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1.
Nat Commun ; 10(1): 4719, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31624269

RESUMO

Mosaic loss of chromosome Y (mLOY) is frequently observed in the leukocytes of ageing men. However, the genetic architecture and biological mechanisms underlying mLOY are not fully understood. In a cohort of 95,380 Japanese men, we identify 50 independent genetic markers in 46 loci associated with mLOY at a genome-wide significant level, 35 of which are unreported. Lead markers overlap enhancer marks in hematopoietic stem cells (HSCs, P ≤ 1.0 × 10-6). mLOY genome-wide association study signals exhibit polygenic architecture and demonstrate strong heritability enrichment in regions surrounding genes specifically expressed in multipotent progenitor (MPP) cells and HSCs (P ≤ 3.5 × 10-6). ChIP-seq data demonstrate that binding sites of FLI1, a fate-determining factor promoting HSC differentiation into platelets rather than red blood cells (RBCs), show a strong heritability enrichment (P = 1.5 × 10-6). Consistent with these findings, platelet and RBC counts are positively and negatively associated with mLOY, respectively. Collectively, our observations improve our understanding of the mechanisms underlying mLOY.

2.
Nat Commun ; 10(1): 4393, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31562340

RESUMO

Human height is a representative phenotype to elucidate genetic architecture. However, the majority of large studies have been performed in European population. To investigate the rare and low-frequency variants associated with height, we construct a reference panel (N = 3,541) for genotype imputation by integrating the whole-genome sequence data from 1,037 Japanese with that of the 1000 Genomes Project, and perform a genome-wide association study in 191,787 Japanese. We report 573 height-associated variants, including 22 rare and 42 low-frequency variants. These 64 variants explain 1.7% of the phenotypic variance. Furthermore, a gene-based analysis identifies two genes with multiple height-increasing rare and low-frequency nonsynonymous variants (SLC27A3 and CYP26B1; PSKAT-O < 2.5 × 10-6). Our analysis shows a general tendency of the effect sizes of rare variants towards increasing height, which is contrary to findings among Europeans, suggesting that height-associated rare variants are under different selection pressure in Japanese and European populations.

3.
Nat Commun ; 10(1): 3765, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31434886

RESUMO

Of the 1.8 billion people worldwide infected with Mycobacterium tuberculosis, 5-15% will develop active tuberculosis (TB). Approximately half will progress to active TB within the first 18 months after infection, presumably because they fail to mount an effective initial immune response. Here, in a genome-wide genetic study of early TB progression, we genotype 4002 active TB cases and their household contacts in Peru. We quantify genetic heritability ([Formula: see text]) of early TB progression to be 21.2% (standard error 0.08). This suggests TB progression has a strong genetic basis, and is comparable to traits with well-established genetic bases. We identify a novel association between early TB progression and variants located in a putative enhancer region on chromosome 3q23 (rs73226617, OR = 1.18; P = 3.93 × 10-8). With in silico and in vitro analyses we identify rs73226617 or rs148722713 as the likely functional variant and ATP1B3 as a potential causal target gene with monocyte specific function.

4.
Nat Hum Behav ; 3(5): 471-477, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31089300

RESUMO

Cigarette smoking is a risk factor for a wide range of human diseases1. To investigate the genetic components associated with smoking behaviours in the Japanese population, we conducted a genome-wide association study of four smoking-related traits using up to 165,436 individuals. In total, we identified seven new loci, including three loci associated with the number of cigarettes per day (EPHX2-CLU, RET and CUX2-ALDH2), three loci associated with smoking initiation (DLC1, CXCL12-TMEM72-AS1 and GALR1-SALL3) and LINC01793-MIR4432HG, associated with the age of smoking initiation. Of these, three loci (LINC01793-MIR4432HG, CXCL12-TMEM72-AS1 and GALR1-SALL3) were found by conducting an additional sex-stratified genome-wide association study. This additional analysis showed heterogeneity of effects between sexes. The cross-sex linkage disequilibrium score regression2,3 analysis also indicated that the genetic component of smoking initiation was significantly different between the sexes. Cross-trait linkage disequilibrium score regression analysis and trait-relevant tissue analysis showed that the number of cigarettes per day has a specific genetic background distinct from those of the other three smoking behaviours. We also report 11 diseases that share genetic basis with smoking behaviours. Although the current study should be carefully considered owing to the lack of replication samples, our findings characterized the genetic architecture of smoking behaviours. Further studies in East Asian populations are warranted to confirm our findings.

