RESUMO
Despite major progress in the treatment of autoimmune diseases in the past two decades, most therapies do not cure disease and can be associated with increased risk of infection through broad suppression of the immune system. However, advances in understanding the causes of autoimmune disease and clinical data from novel therapeutic modalities such as chimeric antigen receptor T cell therapies provide evidence that it may be possible to re-establish immune homeostasis and, potentially, prolong remission or even cure autoimmune diseases. Here, we propose a 'sequential immunotherapy' framework for immune system modulation to help achieve this ambitious goal. This framework encompasses three steps: controlling inflammation; resetting the immune system through elimination of pathogenic immune memory cells; and promoting and maintaining immune homeostasis via immune regulatory agents and tissue repair. We discuss existing drugs and those in development for each of the three steps. We also highlight the importance of causal human biology in identifying and prioritizing novel immunotherapeutic strategies as well as informing their application in specific patient subsets, enabling precision medicine approaches that have the potential to transform clinical care.
Assuntos
Doenças Autoimunes , Autoimunidade , Imunoterapia , Humanos , Imunoterapia/métodos , Doenças Autoimunes/imunologia , Doenças Autoimunes/terapia , Autoimunidade/imunologia , Animais , Medicina de Precisão/métodosRESUMO
Genome-wide association studies (GWASs) have enabled unbiased identification of genetic loci contributing to common complex diseases. Because GWAS loci often harbor many variants and genes, it remains a major challenge to move from GWASs' statistical associations to the identification of causal variants and genes that underlie these association signals. Researchers have applied many statistical and functional fine-mapping strategies to prioritize genetic variants and genes as potential candidates. There is no gold standard in fine-mapping approaches, but consistent results across different approaches can improve confidence in the fine-mapping findings. Here, we combined text mining with a systematic review and formed a catalog of 85 studies with evidence of fine mapping for at least one autoimmune GWAS locus. Across all fine-mapping studies, we compiled 230 GWAS loci with allelic heterogeneity estimates and predictions of causal variants and trait-relevant genes. These 230 loci included 455 combinations of locus-by-disease association signals with 15 autoimmune diseases. Using these estimates, we assessed the probability of mediating disease risk associations across genes in GWAS loci and identified robust signals of causal disease biology. We predict that this comprehensive catalog of GWAS fine-mapping efforts in autoimmune disease will greatly help distill the plethora of information in the field and inform therapeutic strategies.
Assuntos
Doenças Autoimunes/genética , Estudo de Associação Genômica Ampla , HumanosRESUMO
The human proteome is a major source of therapeutic targets. Recent genetic association analyses of the plasma proteome enable systematic evaluation of the causal consequences of variation in plasma protein levels. Here we estimated the effects of 1,002 proteins on 225 phenotypes using two-sample Mendelian randomization (MR) and colocalization. Of 413 associations supported by evidence from MR, 130 (31.5%) were not supported by results of colocalization analyses, suggesting that genetic confounding due to linkage disequilibrium is widespread in naïve phenome-wide association studies of proteins. Combining MR and colocalization evidence in cis-only analyses, we identified 111 putatively causal effects between 65 proteins and 52 disease-related phenotypes ( https://www.epigraphdb.org/pqtl/ ). Evaluation of data from historic drug development programs showed that target-indication pairs with MR and colocalization support were more likely to be approved, evidencing the value of this approach in identifying and prioritizing potential therapeutic targets.
Assuntos
Proteínas Sanguíneas/genética , Predisposição Genética para Doença , Análise da Randomização Mendeliana , Proteoma/genética , Estudo de Associação Genômica Ampla , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Phenome-wide association studies (PheWAS) have been proposed as a possible aid in drug development through elucidating mechanisms of action, identifying alternative indications, or predicting adverse drug events (ADEs). Here, we select 25 single nucleotide polymorphisms (SNPs) linked through genome-wide association studies (GWAS) to 19 candidate drug targets for common disease indications. We interrogate these SNPs by PheWAS in four large cohorts with extensive health information (23andMe, UK Biobank, FINRISK, CHOP) for association with 1683 binary endpoints in up to 697,815 individuals and conduct meta-analyses for 145 mapped disease endpoints. Our analyses replicate 75% of known GWAS associations (P < 0.05) and identify nine study-wide significant novel associations (of 71 with FDR < 0.1). We describe associations that may predict ADEs, e.g., acne, high cholesterol, gout, and gallstones with rs738409 (p.I148M) in PNPLA3 and asthma with rs1990760 (p.T946A) in IFIH1. Our results demonstrate PheWAS as a powerful addition to the toolkit for drug discovery.
