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1.
Hum Mol Genet ; 2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33555323

RESUMO

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gut. Genetic association studies have identified the highly variable human leukocyte antigen (HLA) region as the strongest susceptibility locus for IBD, and specifically DRB1*01:03 as a determining factor for ulcerative colitis (UC). However, for most of the association signal such a delineation could not be made due to tight structures of linkage disequilibrium within the HLA. The aim of this study was therefore to further characterize the HLA signal using a trans-ethnic approach. We performed a comprehensive fine mapping of single HLA alleles in UC in a cohort of 9272 individuals with African American, East Asian, Puerto Rican, Indian and Iranian descent and 40 691 previously analyzed Caucasians, additionally analyzing whole HLA haplotypes. We computationally characterized the binding of associated HLA alleles to human self-peptides and analysed the physico-chemical properties of the HLA proteins and predicted self-peptidomes. Highlighting alleles of the HLA-DRB1*15 group and their correlated HLA-DQ-DR haplotypes, we identified consistent associations (regarding effects directions/magnitudes) across different ethnicities but also identified population-specific signals (regarding differences in allele frequencies). We observed that DRB1*01:03 is mostly present in individuals of Western European descent and hardly present in non-Caucasian individuals. We found peptides predicted to bind to risk HLA alleles to be rich in positively charged amino acids such. We conclude that the HLA plays an important role for UC susceptibility across different ethnicities. This research further implicates specific features of peptides that are predicted to bind risk and protective HLA proteins.

2.
Nat Commun ; 12(1): 1264, 2021 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-33627654

RESUMO

The recent development of imputation methods enabled the prediction of human leukocyte antigen (HLA) alleles from intergenic SNP data, allowing studies to fine-map HLA for immune phenotypes. Here we report an accurate HLA imputation method, CookHLA, which has superior imputation accuracy compared to previous methods. CookHLA differs from other approaches in that it locally embeds prediction markers into highly polymorphic exons to account for exonic variability, and in that it adaptively learns the genetic map within MHC from the data to facilitate imputation. Our benchmarking with real datasets shows that our method achieves high imputation accuracy in a wide range of scenarios, including situations where the reference panel is small or ethnically unmatched.


Assuntos
Antígenos HLA/metabolismo , Alelos , Grupo com Ancestrais do Continente Asiático , Diabetes Mellitus Tipo 1/genética , Genoma Humano/genética , Estudo de Associação Genômica Ampla , Genótipo , Antígenos HLA/genética , Humanos , Modelos Teóricos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
3.
Nat Commun ; 12(1): 1098, 2021 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-33597505

RESUMO

Many diseases exhibit population-specific causal effect sizes with trans-ethnic genetic correlations significantly less than 1, limiting trans-ethnic polygenic risk prediction. We develop a new method, S-LDXR, for stratifying squared trans-ethnic genetic correlation across genomic annotations, and apply S-LDXR to genome-wide summary statistics for 31 diseases and complex traits in East Asians (average N = 90K) and Europeans (average N = 267K) with an average trans-ethnic genetic correlation of 0.85. We determine that squared trans-ethnic genetic correlation is 0.82× (s.e. 0.01) depleted in the top quintile of background selection statistic, implying more population-specific causal effect sizes. Accordingly, causal effect sizes are more population-specific in functionally important regions, including conserved and regulatory regions. In regions surrounding specifically expressed genes, causal effect sizes are most population-specific for skin and immune genes, and least population-specific for brain genes. Our results could potentially be explained by stronger gene-environment interaction at loci impacted by selection, particularly positive selection.


Assuntos
Genética Populacional/métodos , Estudo de Associação Genômica Ampla/métodos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Seleção Genética , Algoritmos , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Genômica/métodos , Haplótipos/genética , Humanos , Modelos Genéticos
4.
Nat Genet ; 52(12): 1346-1354, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33257898

RESUMO

Poor trans-ancestry portability of polygenic risk scores is a consequence of Eurocentric genetic studies and limited knowledge of shared causal variants. Leveraging regulatory annotations may improve portability by prioritizing functional over tagging variants. We constructed a resource of 707 cell-type-specific IMPACT regulatory annotations by aggregating 5,345 epigenetic datasets to predict binding patterns of 142 transcription factors across 245 cell types. We then partitioned the common SNP heritability of 111 genome-wide association study summary statistics of European (average n ≈ 189,000) and East Asian (average n ≈ 157,000) origin. IMPACT annotations captured consistent SNP heritability between populations, suggesting prioritization of shared functional variants. Variant prioritization using IMPACT resulted in increased trans-ancestry portability of polygenic risk scores from Europeans to East Asians across all 21 phenotypes analyzed (49.9% mean relative increase in R2). Our study identifies a crucial role for functional annotations such as IMPACT to improve the trans-ancestry portability of genetic data.