5.
Am J Hum Genet ; 104(5): 879-895, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31006511

RESUMO

Despite significant progress in annotating the genome with experimental methods, much of the regulatory noncoding genome remains poorly defined. Here we assert that regulatory elements may be characterized by leveraging local epigenomic signatures where specific transcription factors (TFs) are bound. To link these two features, we introduce IMPACT, a genome annotation strategy that identifies regulatory elements defined by cell-state-specific TF binding profiles, learned from 515 chromatin and sequence annotations. We validate IMPACT using multiple compelling applications. First, IMPACT distinguishes between bound and unbound TF motif sites with high accuracy (average AUPRC 0.81, SE 0.07; across 8 tested TFs) and outperforms state-of-the-art TF binding prediction methods, MocapG, MocapS, and Virtual ChIP-seq. Second, in eight tested cell types, RNA polymerase II IMPACT annotations capture more cis-eQTL variation than sequence-based annotations, such as promoters and TSS windows (25% average increase in enrichment). Third, integration with rheumatoid arthritis (RA) summary statistics from European (N = 38,242) and East Asian (N = 22,515) populations revealed that the top 5% of CD4+ Treg IMPACT regulatory elements capture 85.7% of RA h2, the most comprehensive explanation for RA h2 to date. In comparison, the average RA h2 captured by compared CD4+ T histone marks is 42.3% and by CD4+ T specifically expressed gene sets is 36.4%. Lastly, we find that IMPACT may be used in many different cell types to identify complex trait associated regulatory elements.

6.
Nat Genet ; 51(3): 379-386, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30718926

RESUMO

To understand the genetics of type 2 diabetes in people of Japanese ancestry, we conducted A meta-analysis of four genome-wide association studies (GWAS; 36,614 cases and 155,150 controls of Japanese ancestry). We identified 88 type 2 diabetes-associated loci (P < 5.0 × 10-8) with 115 independent signals (P < 5.0 × 10-6), of which 28 loci with 30 signals were novel. Twenty-eight missense variants were in linkage disequilibrium (r2 > 0.6) with the lead variants. Among the 28 missense variants, three previously unreported variants had distinct minor allele frequency (MAF) spectra between people of Japanese and European ancestry (MAFJPN > 0.05 versus MAFEUR < 0.01), including missense variants in genes related to pancreatic acinar cells (GP2) and insulin secretion (GLP1R). Transethnic comparisons of the molecular pathways identified from the GWAS results highlight both ethnically shared and heterogeneous effects of a series of pathways on type 2 diabetes (for example, monogenic diabetes and beta cells).


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Diabetes Mellitus Tipo 2/genética , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Adulto , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene/genética , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Desequilíbrio de Ligação/genética , Masculino , Polimorfismo de Nucleotídeo Único/genética
7.
Ann Rheum Dis ; 78(4): 509-518, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30679154

RESUMO

OBJECTIVES: Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterised by autoantibody production and widespread inflammation damaging many organs. Previous genome-wide association studies (GWASs) have revealed over 80 genetic determinants of SLE, but they collectively explain a fraction of the heritability, and only a few were proven in vivo for the involvement in SLE. We conducted a meta-analysis of SLE GWAS in the Japanese population, followed by functional analyses of a susceptibility gene with use of mutant mice. METHODS: We conducted a meta-analysis of two GWASs comprising a total of 1363 cases and 5536 controls using the 1000 Genome Project data as an imputation reference. Enrichment analyses for functional annotations were conducted. We examined Phospholipase D4 (Pld4) mutant mice to assess functional involvement of a genetic determinant. RESULTS: We found a total of 14 significant loci, which included rs2582511 in AHNAK2/PLD4 recently reported in a Chinese study and a novel locus of rs143181706 in MAMLD1 (p=7.9×10-11 and 3.7×10-8, respectively). PLD4 risk allele was associated with anti-dsDNA antibody production. Enrichment analysis of genetic signals revealed involvement of a wide range of immune-related cells and pathways. Pld4 mutant mice revealed remarkably low body weight. The mice demonstrated autoimmune phenotypes compatible with SLE, including splenomegaly and lymphadenopathy, expansion of B cells and hypersecretion of BAFF and production of autoantibodies especially anti-nuclear antibody and anti-dsDNA antibody. CONCLUSIONS:  We found a novel susceptibility gene to SLE. Pld4 mutant mice revealed autoimmune phenotypes suggesting functional involvement of PLD4 with the basics of SLE.