Assuntos
Descoberta de Drogas/métodos , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Asma/genética , Estudos de Coortes , Bases de Dados Factuais , Estudos de Associação Genética , Pleiotropia Genética , Predisposição Genética para Doença , Humanos , Helicase IFIH1 Induzida por Interferon/genética , Lipase/genética , Proteínas de Membrana/genética , Terapia de Alvo Molecular/métodos , Fenótipo , Reprodutibilidade dos Testes , Tromboembolia/genética , Reino UnidoRESUMO
In the originally published version of this Article, financial support was not fully acknowledged. The sentence "KS was supported by the 'Biomedical Research Program' funds at Weill Cornell Medicine in Qatar, a program funded by the Qatar Foundation" has been added to the acknowledgement section in both the PDF and HTML versions of the Article.
RESUMO
Identifying genetic variants associated with circulating protein concentrations (protein quantitative trait loci; pQTLs) and integrating them with variants from genome-wide association studies (GWAS) may illuminate the proteome's causal role in disease and bridge a knowledge gap regarding SNP-disease associations. We provide the results of GWAS of 71 high-value cardiovascular disease proteins in 6861 Framingham Heart Study participants and independent external replication. We report the mapping of over 16,000 pQTL variants and their functional relevance. We provide an integrated plasma protein-QTL database. Thirteen proteins harbor pQTL variants that match coronary disease-risk variants from GWAS or test causal for coronary disease by Mendelian randomization. Eight of these proteins predict new-onset cardiovascular disease events in Framingham participants. We demonstrate that identifying pQTLs, integrating them with GWAS results, employing Mendelian randomization, and prospectively testing protein-trait associations holds potential for elucidating causal genes, proteins, and pathways for cardiovascular disease and may identify targets for its prevention and treatment.
Assuntos
Proteínas Sanguíneas/genética , Doenças Cardiovasculares/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas/genética , Adulto , Doenças Cardiovasculares/metabolismo , Mapeamento Cromossômico , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Transdução de Sinais/genéticaRESUMO
Although plasma proteins have important roles in biological processes and are the direct targets of many drugs, the genetic factors that control inter-individual variation in plasma protein levels are not well understood. Here we characterize the genetic architecture of the human plasma proteome in healthy blood donors from the INTERVAL study. We identify 1,927 genetic associations with 1,478 proteins, a fourfold increase on existing knowledge, including trans associations for 1,104 proteins. To understand the consequences of perturbations in plasma protein levels, we apply an integrated approach that links genetic variation with biological pathway, disease, and drug databases. We show that protein quantitative trait loci overlap with gene expression quantitative trait loci, as well as with disease-associated loci, and find evidence that protein biomarkers have causal roles in disease using Mendelian randomization analysis. By linking genetic factors to diseases via specific proteins, our analyses highlight potential therapeutic targets, opportunities for matching existing drugs with new disease indications, and potential safety concerns for drugs under development.
