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1.
Proc Natl Acad Sci U S A ; 117(1): 552-562, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31871193

RESUMO

Systemic sclerosis (SSc) is a clinically heterogeneous autoimmune disease characterized by mutually exclusive autoantibodies directed against distinct nuclear antigens. We examined HLA associations in SSc and its autoantibody subsets in a large, newly recruited African American (AA) cohort and among European Americans (EA). In the AA population, the African ancestry-predominant HLA-DRB1*08:04 and HLA-DRB1*11:02 alleles were associated with overall SSc risk, and the HLA-DRB1*08:04 allele was strongly associated with the severe antifibrillarin (AFA) antibody subset of SSc (odds ratio = 7.4). These African ancestry-predominant alleles may help explain the increased frequency and severity of SSc among the AA population. In the EA population, the HLA-DPB1*13:01 and HLA-DRB1*07:01 alleles were more strongly associated with antitopoisomerase (ATA) and anticentromere antibody-positive subsets of SSc, respectively, than with overall SSc risk, emphasizing the importance of HLA in defining autoantibody subtypes. The association of the HLA-DPB1*13:01 allele with the ATA+ subset of SSc in both AA and EA patients demonstrated a transancestry effect. A direct correlation between SSc prevalence and HLA-DPB1*13:01 allele frequency in multiple populations was observed (r = 0.98, P = 3 × 10-6). Conditional analysis in the autoantibody subsets of SSc revealed several associated amino acid residues, mostly in the peptide-binding groove of the class II HLA molecules. Using HLA α/ß allelic heterodimers, we bioinformatically predicted immunodominant peptides of topoisomerase 1, fibrillarin, and centromere protein A and discovered that they are homologous to viral protein sequences from the Mimiviridae and Phycodnaviridae families. Taken together, these data suggest a possible link between HLA alleles, autoantibodies, and environmental triggers in the pathogenesis of SSc.

2.
Semin Cell Dev Biol ; 2019 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-31859147

RESUMO

Systemic sclerosis (SSc) is a highly challenging chronic condition that is dominated by the pathogenetic triad of vascular damage, immune dysregulation/autoimmunity and fibrosis in multiple organs. A hallmark of SSc is the remarkable degree of molecular and phenotypic disease heterogeneity, which surpasses that of other complex rheumatic diseases. Disease trajectories in SSc are unpredictable and variable from patient to patient. Disease-modifying therapies for SSc are lacking, long-term morbidity is considerable and mortality remains unacceptably high. Currently-used empirical approaches to disease modification have modest and variable clinical efficacy and impact on survival, are expensive and frequently associated with unfavorable side effects, and none can be considered curative. However, research during the past several years is yielding significant advances with therapeutic potential. In particular, the application of unbiased omics-based discovery technologies to large and well-characterized SSc patient cohorts, coupled with hypothesis-testing experimental research using a variety of model systems is revealing new insights into SSc that allow formulation of a more nuanced appreciation of disease heterogeneity, and a deepening understanding of pathogenesis. Indeed, we are now presented with numerous novel and rationally-based strategies for targeted SSc therapy, several of which are currently, or expected to be shortly, undergoing clinical evaluation. In this review, we discuss promising novel therapeutic targets and rationally-based approaches to disease modification that have the potential to improve long-term outcomes in SSc.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31841044

RESUMO

Systemic sclerosis (SSc) is a complex, multi-organ, autoimmune disease. Lung fibrosis occurs in ~80% of patients with SSc; 25-30% develop progressive interstitial lung disease (ILD). The pathogenesis of fibrosis in SSc associated ILD (SSc-ILD) involves cellular injury, activation/differentiation of mesenchymal cells and morphological/biological changes in epithelial/endothelial cells. Risk factors for progressive SSc-ILD include older age, male sex, lung involvement on baseline high-resolution computed tomography, reduced diffusing capacity for carbon monoxide and reduced forced vital capacity. SSc-ILD is characterized by genetic risk architecture distinct from that associated with idiopathic pulmonary fibrosis (IPF). Presence of anti-Scl-70 antibodies and absence of anti-centromere antibodies indicate increased likelihood of progressive ILD. Elevated levels of serum Krebs von den Lungen-6 (KL6) and CRP are associated with SSc-ILD severity, although whether KL6 independently predicts SSc-ILD progression remains controversial. A promising prognostic indicator is serum chemokine (C-C motif) ligand 18. SSc-ILD shares similarities with IPF, although clear differences exist. Histologically, a non-specific interstitial pneumonia pattern is commonly observed in SSc-ILD, whereas IPF is defined by usual interstitial pneumonia. The course of SSc-ILD is variable, ranging from minor, stable disease to a progressive course, while all IPF patients experience progression of disease. Although appropriately treated SSc-ILD patients have better chances of stabilization and survival, a relentlessly progressive course, akin to IPF, is seen in a minority. Better understanding of cellular and molecular pathogenesis, genetic risk and distinctive features of SSc-ILD, and identification of robust prognostic biomarkers are needed for optimal disease management. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