8.
Nat Genet ; 51(3): 470-480, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30692682

RESUMO

To perform detailed fine-mapping of the major-histocompatibility-complex region, we conducted next-generation sequencing (NGS)-based typing of the 33 human leukocyte antigen (HLA) genes in 1,120 individuals of Japanese ancestry, providing a high-resolution allele catalog and linkage-disequilibrium structure of both classical and nonclassical HLA genes. Together with population-specific deep-whole-genome-sequencing data (n = 1,276), we conducted NGS-based HLA, single-nucleotide-variant and indel imputation of large-scale genome-wide-association-study data from 166,190 Japanese individuals. A phenome-wide association study assessing 106 clinical phenotypes identified abundant, significant genotype-phenotype associations across 52 phenotypes. Fine-mapping highlighted multiple association patterns conferring independent risks from classical HLA genes. Region-wide heritability estimates and genetic-correlation network analysis elucidated the polygenic architecture shared across the phenotypes.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Complexo Principal de Histocompatibilidade/genética , Alelos , Linhagem Celular , Estudos de Associação Genética/métodos , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Desequilíbrio de Ligação/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
9.
Inflamm Regen ; 38: 21, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30410636

RESUMO

In the era of precision medicine, transcriptome analysis of whole gene expression is an essential technology. While DNA microarray has a limited dynamic range and a problem of background hybridization, RNA sequencing (RNA-seq) has a broader dynamic range and a lower background signal that increase the sensitivity and reproducibility. While transcriptome analyses in rheumatoid arthritis (RA) have generally focused on whole peripheral blood mononuclear cells (PBMC), analyses of detailed cell subsets have an increased need for understanding the pathophysiology of disease because the involvement of CD4+ T cells in the pathogenesis of RA has been established. Transcriptome analysis of detailed CD4+ T cell subsets or neutrophils shed new light on the pathophysiology of RA. There are several analyses about the effect of biological treatment. Many studies report the association between type I interferon signature gene expression and response to therapy.

10.
Nucleic Acids Res ; 2018 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-30407537

RESUMO

MicroRNAs (miRNAs) modulate the post-transcriptional regulation of target genes and are related to biology of complex human traits, but genetic landscape of miRNAs remains largely unknown. Given the strikingly tissue-specific miRNA expression profiles, we here expand a previous method to quantitatively evaluate enrichment of genome-wide association study (GWAS) signals on miRNA-target gene networks (MIGWAS) to further estimate tissue-specific enrichment. Our approach integrates tissue-specific expression profiles of miRNAs (∼1800 miRNAs in 179 cells) with GWAS to test whether polygenic signals enrich in miRNA-target gene networks and whether they fall within specific tissues. We applied MIGWAS to 49 GWASs (nTotal = 3 520 246), and successfully identified biologically relevant tissues. Further, MIGWAS could point miRNAs as candidate biomarkers of the trait. As an illustrative example, we performed differentially expressed miRNA analysis between rheumatoid arthritis (RA) patients and healthy controls (n = 63). We identified novel biomarker miRNAs (e.g. hsa-miR-762) by integrating differentially expressed miRNAs with MIGWAS results for RA, as well as novel associated loci with significant genetic risk (rs56656810 at MIR762 at 16q11; n = 91 482, P = 3.6 × 10-8). Our result highlighted that miRNA-target gene network contributes to human disease genetics in a cell type-specific manner, which could yield an efficient screening of miRNAs as promising biomarkers.