5.
Nat Rev Rheumatol ; 2020 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-33139947

RESUMO

The emergence of COVID-19 in early 2020 led to unprecedented changes to rheumatology clinical practice worldwide, including the closure of research laboratories, the restructuring of hospitals and the rapid transition to virtual care. As governments sought to slow and contain the spread of the disease, rheumatologists were presented with the difficult task of managing risks, to their patients as well as to themselves, while learning and implementing new systems for remote health care. Consequently, the COVID-19 pandemic led to a transformation in health infrastructures and telemedicine that could become powerful tools for rheumatologists, despite having some limitations. In this Viewpoint, five experts from different regions discuss their experiences of the pandemic, including the most challenging aspects of this unexpected transition, the advantages and limitations of virtual visits, and potential opportunities going forward.

6.
Am J Hum Genet ; 107(4): 612-621, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32888428

RESUMO

Hypersensitivity reactions to drugs are often unpredictable and can be life threatening, underscoring a need for understanding their underlying mechanisms and risk factors. The extent to which germline genetic variation influences the risk of commonly reported drug allergies such as penicillin allergy remains largely unknown. We extracted data from the electronic health records of more than 600,000 participants from the UK, Estonian, and Vanderbilt University Medical Center's BioVU biobanks to study the role of genetic variation in the occurrence of self-reported penicillin hypersensitivity reactions. We used imputed SNP to HLA typing data from these cohorts to further fine map the human leukocyte antigen (HLA) association and replicated our results in 23andMe's research cohort involving a total of 1.12 million individuals. Genome-wide meta-analysis of penicillin allergy revealed two loci, including one located in the HLA region on chromosome 6. This signal was further fine-mapped to the HLA-B∗55:01 allele (OR 1.41 95% CI 1.33-1.49, p value 2.04 × 10-31) and confirmed by independent replication in 23andMe's research cohort (OR 1.30 95% CI 1.25-1.34, p value 1.00 × 10-47). The lead SNP was also associated with lower lymphocyte counts and in silico follow-up suggests a potential effect on T-lymphocytes at HLA-B∗55:01. We also observed a significant hit in PTPN22 and the GWAS results correlated with the genetics of rheumatoid arthritis and psoriasis. We present robust evidence for the role of an allele of the major histocompatibility complex (MHC) I gene HLA-B in the occurrence of penicillin allergy.


Assuntos
Artrite Reumatoide/genética , Hipersensibilidade a Drogas/genética , Antígenos HLA-B/genética , Polimorfismo de Nucleotídeo Único , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Psoríase/genética , Adulto , Alelos , Artrite Reumatoide/complicações , Artrite Reumatoide/imunologia , Cromossomos Humanos Par 6/química , Hipersensibilidade a Drogas/complicações , Hipersensibilidade a Drogas/etiologia , Hipersensibilidade a Drogas/imunologia , Registros Eletrônicos de Saúde , Europa (Continente) , Feminino , Expressão Gênica , Loci Gênicos , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Antígenos HLA-B/imunologia , Teste de Histocompatibilidade , Humanos , Masculino , Penicilinas/efeitos adversos , Proteína Tirosina Fosfatase não Receptora Tipo 22/imunologia , Psoríase/complicações , Psoríase/imunologia , Autorrelato , Linfócitos T/imunologia , Linfócitos T/patologia , Estados Unidos
7.
Arthritis Rheumatol ; 72(11): 1863-1871, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32969204