5.
Curr Opin Rheumatol ; 31(6): 589-594, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31449135

RESUMO

PURPOSE OF REVIEW: Review the current state of knowledge and recent developments in the field of scleroderma-related calcinosis [systemic sclerosis (SSc)-calcinosis], focusing on emerging information related to pathophysiology. RECENT FINDINGS: Recent studies have begun to characterize that factors that regulate ectopic mineralization, and those that underlie the imbalance of promoters and inhibitors of this process in SSc. SUMMARY: Calcinosis cutis due to ectopic mineralization is a common and highly troublesome complication of SSc. Despite its significant prevalence and clinical impact, the pathogenesis is poorly understood and effective treatment is lacking. More research to better understand the pathophysiology is needed for the identification of novel management strategies for this severe complication of SSc.

6.
Ann Rheum Dis ; 78(10): 1371-1378, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31391177

RESUMO

OBJECTIVE: In the randomised scleroderma: Cyclophosphamide Or Transplantation (SCOT trial) (NCT00114530), myeloablation, followed by haematopoietic stem cell transplantation (HSCT), led to improved clinical outcomes compared with monthly cyclophosphamide (CYC) treatment in systemic sclerosis (SSc). Herein, the study aimed to determine global molecular changes at the whole blood transcript and serum protein levels ensuing from HSCT in comparison to intravenous monthly CYC in 62 participants enrolled in the SCOT study. METHODS: Global transcript studies were performed at pretreatment baseline, 8 months and 26 months postrandomisation using Illumina HT-12 arrays. Levels of 102 proteins were measured in the concomitantly collected serum samples. RESULTS: At the baseline visit, interferon (IFN) and neutrophil transcript modules were upregulated and the cytotoxic/NK module was downregulated in SSc compared with unaffected controls. A paired comparison of the 26 months to the baseline samples revealed a significant decrease of the IFN and neutrophil modules and an increase in the cytotoxic/NK module in the HSCT arm while there was no significant change in the CYC control arm. Also, a composite score of correlating serum proteins with IFN and neutrophil transcript modules, as well as a multilevel analysis showed significant changes in SSc molecular signatures after HSCT while similar changes were not observed in the CYC arm. Lastly, a decline in the IFN and neutrophil modules was associated with an improvement in pulmonary forced vital capacity and an increase in the cytotoxic/NK module correlated with improvement in skin score. CONCLUSION: HSCT contrary to conventional treatment leads to a significant 'correction' in disease-related molecular signatures.

8.
Curr Rheumatol Rep ; 21(6): 29, 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31115730

RESUMO

PURPOSE OF REVIEW: The myofibroblast is the culprit in the pathogenesis of fibrosis in systemic sclerosis (SSc). Activation of morphogen signaling pathways has been shown to be critically involved in organ fibrosis. Remarkably, the cellular receptors and key molecules from these signaling pathways are localized in the primary cilium. The primary cilium is a unique cellular organelle present in virtually all cells. This article summarizes recent studies evaluating the association between primary cilia and morphogen signaling driving myofibroblast transition and subsequent fibrosis. RECENT FINDINGS: Emerging observations implicate dysfunctional primary cilia in fibrosis in many different tissues and organs. Primary cilia seem to be necessary for the initiation of the transition and sustained activation of myofibroblasts. We summarize recent progress in this field and propose the primary cilium as a potential mediator of fibrosis pathogenesis in SSc. Understanding the contributions of primary cilia in fibrosis may ultimately inform the development of entirely new approaches for fibrosis prevention and treatment.