Assuntos
Proteínas Sanguíneas/genética , Genômica , Proteoma/genética , Feminino , Fator de Crescimento de Hepatócito/genética , Humanos , Doenças Inflamatórias Intestinais/genética , Masculino , Mutação de Sentido Incorreto/genética , Mieloblastina/genética , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Proteínas Proto-Oncogênicas/genética , Locos de Características Quantitativas/genética , Vasculite/genética , alfa 1-Antitripsina/genéticaRESUMO
Background: Dyslipidemia, particularly high-density lipoprotein cholesterol (HDL-C), has recently been implicated in the pathogenesis of age-related macular degeneration (AMD), the leading cause of vision loss. However, epidemiological studies have yielded conflicting results. Methods: We investigated the causal role of plasma lipid levels in AMD in multiethnic populations comprising 16 144 advanced AMD cases and 17 832 controls of European descent, together with 2219 cases and 5275 controls of Asian descent, using Mendelian randomization in three models. Model 1 is a conventional meta-analysis which does not account for pleiotropy of instrumental variable (IV) effects. Model 2 is a univariate, inverse variance weighted regression analysis that accounts for potential unbalanced pleiotropy using MR-Egger method. Finally, Model 3 is a multivariate regression analysis that addresses pleiotropy by MR-Egger method and by adjusting for effects on other lipid traits. Results: A 1 standard deviation (SD) higher HDL-cholesterol level was associated with an odds ratio (OR) for AMD of 1.17 (95% confidence interval: 1.07-1.29) in Europeans (P = 6.88 × 10-4) and of 1.58 (1.24-2.00) in Asians (P = 2.92 × 10-4) in Model 3. The corresponding OR estimates were 1.30 (1.09-1.55) in Europeans (P = 3.18 × 10-3) and 1.42 (1.11-1.80) in Asians (P = 4.42 × 10-3) in Model 1, and 1.21 (1.11-1.31) in Europeans (P = 3.12 × 10-5) and 1.51 (1.20-1.91) in Asians (P = 7.61 × 10-4) in Model 2. Conversely, neither LDL-C (Europeans: OR = 0.96, P = 0.272; Asians: OR = 1.02, P = 0.874; Model 3) nor triglyceride levels (Europeans: OR = 0.91, P = 0.102; Asians: OR = 1.06, P = 0.613) were associated with AMD. We also assessed the association between lipid levels and polypoidal choroidal vasculopathy (PCV) in Asians, a subtype of AMD, and found a similar trend for association of PCV with HDL-C levels. Conclusions: Our study shows that high levels of plasma HDL-C are causally associated with an increased risk for advanced AMD in European and Asian populations, implying that strategies reducing HDL-C levels may be useful to prevent and treat AMD.
Assuntos
HDL-Colesterol/sangue , Degeneração Macular/sangue , Degeneração Macular/genética , Análise da Randomização Mendeliana , Adulto , Idoso , Povo Asiático/genética , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Fatores de Risco , População Branca/genéticaRESUMO
The active hormonal form of vitamin D, 1,25-dihydroxyvitamin D (1,25D) is an important modulator of the immune system, inhibiting cellular proliferation and regulating transcription of immune response genes. In order to characterize the genetic basis of variation in the immunomodulatory effects of 1,25D, we mapped quantitative traits of 1,25D response at both the cellular and the transcriptional level. We carried out a genome-wide association scan of percent inhibition of cell proliferation (Imax) induced by 1,25D treatment of peripheral blood mononuclear cells from 88 healthy African-American individuals. Two genome-wide significant variants were identified: rs1893662 in a gene desert on chromosome 18 (p = 2.32 x 10-8) and rs6451692 on chromosome 5 (p = 2.55 x 10-8), which may influence the anti-proliferative activity of 1,25D by regulating the expression of nearby genes such as the chemokine gene, CCL28, and the translation initiation gene, PAIP1. We also identified 8 expression quantitative trait loci at a FDR<0.10 for transcriptional response to 1,25D treatment, which include the transcriptional regulator ets variant 3-like (ETV3L) and EH-domain containing 4 (EHD4). In addition, we identified response eQTLs in vitamin D receptor binding sites near genes differentially expressed in response to 1,25D, such as FERM Domain Containing 6 (FRMD6), which plays a critical role in regulating both cell proliferation and apoptosis. Combining information from the GWAS of Imax and the response eQTL mapping enabled identification of putative Imax-associated candidate genes such as PAIP1 and the transcriptional repressor gene ZNF649. Overall, the variants identified in this study are strong candidates for immune traits and diseases linked to vitamin D, such as multiple sclerosis.