RESUMO

OBJECTIVE: To identify interactions between genetic factors and current or recent smoking in relation to risk of developing systemic lupus erythematosus (SLE). METHODS: For the study, 673 patients with SLE (diagnosed according to the American College of Rheumatology 1997 updated classification criteria) were matched by age, sex, and race (first 3 genetic principal components) to 3,272 control subjects without a history of connective tissue disease. Smoking status was classified as current smoking/having recently quit smoking within 4 years before diagnosis (or matched index date for controls) versus distant past/never smoking. In total, 86 single-nucleotide polymorphisms and 10 classic HLA alleles previously associated with SLE were included in a weighted genetic risk score (wGRS), with scores dichotomized as either low or high based on the median value in control subjects (low wGRS being defined as less than or equal to the control median; high wGRS being defined as greater than the control median). Conditional logistic regression models were used to estimate both the risk of SLE and risk of anti-double-stranded DNA autoantibody-positive (dsDNA+) SLE. Additive interactions were assessed using the attributable proportion (AP) due to interaction, and multiplicative interactions were assessed using a chi-square test (with 1 degree of freedom) for the wGRS and for individual risk alleles. Separate repeated analyses were carried out among subjects of European ancestry only. RESULTS: The mean ± SD age of the SLE patients at the time of diagnosis was 36.4 ± 15.3 years. Among the 673 SLE patients included, 92.3% were female and 59.3% were dsDNA+. Ethnic distributions were as follows: 75.6% of European ancestry, 4.5% of Asian ancestry, 11.7% of African ancestry, and 8.2% classified as other ancestry. A high wGRS (odds ratio [OR] 2.0, P = 1.0 × 10-51 versus low wGRS) and a status of current/recent smoking (OR 1.5, P = 0.0003 versus distant past/never smoking) were strongly associated with SLE risk, with significant additive interaction (AP 0.33, P = 0.0012), and associations with the risk of anti-dsDNA+ SLE were even stronger. No significant multiplicative interactions with the total wGRS (P = 0.58) or with the HLA-only wGRS (P = 0.06) were found. Findings were similar in analyses restricted to only subjects of European ancestry. CONCLUSION: The strong additive interaction between an updated SLE genetic risk score and current/recent smoking suggests that smoking may influence specific genes in the pathogenesis of SLE.

8.
bioRxiv ; 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32793902

RESUMO

Immunosuppressive and anti-cytokine treatment may have a protective effect for patients with COVID-19. Understanding the immune cell states shared between COVID-19 and other inflammatory diseases with established therapies may help nominate immunomodulatory therapies. Using an integrative strategy, we built a reference by meta-analyzing > 300,000 immune cells from COVID-19 and 5 inflammatory diseases including rheumatoid arthritis (RA), Crohn's disease (CD), ulcerative colitis (UC), lupus, and interstitial lung disease. Our cross-disease analysis revealed that an FCN1 + inflammatory macrophage state is common to COVID-19 bronchoalveolar lavage samples, RA synovium, CD ileum, and UC colon. We also observed that a CXCL10 + CCL2 + inflammatory macrophage state is abundant in severe COVID-19, inflamed CD and RA, and expresses inflammatory genes such as GBP1, STAT1 , and IL1B . We found that the CXCL10 + CCL2 + macrophages are transcriptionally similar to blood-derived macrophages stimulated with TNF- α and IFN- γ ex vivo . Our findings suggest that IFN- γ , alongside TNF- α , might be a key driver of this abundant inflammatory macrophage phenotype in severe COVID-19 and other inflammatory diseases, which may be targeted by existing immunomodulatory therapies.

9.
Bioinformatics ; 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32735319

RESUMO

SUMMARY: Fine-mapping human leukocyte antigen (HLA) genes involved in disease susceptibility to individual alleles or amino acid residues has been challenging. Using information regarding HLA alleles obtained from HLA typing, HLA imputation, or HLA inference, our software expands the alleles to amino acid sequences using the most recent IMGT/HLA database, and prepares a dataset suitable for fine-mapping analysis. Our software also provides useful functionalities such as various association tests, visualization tools, and nomenclature conversion. AVAILABILITY: https://github.com/WansonChoi/HATK.

10.
Sci Adv ; 6(26): eaba4353, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32637608

RESUMO

Fibroblast-like synoviocytes (FLS) are joint-lining cells that promote rheumatoid arthritis (RA) pathology. Current disease-modifying antirheumatic agents (DMARDs) operate through systemic immunosuppression. FLS-targeted approaches could potentially be combined with DMARDs to improve control of RA without increasing immunosuppression. Here, we assessed the potential of immunoglobulin-like domains 1 and 2 (Ig1&2), a decoy protein that activates the receptor tyrosine phosphatase sigma (PTPRS) on FLS, for RA therapy. We report that PTPRS expression is enriched in synovial lining RA FLS and that Ig1&2 reduces migration of RA but not osteoarthritis FLS. Administration of an Fc-fusion Ig1&2 attenuated arthritis in mice without affecting innate or adaptive immunity. Furthermore, PTPRS was down-regulated in FLS by tumor necrosis factor (TNF) via a phosphatidylinositol 3-kinase-mediated pathway, and TNF inhibition enhanced PTPRS expression in arthritic joints. Combination of ineffective doses of TNF inhibitor and Fc-Ig1&2 reversed arthritis in mice, providing an example of synergy between FLS-targeted and immunosuppressive DMARD therapies.