12.
Nat Commun ; 9(1): 1977, 2018 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-29773799

RESUMO

Population studies elucidating the genetic architecture of reproductive ageing have been largely limited to European ancestries, restricting the generalizability of the findings and overlooking possible key genes poorly captured by common European genetic variation. Here, we report 26 loci (all P < 5 × 10-8) for reproductive ageing, i.e. puberty timing or age at menopause, in a non-European population (up to 67,029 women of Japanese ancestry). Highlighted genes for menopause include GNRH1, which supports a primary, rather than passive, role for hypothalamic-pituitary GnRH signalling in the timing of menopause. For puberty timing, we demonstrate an aetiological role for receptor-like protein tyrosine phosphatases by combining evidence across population genetics and pre- and peri-pubertal changes in hypothalamic gene expression in rodent and primate models. Furthermore, our findings demonstrate widespread differences in allele frequencies and effect estimates between Japanese and European associated variants, highlighting the benefits and challenges of large-scale trans-ethnic approaches.

13.
Nat Commun ; 9(1): 1631, 2018 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-29691385

RESUMO

Understanding natural selection is crucial to unveiling evolution of modern humans. Here, we report natural selection signatures in the Japanese population using 2234 high-depth whole-genome sequence (WGS) data (25.9×). Using rare singletons, we identify signals of very recent selection for the past 2000-3000 years in multiple loci (ADH cluster, MHC region, BRAP-ALDH2, SERHL2). In large-scale genome-wide association study (GWAS) dataset (n = 171,176), variants with selection signatures show enrichment in heterogeneity of derived allele frequency spectra among the geographic regions of Japan, highlighted by two major regional clusters (Hondo and Ryukyu). While the selection signatures do not show enrichment in archaic hominin-derived genome sequences, they overlap with the SNPs associated with the modern human traits. The strongest overlaps are observed for the alcohol or nutrition metabolism-related traits. Our study illustrates the value of high-depth WGS to understand evolution and their relationship with disease risk.

14.
J Rheumatol ; 45(7): 905-914, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29657145

RESUMO

OBJECTIVE: Shared epitope (SE) alleles are the most significant genetic susceptibility locus in rheumatoid arthritis (RA); however, their target populations in CD4+ T cells are not well elucidated. We analyzed the association between SE alleles and the T cell receptor (TCR) repertoire diversity of naive and memory CD4+ T cells using next-generation sequencing (NGS). METHODS: The TCR beta chains in naive and memory CD4+ T cells from the peripheral blood of 22 patients with RA and 18 age- and sex-matched healthy donors (HD) were analyzed by NGS. The Renyi entropy was used to evaluate TCR repertoire diversity and its correlations with SE alleles and other variables were examined. Serum cytokine levels were measured by multiplex ELISA. RESULTS: The TCR repertoire diversity in memory CD4+ T cells was reduced in SE allele-positive patients with RA compared with HD, and showed a significant negative correlation with the SE allele dosage in RA. The TCR repertoire diversity of naive and memory T cells was also negatively correlated with disease activity, and the SE allele dosage and disease activity were independently associated with reduced TCR repertoire diversity. TCR repertoire diversity showed a significant positive correlation with the serum interleukin 2 levels. CONCLUSION: SE alleles and disease activity were negatively correlated with the TCR repertoire diversity of CD4+ T cells in RA. Considering the pivotal role of CD4+ T cells in RA, restoring the altered TCR repertoire diversity will provide a potential RA therapeutic target.

15.
Ann Rheum Dis ; 77(4): 602-611, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29331962

RESUMO

OBJECTIVES: Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare autoimmune diseases in which both genetic and environmental factors play important roles. To identify genetic factors of IIM including polymyositis, dermatomyositis (DM) and clinically amyopathic DM (CADM), we performed the first genome-wide association study for IIM in an Asian population. METHODS: We genotyped and tested 496 819 single nucleotide polymorphism for association using 576 patients with IIM and 6270 control subjects. We also examined the causal mechanism of disease-associated variants by in silico analyses using publicly available data sets as well as by in in vitro analyses using reporter assays and apoptosis assays. RESULTS: We identified a variant in WDFY4 that was significantly associated with CADM (rs7919656; OR=3.87; P=1.5×10-8). This variant had a cis-splicing quantitative trait locus (QTL) effect for a truncated WDFY4isoform (tr-WDFY4), with higher expression in the risk allele. Transexpression QTL analysis of this variant showed a positive correlation with the expression of NF-κB associated genes. Furthermore, we demonstrated that both WDFY4 and tr-WDFY4 interacted with pattern recognition receptors such as TLR3, TLR4, TLR9 and MDA5 and augmented the NF-κB activation by these receptors. WDFY4 isoforms also enhanced MDA5-induced apoptosis to a greater extent in the tr-WDFY4-transfected cells. CONCLUSIONS: As CADM is characterised by the appearance of anti-MDA5 autoantibodies and severe lung inflammation, the WDFY4 variant may play a critical role in the pathogenesis of CADM.