Assuntos
Calcitriol/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Variação Genética , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Transcrição Gênica , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Mapeamento Cromossômico , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Receptores de Calcitriol/metabolismo , Sequências Reguladoras de Ácido NucleicoRESUMO
BACKGROUND & AIMS: Inflammatory bowel disease (IBD) has familial aggregation in African Americans (AAs), but little is known about the molecular genetic susceptibility. Mapping studies using the Immunochip genotyping array expand the number of susceptibility loci for IBD in Caucasians to 163, but the contribution of the 163 loci and European admixture to IBD risk in AAs is unclear. We performed a genetic mapping study using the Immunochip to determine whether IBD susceptibility loci in Caucasians also affect risk in AAs and identify new associated loci. METHODS: We recruited AAs with IBD and without IBD (controls) from 34 IBD centers in the United States; additional controls were collected from 4 other Immunochip studies. Association and admixture loci were mapped for 1088 patients with Crohn's disease, 361 with ulcerative colitis, 62 with IBD type unknown, and 1797 controls; 130,241 autosomal single-nucleotide polymorphisms (SNPs) were analyzed. RESULTS: The strongest associations were observed between ulcerative colitis and HLA rs9271366 (P = 7.5 × 10(-6)), Crohn's disease and 5p13.1 rs4286721 (P = 3.5 × 10(-6)), and IBD and KAT2A rs730086 (P = 2.3 × 10(-6)). Additional suggestive associations (P < 4.2 × 10(-5)) were observed between Crohn's disease and IBD and African-specific SNPs in STAT5A and STAT3; between IBD and SNPs in IL23R, IL12B, and C2orf43; and between ulcerative colitis and SNPs near HDAC11 and near LINC00994. The latter 3 loci have not been previously associated with IBD, but require replication. Established Caucasian associations were replicated in AAs (P < 3.1 × 10(-4)) at NOD2, IL23R, 5p15.3, and IKZF3. Significant admixture (P < 3.9 × 10(-4)) was observed for 17q12-17q21.31 (IZKF3 through STAT3), 10q11.23-10q21.2, 15q22.2-15q23, and 16p12.2-16p12.1. Network analyses showed significant enrichment (false discovery rate <1 × 10(-5)) in genes that encode members of the JAK-STAT, cytokine, and chemokine signaling pathways, as well those involved in pathogenesis of measles. CONCLUSIONS: In a genetic analysis of 3308 AA IBD cases and controls, we found that many variants associated with IBD in Caucasians also showed association evidence with these diseases in AAs; we also found evidence for variants and loci not previously associated with IBD. The complex genetic factors that determine risk for or protection against IBD in different populations require further study.
Assuntos
Negro ou Afro-Americano/genética , Doenças Inflamatórias Intestinais/genética , Polimorfismo de Nucleotídeo Único , População Branca/genética , Adulto , Idoso , Colite Ulcerativa/genética , Doença de Crohn/genética , Feminino , Loci Gênicos , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Estados Unidos/etnologia , Adulto JovemRESUMO
To reduce treatment of indolent prostate cancer (PCa), biomarkers are needed to improve identification of patients with a low-risk of having aggressive disease. Over-treatment of these patients occurs because of uncertainty in the aggressiveness of the entire tumor based on the biopsies, which do not accurately sample multifocal tumors. Circulating microRNAs (miRNAs) are stable serum markers and differential miRNA levels occur in men with PCa. The goal of this study was to identify circulating miRNAs that were associated with aggressive or indolent PCa. We measured circulating miRNAs in 150 patients prior to surgery and compared the miRNA levels to the pathology of the entire radical prostatectomy specimen. For this study we used an exceptionally well-characterized cohort of patients who had benign prostatic hyperplasia (BPH), low-grade or high-grade PCa. Low-grade was defined as patients with 100% Gleason grade 3 tumor as determined by step-wise sectioning. High-grade PCa patients had 30-90% Gleason grade 4+5 in the tumor. BPH patients had at least two biopsies negative for PCa. Twenty one miRNAs were selected for analysis. The miRNAs were quantified by RT-qPCR and analyzed by logistic regression. High levels of 14 miRNAs were exclusively present in the serum from patients with low-grade PCa or BPH, compared to men with high-grade PCa who had consistently low levels. The expression levels of the 14 miRNAs were combined into a "miR Score" which had a negative predictive value (NPV) of 0.939 to predict absence of high-grade PCa among PCa and BPH patients. Biochemical recurrence (BCR) was known for the PCa patients and a combined "miR Risk Score" accurately classified a subset of patients with low risk of BCR (NPV 0.941). In summary, measurement of serum miRNAs may have pre-surgical utility in combination with clinical risk calculators to identify patients with low risk of harboring aggressive PCa.