9.
Nat Rev Rheumatol ; 15(4): 208-224, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30796362

RESUMO

Systemic sclerosis (SSc) has the highest cause-specific mortality of all the connective tissue diseases, and the aetiology of this complex and heterogeneous condition remains an enigma. Current disease-modifying therapies for SSc predominantly target inflammatory and vascular pathways but have variable and unpredictable clinical efficacy, and none is curative. Moreover, many of these therapies possess undesirable safety profiles and have no appreciable effect on long-term mortality. This Review describes the most promising of the existing therapeutic targets for SSc and places them in the context of our evolving understanding of the pathophysiology of this disease. As well as taking an in-depth look at the immune, inflammatory, vascular and fibrotic pathways implicated in the pathogenesis of SSc, this Review discusses emerging treatment targets and therapeutic strategies. The article concludes with an overview of important unanswered questions in SSc research that might inform the design of future studies of treatments aimed at modifying the course of this disease.

11.
Arthritis Rheumatol ; 71(6): 964-971, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30614663

RESUMO

OBJECTIVE: To generate a core set of items to develop classification criteria for scleroderma renal crisis (SRC) using consensus methodology. METHODS: An international, multidisciplinary panel of experts was invited to participate in a 3-round Delphi exercise developed using a survey based on items identified by a scoping review. In round 1, participants were asked to identify omissions and clarify ambiguities regarding the items in the survey. In round 2, participants were asked to rate the validity and feasibility of the items using Likert-type scales ranging from 1 to 9 (where 1 = very invalid/unfeasible, 5 = uncertain, and 9 = very valid/feasible). In round 3, participants reviewed the results and comments from round 2 and were asked to provide final ratings. Items rated as highly valid and feasible (median scores ≥7 for each) in round 3 were selected as the provisional core set of items. A consensus meeting using a nominal group technique was conducted to further reduce the core set of items. RESULTS: Ninety-nine experts from 16 countries participated in the Delphi exercise. Of the 31 items in the survey, consensus was achieved on 13, in the categories hypertension, renal insufficiency, proteinuria, and hemolysis. Eleven experts took part in the nominal group technique discussion, where consensus was achieved in 5 domains: blood pressure, acute kidney injury, microangiopathic hemolytic anemia, target organ dysfunction, and renal histopathology. CONCLUSION: A core set of items that characterize SRC was identified using consensus methodology. This core set will be used in future data-driven phases of this project to develop classification criteria for SRC.


Assuntos
Lesão Renal Aguda/classificação , Hipertensão Maligna/classificação , Rim/patologia , Escleroderma Sistêmico/complicações , Lesão Renal Aguda/etiologia , Anemia Hemolítica/classificação , Anemia Hemolítica/etiologia , Pressão Sanguínea , Técnica Delfos , Humanos , Hipertensão/classificação , Hipertensão/etiologia , Hipertensão Maligna/etiologia , Proteinúria/classificação , Proteinúria/etiologia , Índice de Gravidade de Doença
12.
ChemMedChem ; 14(1): 78-82, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30376607

RESUMO

Antibiotics with novel mechanisms of action are desperately needed to combat the increasing rates of multidrug-resistant infections. Bacterial pantothenate kinase (PanK) has emerged as a target of interest to cut off the biosynthesis of coenzyme A. Herein we report the results of an in vitro high-throughput screen of over 10 000 small molecules against Bacillus anthracis PanK, as well as a follow-up screen of hits against PanK isolated from Pseudomonas aeruginosa and Burkholderia cenocepacia. Nine hits are structurally categorized and analyzed to set the stage for future drug development.


Assuntos
Antibacterianos/farmacologia , Bacillus anthracis/efeitos dos fármacos , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Bacillus anthracis/enzimologia , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade
13.
J Rheumatol ; 46(2): 176-183, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30275260