16.
J Autoimmun ; 89: 21-29, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29146547

RESUMO

We analyzed the transcriptome of detailed CD4+ T cell subsets including them after abatacept treatment, and examined the difference among CD4+ T cell subsets and identified gene sets that are closely associated disease activity and abatacept treatment. Seven CD4+ T cell subsets (naive, Th1, Th17, Th1/17, nonTh1/17, Tfh and Treg) were sorted from PBMCs taken from 10 RA patients and 10 healthy controls, and three RA patients donated samples before and 6 months after abatacept treatment. Paired-end RNA sequencing was performed using HiSeq 2500. A total of 149 samples except for 12 outliers were analyzed. Overview of expression pattern of RA revealed that administration of abatacept exerts a large shift toward the expression pattern of HC. Most of differentially expressed gene (DEG) upregulated in RA (n = 1776) were downregulated with abatacept treatment (n = 1349). Inversely, most of DEG downregulated in RA (n = 1860) were upregulated with abatacept treatment (n = 1294). This DEG-based analysis revealed shared pathway changes in RA CD4+ T cell subsets. Knowledge-based pathway analysis revealed the upregulation of activation-related pathways in RA that was substantially ameliorated by abatacept. Weighted gene co-expression network analysis (WGCNA) evaluated CD4+ T cells collectively and identified a gene module that consisted of 227 genes and was correlated with DAS28-CRP (Spearman's rho = 0.46, p = 4 × 10-9) and abatacept administration (Spearman's rho = -0.91, p = 5 × 10-57). The most highly connected 30 genes of this module included ZAP70 and JAK3, and pathway analysis of this module revealed dysregulation of the TCR signaling pathway network, which was ameliorated by abatacept.

17.
Clin Immunol ; 186: 9-13, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28867252

RESUMO

Genome-wide association studies have identified hundreds of risk variants associated with human autoimmune diseases. Recent evidence suggests that a substantial portion of them affect gene expression in specific cell types. To obtain the functional insights of GWAS findings, comprehensive characterization of genetic variants in human genome is a key task. In parallel with GWAS, many researches in functional genomics have been conducted in the past decade, and our understandings of cell type-specific gene regulatory system have been substantially improved. In this review, we will introduce the main research topics in functional genomics, and explain their utility to understand biological mechanisms of autoimmune diseases.

18.
Nat Genet ; 49(7): 1120-1125, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28553958

RESUMO

Recent evidence suggests that a substantial portion of complex disease risk alleles modify gene expression in a cell-specific manner. To identify candidate causal genes and biological pathways of immune-related complex diseases, we conducted expression quantitative trait loci (eQTL) analysis on five subsets of immune cells (CD4+ T cells, CD8+ T cells, B cells, natural killer (NK) cells and monocytes) and unfractionated peripheral blood from 105 healthy Japanese volunteers. We developed a three-step analytical pipeline comprising (i) prediction of individual gene expression using our eQTL database and public epigenomic data, (ii) gene-level association analysis and (iii) prediction of cell-specific pathway activity by integrating the direction of eQTL effects. By applying this pipeline to rheumatoid arthritis data sets, we identified candidate causal genes and a cytokine pathway (upregulation of tumor necrosis factor (TNF) in CD4+ T cells). Our approach is an efficient way to characterize the polygenic contributions and potential biological mechanisms of complex diseases.