Assuntos
MicroRNAs/sangue , Neoplasias da Próstata/patologia , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Intervalo Livre de Doença , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Razão de Chances , Antígeno Prostático Específico/sangue , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/mortalidade , Reação em Cadeia da Polimerase em Tempo Real , Estudos RetrospectivosRESUMO
Many drugs used to treat inflammatory diseases are ineffective in a substantial proportion of patients. Identifying patients that are likely to respond to specific therapies would facilitate personalized treatment strategies that could improve outcomes while reducing costs and risks of adverse events. Despite these clear benefits, there are limited examples of predictive biomarkers of drug efficacy currently implemented into clinical practice for inflammatory diseases. We review efforts to identify genetic and nongenetic biomarkers of drug response in these diseases and consider potential benefits from combining multiple sources of biological data into multifeature predictive models.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Asma/tratamento farmacológico , Biomarcadores Farmacológicos , Marcadores Genéticos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Artrite Reumatoide/genética , Asma/genética , Humanos , Doenças Inflamatórias Intestinais/genética , Farmacogenética , Medicina de PrecisãoRESUMO
OBJECTIVES: Whereas paclitaxel treatment is associated with leukopenia, the mechanisms that underlie this effect are not well-characterized. In addition, despite the importance of glucocorticoid signaling in cancer treatment, the genomic effects of glucocorticoid receptor antagonism by mifepristone treatment in primary human cells have never been described. METHODS: As part of a randomized phase 1 clinical trial, we used microarrays to profile gene expression in peripheral blood cells sampled from each of four patients at baseline, after placebo/nanoparticle albumin-bound paclitaxel (nab-paclitaxel) treatment (cycle 1), and after mifepristone/nab-paclitaxel treatment (cycle 2). RESULTS: We found that 63 genes were differentially expressed following treatment with nab-paclitaxel, including multiple genes in the tubulin pathway. We also found 606 genes that were differentially expressed in response to mifepristone; genes downregulated by mifepristone overlapped significantly with those previously identified as being upregulated by dexamethasone. CONCLUSION: These results provide insights into the mechanisms of paclitaxel and glucocorticoid receptor inhibition in peripheral blood cells.
Assuntos
Albuminas/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Mifepristona/administração & dosagem , Paclitaxel/administração & dosagem , Receptores de Glucocorticoides/antagonistas & inibidores , Albuminas/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama/sangue , Neoplasias da Mama/genética , Dexametasona/farmacologia , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Mifepristona/farmacologia , Análise de Sequência com Séries de Oligonucleotídeos , Paclitaxel/farmacologiaRESUMO
BACKGROUND: Glucocorticoids (GCs) are steroid hormones used to induce remission in moderate-to-severe inflammatory bowel disease (IBD). A substantial fraction of patients do not respond to GC treatment and require alternate therapies or surgery. At present, non-response can only be assessed empirically by observing continued disease activity. METHODS: To identify potential biomarkers of GC response, we retrospectively identified and recruited 18 GC-responsive and 18 GC-nonresponsive IBD patients. This sample included 14 patients with ulcerative colitis (UC) and 22 patients with Crohn's disease (CD), all previously treated with steroids. In peripheral blood mononuclear cells from each patient, we performed in vitro assays to measure GC inhibition of three different immune stimulants (phytohemagglutinin [PHA], α-CD3/α-CD28, and lipopolysaccharide [LPS]). RESULTS: In both diseases, we found that inhibition of PHA-mediated T cell proliferation was significantly associated with clinical GC response (P=0.04). Inhibition of proliferation due to direct T cell receptor stimulation using α-CD3/α-CD28 was also significantly associated with clinical GC response in UC patients (P=0.009), but not in CD patients (P=0.78). Interestingly, inhibition of LPS-mediated cytokine secretion showed the strongest association with clinical GC response across both diseases (P=0.005). CONCLUSIONS: We show that inhibition of LPS stimulation is more strongly associated with clinical GC response in IBD patients than inhibition of PHA and α-CD3/α-CD28-mediated proliferation. These results support an important role of bacterial recognition and innate immunity in the etiology of IBD. This assay could be a powerful predictor of clinical response to GCs.