RESUMO

OBJECTIVE: We sought to identify predictors of mortality and cardiopulmonary hospitalizations in patients at risk for pulmonary hypertension (PH) and enrolled in PHAROS, a prospective cohort study to investigate the natural history of PH in systemic sclerosis (SSc). METHODS: The at-risk population for PH was defined by the following entry criteria: echocardiogram systolic pulmonary arterial pressure > 40 mmHg, or DLCO < 55% predicted or ratio of % forced vital capacity/%DLCO > 1.6, measured by pulmonary function testing. Baseline clinical measures were evaluated as predictors of hospitalization and death between 2005 and 2014. Cox proportional hazards models were censored at date of PH onset or latest study visit and adjusted for age, sex, race, and disease duration. RESULTS: Of the 236 at-risk subjects who were followed for a median of 4 years (range 0.4-8.5 yrs), 35 developed PH after entering PHAROS (reclassified as PH group). In the at-risk group, higher mortality was strongly associated with male sex, low %DLCO, exercise oxygen desaturation, anemia, abnormal dyspnea scores, and baseline pericardial effusion. Risks for cardiopulmonary hospitalization were associated with increased dyspnea and pericardial effusions, although PH patients with DLCO < 50% had the highest risk of cardiopulmonary hospitalizations. CONCLUSION: Risk factors for poor outcome in patients with SSc who are at risk for PH were similar to others with SSc-PH and SSc-pulmonary arterial hypertension, including male sex, DLCO < 50%, exercise oxygen desaturation, and pericardial effusions. This group should undergo right heart catheterization and receive appropriate intervention if PH is confirmed.

14.
Front Immunol ; 9: 2434, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30405628

RESUMO

Systemic sclerosis (SSc) is a poorly understood heterogeneous condition with progressive multi-organ fibrosis. Recent genetic and genomic evidence suggest a pathogenic role for dysregulated innate immunity and toll-like receptor (TLR) activity in SSc. Levels of both TLR4, as well as certain endogenous TLR ligands, are elevated in skin and lung tissues from patients with SSc and correlate with clinical disease parameters. Conversely, genetic targeting of TLR4 or its endogenous "damage-associated" ligands ameliorates progressive tissue fibrosis. Targeting TLR4 signaling therefore represents a pharmacological strategy to prevent intractable fibrosis. We examined the effect of TAK242, a small molecule TLR4 inhibitor, in preclinical fibrosis models and in SSc fibroblasts. TAK242 treatment prevented, promoted regression of, bleomycin-induced dermal and pulmonary fibrosis, and reduced the expression of several pro-fibrotic mediators. Furthermore, TAK242 ameliorated peritoneal fibrosis and reduced spontaneous hypodermal thickness in TSK/+ mice. Importantly, TAK242 abrogated collagen synthesis and myofibroblasts differentiation in explanted constitutively active SSc fibroblast. Altogether, these findings identify TAK242 as an anti-fibrotic agent in preclinical models of organ fibrosis. TAK242 might potentially represent a novel strategy for the treatment of SSc and other fibrotic diseases.


Assuntos
Fibroblastos/fisiologia , Fibrose Pulmonar/metabolismo , Escleroderma Sistêmico/metabolismo , Pele/patologia , Receptor 4 Toll-Like/metabolismo , Animais , Bleomicina , Células Cultivadas , Modelos Animais de Doenças , Feminino , Fibrose , Humanos , Camundongos , Camundongos Endogâmicos C3H , Camundongos Transgênicos , Mutação/genética , Fibrose Pulmonar/induzido quimicamente , Transdução de Sinais , Sulfonamidas/farmacologia , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/genética
16.
Pharmacol Ther ; 192: 163-169, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30081049

RESUMO

Systemic sclerosis (SSc) is an idiopathic autoimmune disease characterised by inflammation, vascular problems, cytokine dysregulation and ultimately fibrosis, which accounts for poor prognosis and eventual mortality. At present no curative treatments exist, hence there is an urgent need to better understand the aetiology and develop improved therapies accordingly. Although still widely debated, significant evidence points to upregulation of the innate immune response via the activity of Toll-like receptors (TLRs) and the NLRP3 inflammasome as the start points in a cascade of signaling events which drives excessive extracellular matrix protein production, causing fibrosis. Herein the recent breakthroughs which have implicated TLR signaling and the NLRP3 inflammasome in SSc and the novel therapeutic possibilities this introduces to the field will be discussed.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Escleroderma Sistêmico/tratamento farmacológico , Receptores Toll-Like/metabolismo , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Humanos , Imunidade Inata/efeitos dos fármacos , Imunossupressores/uso terapêutico , Terapia de Alvo Molecular , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/metabolismo , Transdução de Sinais/efeitos dos fármacos
17.
Sci Rep ; 8(1): 11843, 2018 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-30087356