11.
N Engl J Med ; 383(3): 218-228, 2020 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-32668112

RESUMO

BACKGROUND: Rheumatoid arthritis, like many inflammatory diseases, is characterized by episodes of quiescence and exacerbation (flares). The molecular events leading to flares are unknown. METHODS: We established a clinical and technical protocol for repeated home collection of blood in patients with rheumatoid arthritis to allow for longitudinal RNA sequencing (RNA-seq). Specimens were obtained from 364 time points during eight flares over a period of 4 years in our index patient, as well as from 235 time points during flares in three additional patients. We identified transcripts that were differentially expressed before flares and compared these with data from synovial single-cell RNA-seq. Flow cytometry and sorted-blood-cell RNA-seq in additional patients were used to validate the findings. RESULTS: Consistent changes were observed in blood transcriptional profiles 1 to 2 weeks before a rheumatoid arthritis flare. B-cell activation was followed by expansion of circulating CD45-CD31-PDPN+ preinflammatory mesenchymal, or PRIME, cells in the blood from patients with rheumatoid arthritis; these cells shared features of inflammatory synovial fibroblasts. Levels of circulating PRIME cells decreased during flares in all 4 patients, and flow cytometry and sorted-cell RNA-seq confirmed the presence of PRIME cells in 19 additional patients with rheumatoid arthritis. CONCLUSIONS: Longitudinal genomic analysis of rheumatoid arthritis flares revealed PRIME cells in the blood during the period before a flare and suggested a model in which these cells become activated by B cells in the weeks before a flare and subsequently migrate out of the blood into the synovium. (Funded by the National Institutes of Health and others.).


Assuntos
Artrite Reumatoide/sangue , Linfócitos B/fisiologia , Expressão Gênica , Células-Tronco Mesenquimais , Análise de Sequência de RNA/métodos , Adulto , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Feminino , Fibroblastos/metabolismo , Citometria de Fluxo , Humanos , Masculino , Células-Tronco Mesenquimais/metabolismo , Pessoa de Meia-Idade , Gravidade do Paciente , Inquéritos e Questionários , Exacerbação dos Sintomas , Líquido Sinovial/citologia
12.
Nature ; 582(7811): 259-264, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32499639

RESUMO

The synovium is a mesenchymal tissue composed mainly of fibroblasts, with a lining and sublining that surround the joints. In rheumatoid arthritis the synovial tissue undergoes marked hyperplasia, becomes inflamed and invasive, and destroys the joint1,2. It has recently been shown that a subset of fibroblasts in the sublining undergoes a major expansion in rheumatoid arthritis that is linked to disease activity3-5; however, the molecular mechanism by which these fibroblasts differentiate and expand is unknown. Here we identify a critical role for NOTCH3 signalling in the differentiation of perivascular and sublining fibroblasts that express CD90 (encoded by THY1). Using single-cell RNA sequencing and synovial tissue organoids, we found that NOTCH3 signalling drives both transcriptional and spatial gradients-emanating from vascular endothelial cells outwards-in fibroblasts. In active rheumatoid arthritis, NOTCH3 and Notch target genes are markedly upregulated in synovial fibroblasts. In mice, the genetic deletion of Notch3 or the blockade of NOTCH3 signalling attenuates inflammation and prevents joint damage in inflammatory arthritis. Our results indicate that synovial fibroblasts exhibit a positional identity that is regulated by endothelium-derived Notch signalling, and that this stromal crosstalk pathway underlies inflammation and pathology in inflammatory arthritis.


Assuntos
Artrite Reumatoide/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patologia , Receptor Notch3/metabolismo , Transdução de Sinais , Membrana Sinovial/patologia , Animais , Artrite Reumatoide/genética , Artrite Reumatoide/patologia , Células Endoteliais/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Receptor Notch3/antagonistas & inibidores , Receptor Notch3/deficiência , Receptor Notch3/genética , Antígenos Thy-1/metabolismo
13.
Nature ; 582(7811): 234-239, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32499652