Assuntos
Proliferação de Células/efeitos dos fármacos , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Glucocorticoides/farmacologia , Linfócitos T/fisiologia , Imunidade Adaptativa , Adulto , Biomarcadores , Antígenos CD28/metabolismo , Complexo CD3/farmacologia , Células Cultivadas , Colite Ulcerativa/imunologia , Doença de Crohn/imunologia , Resistência a Medicamentos , Feminino , Humanos , Imunidade Inata , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Pessoa de Meia-Idade , Fito-Hemaglutininas/farmacologia , Estudos Retrospectivos , Linfócitos T/metabolismo , Adulto JovemRESUMO
Glucocorticoids (GC) and 1,25-dihydroxyvitamin D3 (1,25(OH)2 D3) are steroid hormones with anti-inflammatory properties with enhanced effects when combined. We previously showed that transcriptional response to GCs was correlated with inter-individual and inter-ethnic cellular response. Here, we profiled cellular and transcriptional responses to 1,25(OH)2 D3 from the same donors. We studied cellular response to combined treatment with GCs and 1,25(OH)2 D3 in a subset of individuals least responsive to GCs. We found that combination treatment had significantly greater inhibition of proliferation than with either steroid hormone alone. Overlapping differentially expressed (DE) genes between the two hormones were enriched for adaptive and innate immune processes. Non-overlapping differentially expressed genes with 1,25(OH)2 D3 treatment were enriched for pathways involving the electron transport chain, while with GC treatment, non-overlapping genes were enriched for RNA-related processes. These results suggest that 1,25(OH)2 D3 enhances GC anti-inflammatory properties through a number of shared and non-shared transcriptionally-mediated pathways.
Assuntos
Calcitriol/farmacologia , Proliferação de Células/efeitos dos fármacos , Glucocorticoides/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacos , Imunidade Adaptativa/genética , Adulto , Dexametasona/farmacologia , Sinergismo Farmacológico , Transporte de Elétrons/genética , Feminino , Redes Reguladoras de Genes/efeitos dos fármacos , Redes Reguladoras de Genes/genética , Humanos , Imunidade Inata/genética , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Transdução de Sinais/genética , Transcriptoma/efeitos dos fármacos , Transcriptoma/genética , Vitaminas/farmacologia , Adulto JovemRESUMO
Clinical response to glucocorticoids, steroid hormones widely used as pharmaceuticals, varies extensively in that many individuals (â¼30%) show a weak response to treatment. Although little is known about the molecular basis of this variation, regulatory polymorphisms are likely to play a key role given that glucocorticoids act largely through activation of a transcription factor, the glucocorticoid receptor. In an effort to characterize the molecular basis of variation in glucocorticoid sensitivity, we measured in vitro lymphocyte glucocorticoid sensitivity and transcriptome-wide response to glucocorticoids in peripheral-blood mononuclear cells from African American healthy donors. We found that variation in lymphocyte glucocorticoid sensitivity was correlated with transcriptional response at 27 genes (false-discovery rate < 0.1). Furthermore, a genome-wide association scan revealed a quantitative trait locus (QTL) for lymphocyte glucocorticoid sensitivity (rs11129354, p = 4 × 10(-8)); it was also associated with transcriptional response at multiple genes, including many (14/27) where transcriptional response was correlated with lymphocyte glucocorticoid sensitivity. Using allelic-imbalance assays, we show that this QTL is a glucocorticoid-dependent cis-regulatory polymorphism for RBMS3, which encodes an RNA-binding protein known as a tumor suppressor. We found that siRNA-mediated knockdown of RBMS3 expression increased cellular proliferation in PBMCs, consistent with the role of the gene as a negative regulator of proliferation. We propose that differences in lymphocyte glucocorticoid sensitivity reflect variation in transcriptional response, which is influenced by a glucocorticoid-dependent regulatory polymorphism that acts in cis relative to RBMS3 and in trans to affect the transcriptional response of multiple distant genes.