RESUMO

The hallmarks of systemic sclerosis (SSc) are autoimmunity, microangiopathy and fibrosis. Skin fibrosis is accompanied by attrition of the dermal white adipose tissue layer, and alterations in the levels and function of adiponectin. Since these findings potentially implicate adiponectin in the pathogenesis of SSc, we employed a novel pharmacological approach to augment adiponectin signaling using AdipoRon, an orally active adiponectin receptor agonist. Chronic treatment with AdipoRon significantly ameliorated bleomycin-induced dermal fibrosis in mice. AdipoRon attenuated fibroblast activation, adipocyte-to-myofibroblast transdifferentiation, Th2/Th17-skewed polarization of the immune response, vascular injury and endothelial-to-mesenchymal transition within the lesional skin. In vitro, AdipoRon abrogated profibrotic responses elicited by TGF-ß in normal fibroblasts, and reversed the inherently-activated profibrotic phenotype of SSc fibroblasts. In view of these broadly beneficial effects on all three cardinal pathomechanisms underlying the clinical manifestations of SSc, pharmacological augmentation of adiponectin signaling might represent a novel strategy for the treatment of SSc.


Assuntos
Inflamação/prevenção & controle , Piperidinas/farmacologia , Receptores de Adiponectina/agonistas , Escleroderma Sistêmico/tratamento farmacológico , Pele/patologia , Lesões do Sistema Vascular/prevenção & controle , Administração Oral , Animais , Bleomicina , Modelos Animais de Doenças , Feminino , Fibrose/induzido quimicamente , Fibrose/prevenção & controle , Humanos , Inflamação/induzido quimicamente , Camundongos Endogâmicos C57BL , Piperidinas/administração & dosagem , Receptores de Adiponectina/metabolismo , Escleroderma Sistêmico/metabolismo , Escleroderma Sistêmico/patologia , Transdução de Sinais/efeitos dos fármacos , Lesões do Sistema Vascular/patologia
18.
Arthritis Res Ther ; 20(1): 145, 2018 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-29996896

RESUMO

BACKGROUND: A pivotal role for adipose tissue homeostasis in systemic sclerosis (SSc) skin fibrosis is increasingly recognized. The nuclear receptor PPAR-γ is the master regulator of adipogenesis. Peroxisome proliferator activated receptor-γ (PPAR-γ) has antifibrotic effects by blocking transforming growth factor-ß (TGF-ß) and is dysregulated in SSc. To unravel the impact of dysregulated PPAR-γ in SSc, we focused on nuclear corepressor (NCoR), which negatively regulates PPAR-γ activity and suppresses adipogenesis. METHODS: An NCoR-regulated gene signature was measured in the SSc skin transcriptome. Experimental skin fibrosis was examined in mice with adipocyte-specific NCoR ablation. RESULTS: SSc skin biopsies demonstrated deregulated NCoR signaling. A 43-gene NCoR gene signature showed strong positive correlation with PPAR-γ signaling (R = 0.919, p < 0.0001), whereas negative correlations with TGF-ß signaling (R = - 0.796, p < 0.0001) and the modified Rodnan skin score (R = - 0.49, p = 0.004) were found. Mice with adipocyte-specific NCoR ablation demonstrated significant protection from experimental skin fibrosis and inflammation. The protective effects were mediated primarily through endogenous PPAR-γ. CONCLUSIONS: Our results implicate, for the first time, to our knowledge, deregulated NCoR/PPAR-γ pathways in SSc, and they support a role of adipocyte modulation of skin fibrosis. Pharmacologic restoration of NCoR/PPAR-γ signaling may represent a novel strategy to control skin fibrosis in SSc.