RESUMO

On average, Peruvian individuals are among the shortest in the world1. Here we show that Native American ancestry is associated with reduced height in an ethnically diverse group of Peruvian individuals, and identify a population-specific, missense variant in the FBN1 gene (E1297G) that is significantly associated with lower height. Each copy of the minor allele (frequency of 4.7%) reduces height by 2.2 cm (4.4 cm in homozygous individuals). To our knowledge, this is the largest effect size known for a common height-associated variant. FBN1 encodes the extracellular matrix protein fibrillin 1, which is a major structural component of microfibrils. We observed less densely packed fibrillin-1-rich microfibrils with irregular edges in the skin of individuals who were homozygous for G1297 compared with individuals who were homozygous for E1297. Moreover, we show that the E1297G locus is under positive selection in non-African populations, and that the E1297 variant shows subtle evidence of positive selection specifically within the Peruvian population. This variant is also significantly more frequent in coastal Peruvian populations than in populations from the Andes or the Amazon, which suggests that short stature might be the result of adaptation to factors that are associated with the coastal environment in Peru.


Assuntos
Estatura/genética , Fibrilina-1/genética , Mutação de Sentido Incorreto , Seleção Genética , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Hereditariedade , Humanos , Índios Sul-Americanos/genética , Masculino , Microfibrilas/química , Microfibrilas/genética , Peru
14.
JCI Insight ; 5(12)2020 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-32396533

RESUMO

Lupus nephritis, one of the most serious manifestations of systemic lupus erythematosus (SLE), has a heterogeneous clinical and pathological presentation. For example, proliferative nephritis identifies a more aggressive disease class that requires immunosuppression. However, the current classification system relies on the static appearance of histopathological morphology, which does not capture differences in the inflammatory response. Therefore, a biomarker grounded in the disease biology is needed in order to understand the molecular heterogeneity of lupus nephritis and identify immunologic mechanism and pathways. Here, we analyzed the patterns of 1000 urine protein biomarkers in 30 patients with active lupus nephritis. We found that patients stratify over a chemokine gradient inducible by IFN-γ. Higher values identified patients with proliferative lupus nephritis. After integrating the urine proteomics with the single-cell transcriptomics of kidney biopsies, we observed that the urinary chemokines defining the gradient were predominantly produced by infiltrating CD8+ T cells, along with natural killer and myeloid cells. The urine chemokine gradient significantly correlated with the number of kidney-infiltrating CD8+ cells. These findings suggest that urine proteomics can capture the complex biology of the kidney in lupus nephritis. Patient-specific pathways could be noninvasively tracked in the urine in real time, enabling diagnosis and personalized treatment.

15.
Sci Transl Med ; 12(545)2020 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-32461333

RESUMO

It is challenging to quickly diagnose slowly progressing diseases. To prioritize multiple related diagnoses, we developed G-PROB (Genetic Probability tool) to calculate the probability of different diseases for a patient using genetic risk scores. We tested G-PROB for inflammatory arthritis-causing diseases (rheumatoid arthritis, systemic lupus erythematosus, spondyloarthropathy, psoriatic arthritis, and gout). After validating on simulated data, we tested G-PROB in three cohorts: 1211 patients identified by International Classification of Diseases (ICD) codes within the eMERGE database, 245 patients identified through ICD codes and medical record review within the Partners Biobank, and 243 patients first presenting with unexplained inflammatory arthritis and with final diagnoses by record review within the Partners Biobank. Calibration of G-probabilities with disease status was high, with regression coefficients from 0.90 to 1.08 (1.00 is ideal). G-probabilities discriminated true diagnoses across the three cohorts with pooled areas under the curve (95% CI) of 0.69 (0.67 to 0.71), 0.81 (0.76 to 0.84), and 0.84 (0.81 to 0.86), respectively. For all patients, at least one disease could be ruled out, and in 45% of patients, a likely diagnosis was identified with a 64% positive predictive value. In 35% of cases, the clinician's initial diagnosis was incorrect. Initial clinical diagnosis explained 39% of the variance in final disease, which improved to 51% (P < 0.0001) after adding G-probabilities. Converting genotype information before a clinical visit into an interpretable probability value for five different inflammatory arthritides could potentially be used to improve the diagnostic efficiency of rheumatic diseases in clinical practice.