Assuntos
Glucocorticoides/genética , Glucocorticoides/metabolismo , Linfócitos/fisiologia , Alelos , Estudo de Associação Genômica Ampla/métodos , Humanos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/fisiologia , Linfócitos/metabolismo , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Proteínas de Ligação a RNA/genética , Transativadores/genética , Transcrição Gênica , TranscriptomaRESUMO
Glucocorticoids (GCs) are key mediators of stress response and are widely used as pharmacological agents to treat immune diseases, such as asthma and inflammatory bowel disease, and certain types of cancer. GCs act mainly by activating the GC receptor (GR), which interacts with other transcription factors to regulate gene expression. Here, we combined different functional genomics approaches to gain molecular insights into the mechanisms of action of GC. By profiling the transcriptional response to GC over time in 4 Yoruba (YRI) and 4 Tuscans (TSI) lymphoblastoid cell lines (LCLs), we suggest that the transcriptional response to GC is variable not only in time, but also in direction (positive or negative) depending on the presence of specific interacting transcription factors. Accordingly, when we performed ChIP-seq for GR and NF-κB in two YRI LCLs treated with GC or with vehicle control, we observed that features of GR binding sites differ for up- and down-regulated genes. Finally, we show that eQTLs that affect expression patterns only in the presence of GC are 1.9-fold more likely to occur in GR binding sites, compared to eQTLs that affect expression only in its absence. Our results indicate that genetic variation at GR and interacting transcription factors binding sites influences variability in gene expression, and attest to the power of combining different functional genomic approaches.
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Anti-Inflamatórios/farmacologia , Glucocorticoides/farmacologia , NF-kappa B/metabolismo , Receptores de Glucocorticoides/metabolismo , Transcriptoma/efeitos dos fármacos , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Ligação Proteica , Locos de Características Quantitativas/efeitos dos fármacosRESUMO
Genetic effects on gene regulation make a substantial contribution to phenotypic diversity, yet their mechanisms remain elusive. Here, we discuss the potential insights to be gained from mapping gene-environment interactions at regulatory polymorphisms (i.e., genetic variation that affects gene expression under specific environmental conditions). We highlight a novel statistical method to identify specific patterns of gene-environment interaction at these regulatory polymorphisms. Reviewing its application to a study that mapped gene expression in the presence and absence of glucocorticoids, we discuss the mechanistic insights that this approach provides.
Assuntos
Interação Gene-Ambiente , Fenótipo , Polimorfismo Genético , Animais , Mapeamento Cromossômico , Regulação da Expressão Gênica , Variação Genética , Glucocorticoides/metabolismo , Humanos , Locos de Características Quantitativas , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Glucocorticoids (GCs) mediate physiological responses to environmental stress and are commonly used as pharmaceuticals. GCs act primarily through the GC receptor (GR, a transcription factor). Despite their clear biomedical importance, little is known about the genetic architecture of variation in GC response. Here we provide an initial assessment of variability in the cellular response to GC treatment by profiling gene expression and protein secretion in 114 EBV-transformed B lymphocytes of African and European ancestry. We found that genetic variation affects the response of nearby genes and exhibits distinctive patterns of genotype-treatment interactions, with genotypic effects evident in either only GC-treated or only control-treated conditions. Using a novel statistical framework, we identified interactions that influence the expression of 26 genes known to play central roles in GC-related pathways (e.g. NQO1, AIRE, and SGK1) and that influence the secretion of IL6.