Assuntos
Artrite Reumatoide/genética , Herança Multifatorial , Adulto , Alelos , Artrite Reumatoide/etnologia , Artrite Reumatoide/imunologia , Grupo com Ancestrais do Continente Asiático/genética , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Citocinas/genética , Feminino , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Sistema Imunitário , Inflamação/genética , Masculino , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Risco
19.
PLoS One ; 12(1): e0169646, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28052118

RESUMO

TGF-ß is a pleotropic cytokine involved in various biological processes. Of the three isoforms of TGF-ß, TGF-ß1 has long been recognized as an important inhibitory cytokine in the immune system and has been reported to inhibit B cell function in both mice and humans. Recently, it has been suggested that TGF-ß3 may play an important role in the regulation of immune system in mice. Murine CD4+CD25-LAG3+ regulatory T cells suppress B cell function through the production of TGF-ß3, and it has been reported that TGF-ß3 is therapeutic in a mouse model of systemic lupus erythematosus. The effect of TGF-ß3 on human B cells has not been reported, and we herein examined the effect of TGF-ß3 on human B cells. TGF-ß3 suppressed B cell survival, proliferation, differentiation into plasmablasts, and antibody secretion. Although the suppression of human B cells by TGF-ß1 has long been recognized, the precise mechanism for the suppression of B cell function by TGF-ß1 remains elusive; therefore, we examined the effect of TGF-ß1 and ß3 on pathways important in B cell activation and differentiation. TGF-ß1 and TGF-ß3 inhibited some of the key molecules of the cell cycle, as well as transcription factors important in B cell differentiation into antibody secreting cells such as IRF4, Blimp-1, and XBP1. TGF-ß1 and ß3 also inhibited B cell receptor signaling. Our results suggest that TGF-ß3 modifying therapy might be therapeutic in autoimmune diseases with B cell dysregulation in humans.


Assuntos
Formação de Anticorpos/efeitos dos fármacos , Linfócitos B/imunologia , Fator de Crescimento Transformador beta3/farmacologia , Células Produtoras de Anticorpos/efeitos dos fármacos , Células Produtoras de Anticorpos/metabolismo , Linfócitos B/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Citidina Desaminase/genética , Citidina Desaminase/metabolismo , Humanos , Imunoglobulina A/genética , Imunoglobulina A/metabolismo , Imunoglobulina G/genética , Imunoglobulina G/metabolismo , Fosforilação/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Smad/metabolismo , Quinase Syk/metabolismo , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta1/farmacologia
20.
BMC Nephrol ; 18(1): 40, 2017 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-28129738

RESUMO

BACKGROUND: A pathergy reaction is defined as a hyperreactivity of the skin in response to minimal trauma, which is important in the diagnosis of Behçet's disease (BD). However, a pathergy reaction may not be restricted to the skin, and little is known about whether an invasive medical procedure can induce the reaction. Here we present a pathergy reaction induced by renal biopsy, an invasive procedure. CASE PRESENTATION: A 46-year-old man who was diagnosed with IgA vasculitis (IgAV) at the age of 38 was treated with prednisolone and mizoribine. However, complications such as common carotid arteritis or recurrent oral ulcer suggested the possibility of another pathophysiology. Later, increasing urine protein developed, suggesting disease aggravation. However, renal biopsy showed arteriosclerotic changes caused mainly by hypertension, negating exacerbation. After renal biopsy, his renal dysfunction and body temperature fluctuated, and detailed examinations revealed recurrent oral and genital ulcers and a folliculitis-like rash on his scrotum. Later, he complained of myodesopsia caused by hemorrhage in the ocular fundus due to occlusive vasculitis. Complete BD was diagnosed after development of the symptoms, and he was treated with prednisolone and colchicine. CONCLUSION: Co-occurrence of BD with IgAV is very rare and may be associated with immune disorders. Interestingly, a renal biopsy revealed BD, which was masked by the presence of IgAV, and elucidated the etiology of the unexplainable symptoms. To the best of our knowledge, this is the first report of renal pathergy. This case enlightens clinicians to the fact that not only a needle stimulation but also an invasive procedure can cause a pathergy reaction.


Assuntos
Síndrome de Behçet/complicações , Glomerulonefrite por IGA/complicações , Vasculite/complicações , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/tratamento farmacológico , Síndrome de Behçet/imunologia , Colchicina/uso terapêutico , Glomerulonefrite por IGA/tratamento farmacológico , Glomerulonefrite por IGA/imunologia , Glomerulonefrite por IGA/patologia , Glucocorticoides/uso terapêutico , Humanos , Imunoglobulina A/imunologia , Rim/imunologia , Rim/patologia , Rim/ultraestrutura , Masculino , Pessoa de Meia-Idade , Prednisolona/uso terapêutico , Moduladores de Tubulina/uso terapêutico , Vasculite/tratamento farmacológico , Vasculite/imunologia
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