17.
Proc Natl Acad Sci U S A ; 117(10): 5532-5541, 2020 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-32079724

RESUMO

The role of stromal fibroblasts in chronic inflammation is unfolding. In rheumatoid arthritis, leukocyte-derived cytokines TNF and IL-17A work together, activating fibroblasts to become a dominant source of the hallmark cytokine IL-6. However, IL-17A alone has minimal effect on fibroblasts. To identify key mediators of the synergistic response to TNF and IL-17A in human synovial fibroblasts, we performed time series, dose-response, and gene-silencing transcriptomics experiments. Here we show that in combination with TNF, IL-17A selectively induces a specific set of genes mediated by factors including cut-like homeobox 1 (CUX1) and IκBζ (NFKBIZ). In the promoters of CXCL1, CXCL2, and CXCL3, we found a putative CUX1-NF-κB binding motif not found elsewhere in the genome. CUX1 and NF-κB p65 mediate transcription of these genes independent of LIFR, STAT3, STAT4, and ELF3. Transcription of NFKBIZ, encoding the atypical IκB factor IκBζ, is IL-17A dose-dependent, and IκBζ only mediates the transcriptional response to TNF and IL-17A, but not to TNF alone. In fibroblasts, IL-17A response depends on CUX1 and IκBζ to engage the NF-κB complex to produce chemoattractants for neutrophil and monocyte recruitment.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Artrite Reumatoide/metabolismo , Fibroblastos/metabolismo , Proteínas de Homeodomínio/metabolismo , Inflamação/metabolismo , Interleucina-17/fisiologia , Proteínas Repressoras/metabolismo , Fatores de Transcrição/metabolismo , Transcriptoma/fisiologia , Fator de Necrose Tumoral alfa/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Artrite Reumatoide/genética , Células Cultivadas , Quimiocina CXCL1/genética , Quimiocina CXCL2/genética , Quimiocinas CXC/genética , Fatores Quimiotáticos/genética , Fibroblastos/efeitos dos fármacos , Proteínas de Homeodomínio/genética , Humanos , Inflamação/genética , Interleucina-17/farmacologia , Interleucina-6/genética , Metaloproteinase 3 da Matriz/metabolismo , Monócitos/efeitos dos fármacos , Monócitos/fisiologia , RNA Interferente Pequeno/genética , Proteínas Repressoras/genética , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Líquido Sinovial , Fator de Transcrição RelA/metabolismo , Fatores de Transcrição/genética , Transcriptoma/efeitos da radiação , Fator de Necrose Tumoral alfa/farmacologia
18.
Nat Genet ; 52(3): 247-253, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32066938

RESUMO

Genetic studies have revealed that autoimmune susceptibility variants are over-represented in memory CD4+ T cell regulatory elements1-3. Understanding how genetic variation affects gene expression in different T cell physiological states is essential for deciphering genetic mechanisms of autoimmunity4,5. Here, we characterized the dynamics of genetic regulatory effects at eight time points during memory CD4+ T cell activation with high-depth RNA-seq in healthy individuals. We discovered widespread, dynamic allele-specific expression across the genome, where the balance of alleles changes over time. These genes were enriched fourfold within autoimmune loci. We found pervasive dynamic regulatory effects within six HLA genes. HLA-DQB1 alleles had one of three distinct transcriptional regulatory programs. Using CRISPR-Cas9 genomic editing we demonstrated that a promoter variant is causal for T cell-specific control of HLA-DQB1 expression. Our study shows that genetic variation in cis-regulatory elements affects gene expression in a manner dependent on lymphocyte activation status, contributing to the interindividual complexity of immune responses.


Assuntos
Autoimunidade/genética , Variação Genética , Antígenos HLA/genética , Cadeias beta de HLA-DQ/genética , Ativação Linfocitária/genética , Regiões Promotoras Genéticas/genética , Alelos , Linfócitos T CD4-Positivos , Sistemas CRISPR-Cas , Linhagem Celular , Regulação da Expressão Gênica , Loci Gênicos , Técnicas de Genotipagem , Antígenos HLA/metabolismo , Cadeias beta de HLA-DQ/metabolismo , Humanos , Imunidade Celular , Linfócitos T Reguladores
19.
Immunol Rev ; 294(1): 188-204, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31782165

RESUMO

Rheumatoid arthritis (RA) risk has a large genetic component (~60%) that is still not fully understood. This has hampered the design of effective treatments that could promise lifelong remission. RA is a polygenic disease with 106 known genome-wide significant associated loci and thousands of small effect causal variants. Our current understanding of RA risk has suggested cell-type-specific contexts for causal variants, implicating CD4 + effector memory T cells, as well as monocytes, B cells and stromal fibroblasts. While these cellular states and categories are still mechanistically broad, future studies may identify causal cell subpopulations. These efforts are propelled by advances in single cell profiling. Identification of causal cell subpopulations may accelerate therapeutic intervention to achieve lifelong remission.

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