Assuntos
Adipócitos/metabolismo , Correpressor 1 de Receptor Nuclear/metabolismo , PPAR gama/metabolismo , Escleroderma Sistêmico/patologia , Adipócitos/patologia , Adulto , Idoso , Animais , Feminino , Fibrose , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Escleroderma Sistêmico/metabolismo , Pele/patologia
19.
JCI Insight ; 3(13)2018 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-29997297

RESUMO

Persistent fibrosis in multiple organs is the hallmark of systemic sclerosis (SSc). Recent genetic and genomic studies implicate TLRs and their damage-associated molecular pattern (DAMP) endogenous ligands in fibrosis. To test the hypothesis that TLR4 and its coreceptor myeloid differentiation 2 (MD2) drive fibrosis persistence, we measured MD2/TLR4 signaling in tissues from patients with fibrotic SSc, and we examined the impact of MD2 targeting using a potentially novel small molecule. Levels of MD2 and TLR4, and a TLR4-responsive gene signature, were enhanced in SSc skin biopsies. We developed a small molecule that selectively blocks MD2, which is uniquely required for TLR4 signaling. Targeting MD2/TLR4 abrogated inducible and constitutive myofibroblast transformation and matrix remodeling in fibroblast monolayers, as well as in 3-D scleroderma skin equivalents and human skin explants. Moreover, the selective TLR4 inhibitor prevented organ fibrosis in several preclinical disease models and mouse strains, and it reversed preexisting fibrosis. Fibroblast-specific deletion of TLR4 in mice afforded substantial protection from skin and lung fibrosis. By comparing experimentally generated fibroblast TLR4 gene signatures with SSc skin biopsy gene expression datasets, we identified a subset of SSc patients displaying an activated TLR4 signature. Together, results from these human and mouse studies implicate MD2/TLR4-dependent fibroblast activation as a key driver of persistent organ fibrosis. The results suggest that SSc patients with high TLR4 activity might show optimal therapeutic response to selective inhibitors of MD2/TLR4 complex formation.


Assuntos
Fibroblastos/metabolismo , Fibrose/metabolismo , Pulmão/metabolismo , Pele/metabolismo , Receptor 4 Toll-Like/metabolismo , Adulto , Alarminas/metabolismo , Animais , Autoimunidade , Biópsia , Feminino , Fibrose/patologia , Deleção de Genes , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Pulmão/patologia , Antígeno 96 de Linfócito/genética , Antígeno 96 de Linfócito/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Miofibroblastos , Escleroderma Sistêmico , Transdução de Sinais , Pele/patologia , Receptor 4 Toll-Like/efeitos dos fármacos , Receptor 4 Toll-Like/genética , Regulação para Cima
20.
Arthritis Rheumatol ; 70(10): 1654-1660, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29732714

RESUMO

OBJECTIVE: Whole-exome sequencing (WES) studies in systemic sclerosis (SSc) patients of European American (EA) ancestry have identified variants in the ATP8B4 gene and enrichment of variants in genes in the extracellular matrix (ECM)-related pathway that increase SSc susceptibility. This study was undertaken to evaluate the association of the ATP8B4 gene and the ECM-related pathway with SSc in a cohort of African American (AA) patients. METHODS: SSc patients of AA ancestry were enrolled from 23 academic centers across the US under the Genome Research in African American Scleroderma Patients consortium. Unrelated AA individuals without serologic evidence of autoimmunity who were enrolled in the Howard University Family Study were used as unaffected controls. Functional variants in genes reported in the 2 WES studies in EA patients with SSc were selected for gene association testing using the optimized sequence kernel association test (SKAT-O) and pathway analysis by Ingenuity Pathway Analysis in 379 patients and 411 controls. RESULTS: Principal components analysis demonstrated that the patients and controls had similar ancestral backgrounds, with roughly equal proportions of mean European admixture. Using SKAT-O, we examined the association of individual genes that were previously reported in EA patients and none remained significant, including ATP8B4 (P = 0.98). However, we confirmed the previously reported association of the ECM-related pathway with enrichment of variants within the COL13A1, COL18A1, COL22A1, COL4A3, COL4A4, COL5A2, PROK1, and SERPINE1 genes (corrected P = 1.95 × 10-4 ). CONCLUSION: In the largest genetic study in AA patients with SSc to date, our findings corroborate the role of functional variants that aggregate in a fibrotic pathway and increase SSc susceptibility.


Assuntos
Afro-Americanos/genética , Redes Reguladoras de Genes/genética , Predisposição Genética para Doença/etnologia , Escleroderma Sistêmico/etnologia , Escleroderma Sistêmico/genética , Adenosina Trifosfatases/genética , Adulto , Grupo com Ancestrais do Continente Europeu/genética , Proteínas da Matriz Extracelular/genética , Feminino , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Componente Principal , Sequenciamento Completo do Exoma
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