos
Hidradenite Supurativa , Masculino , Humanos , Feminino , Hidradenite Supurativa/etiologia , Sexismo , Citocinas , Células Th17 , AbscessoRESUMO
Background The renal mechanisms involved in the maintenance of human hypertension and resistance to treatment are not well understood. Animal studies suggest that chronic renal inflammation contributes to hypertension. We studied cells shed in first-morning urine samples from individuals who were hypertensive who exhibited difficult-to-control blood pressure (BP). We performed bulk RNA sequencing of these shed cells to develop transcriptome-wide associations with BP. We also analyzed nephron-specific genes and used an unbiased bioinformatic approach to find signaling pathways activated in difficult-to-control hypertension. Methods and Results Participants who completed the SPRINT (Systolic Blood Pressure Intervention Trial) at a single trial site were recruited, and cells shed in first-morning urine samples collected. A total of 47 participants were divided into 2 groups based on hypertension control. The BP-difficult group (n=29) had systolic BP>140 mm Hg, >120 mm Hg after intensive treatment for hypertension, or required more than the median number of antihypertensive drugs used in SPRINT. The easy-to-control BP group (n=18) comprised the remainder of the participants. A total of 60 differentially expressed genes were identified with a >2-fold change in the BP-difficult group. In BP-difficult participants, 2 of the most upregulated genes were associated with inflammation: Tumor Necrosis Factor Alpha Induced Protien 6 (fold change, 7.76; P=0.006) and Serpin Family B Member 9 (fold change, 5.10; P=0.007). Biological pathway analysis revealed an overrepresentation of inflammatory networks, including interferon signaling, granulocyte adhesion and diapedesis, and Janus Kinase family kinases in the BP-difficult group (P<0.001). Conclusions We conclude that transcriptomes from cells shed in first-morning urine identify a gene expression profile in difficult-to-control hypertension that associates with renal inflammation.
Assuntos
Hipertensão , Nefrite , Humanos , Transcriptoma , Hipertensão/tratamento farmacológico , Pressão Sanguínea/fisiologia , Anti-Hipertensivos/uso terapêutico , Anti-Hipertensivos/farmacologia , Nefrite/genética , Nefrite/complicações , Inflamação/complicaçõesRESUMO
Keratoacanthoma (KA) is a common keratinocyte neoplasm that is regularly classified as a type of cutaneous squamous cell carcinoma (cSCC) despite demonstrating benign behavior. Differentiating KA from well-differentiated cSCC is difficult in many cases due to the substantial overlap of clinical and histological features. Currently, no reliable discriminating markers have been defined, and consequently, KAs are often treated similarly to cSCC, creating unnecessary surgical morbidity and healthcare costs. In this study, we used RNA sequencing to identify key differences in transcriptomes between KA and cSCC, which suggested divergent keratinocyte populations between each tumor. Imaging mass cytometry was then used to identify single-cell tissue characteristics, including cellular phenotype, frequency, topography, functional status, and interactions between KA and well-differentiated cSCC. We found that cSCC had significantly increased proportions of Ki67+ keratinocytes among tumor keratinocytes, which were dispersed significantly throughout non-basal keratinocyte communities. In cSCC, regulatory T-cells were more prevalent and held greater suppressive capacity. Furthermore, cSCC regulatory T-cells, tumor-associated macrophages, and fibroblasts had significant associations with Ki67+ keratinocytes as opposed to avoidances with KA, indicating a more immunosuppressive environment. Our data suggest that multicellular spatial features can serve as a foundation to enhance the histological discrimination of ambiguous KA and cSCC lesions.