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1.
Sci Rep ; 10(1): 16980, 2020 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-33046825

RESUMO

Macrophage migration inhibitory factor (MIF) is a cytokine found to be associated with chronic obstructive pulmonary disease (COPD). However, there is no consensus on how MIF levels differ in COPD compared to control conditions and there are no reports on MIF expression in lung tissue. Here we studied gene expression of members of the MIF family MIF, D-Dopachrome Tautomerase (DDT) and DDT-like (DDTL) in a lung tissue dataset with 1087 subjects and identified single nucleotide polymorphisms (SNPs) regulating their gene expression. We found higher MIF and DDT expression in COPD patients compared to non-COPD subjects and found 71 SNPs significantly influencing gene expression of MIF and DDTL. Furthermore, the platform used to measure MIF (microarray or RNAseq) was found to influence the splice variants detected and subsequently the direction of the SNP effects on MIF expression. Among the SNPs found to regulate MIF expression, the major LD block identified was linked to rs5844572, a SNP previously found to be associated with lower diffusion capacity in COPD. This suggests that MIF may be contributing to the pathogenesis of COPD, as SNPs that influence MIF expression are also associated with symptoms of COPD. Our study shows that MIF levels are affected not only by disease but also by genetic diversity (i.e. SNPs). Since none of our significant eSNPs for MIF or DDTL have been described in GWAS for COPD or lung function, MIF expression in COPD patients is more likely a consequence of disease-related factors rather than a cause of the disease.

2.
Clin Epigenetics ; 12(1): 145, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33008450

RESUMO

BACKGROUND: Mesenchymal fibroblasts are ubiquitous cells that maintain the extracellular matrix of organs. Within the lung, airway and parenchymal fibroblasts are crucial for lung development and are altered with disease, but it has been difficult to understand their roles due to the lack of distinct molecular markers. We studied genome-wide DNA methylation and gene expression in airway and parenchymal lung fibroblasts from healthy and asthmatic donors, to identify a robust cell marker and to determine if these cells are molecularly distinct in asthma. RESULTS: Airway (N = 8) and parenchymal (N = 15) lung fibroblasts from healthy individuals differed in the expression of 158 genes, and DNA methylation of 3936 CpGs (Bonferroni adjusted p value < 0.05). Differential DNA methylation between cell types was associated with differential expression of 42 genes, but no single DNA methylation CpG feature (location, effect size, number) defined the interaction. Replication of gene expression and DNA methylation in a second cohort identified TWIST1 gene expression, DNA methylation and protein expression as a cell marker of airway and parenchymal lung fibroblasts, with DNA methylation having 100% predictive discriminatory power. DNA methylation was differentially altered in parenchymal (112 regions) and airway fibroblasts (17 regions) with asthmatic status, with no overlap between regions. CONCLUSIONS: Differential methylation of TWIST1 is a robust cell marker of airway and parenchymal lung fibroblasts. Airway and parenchymal fibroblast DNA methylation are differentially altered in individuals with asthma, and the role of both cell types should be considered in the pathogenesis of asthma.

3.
J Infect Dis ; 2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-32959881

RESUMO

BACKGROUND: Whether accelerated aging develops over the course of chronic HIV infection or can be observed prior to significant immunosuppression on is unknown. We studied DNA methylation in blood to estimate cellular aging in persons living with HIV (PLWH) prior to the initiation of antiretroviral therapy. METHODS: 378 antiretroviral therapy-naïve PLWH with CD4 T cell counts >500 cells/mm 3 enrolled in the Strategic Timing of Antiretroviral Therapy trial (Pulmonary Substudy) were compared to 34 HIV-negative controls. DNA methylation was performed using the Illumina MethylationEPIC BeadChip. Differentially methylated positions (DMPs) and regions (DMRs) in PLWH compared to controls were identified using a robust linear model. Methylation age was calculated using a previously described epigenetic clock. RESULTS: There were a total of 56,639 DMPs and 6,103 DMRs at a false discovery rate<0.1. The top 5 DMPs corresponded to genes NLRC5, VRK2, B2M, and GPR6 and were highly enriched for cancer-related pathways. PLWH had significantly higher methylation age compared to HIV-negative controls (p=0.001), with black race, low CD4, high CD8 T cell counts, and duration of HIV being risk factors for age acceleration. CONCLUSIONS: PLWH prior to the initiation of antiretroviral therapy and with preserved immune status show evidence of advanced methylation aging.

4.
Lancet Respir Med ; 8(7): 696-708, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32649918

RESUMO

BACKGROUND: Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes. METHODS: We constructed a polygenic risk score using a genome-wide association study of lung function (FEV1 and FEV1/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV1/FVC <0·7 and FEV1 <80% of predicted). Associations were tested using logistic regression models, adjusting for age, sex, height, smoking pack-years, and principal components of genetic ancestry. We assessed predictive performance of models by area under the curve. In a subset of studies, we also studied quantitative and qualitative CT imaging phenotypes that reflect parenchymal and airway pathology, and patterns of reduced lung growth. FINDINGS: The polygenic risk score was associated with COPD in European (odds ratio [OR] per SD 1·81 [95% CI 1·74-1·88] and non-European (1·42 [1·34-1·51]) populations. Compared with the first decile, the tenth decile of the polygenic risk score was associated with COPD, with an OR of 7·99 (6·56-9·72) in European ancestry and 4·83 (3·45-6·77) in non-European ancestry cohorts. The polygenic risk score was superior to previously described genetic risk scores and, when combined with clinical risk factors (ie, age, sex, and smoking pack-years), showed improved prediction for COPD compared with a model comprising clinical risk factors alone (AUC 0·80 [0·79-0·81] vs 0·76 [0·75-0·76]). The polygenic risk score was associated with CT imaging phenotypes, including wall area percent, quantitative and qualitative measures of emphysema, local histogram emphysema patterns, and destructive emphysema subtypes. The polygenic risk score was associated with a reduced lung growth pattern. INTERPRETATION: A risk score comprised of genetic variants can identify a small subset of individuals at markedly increased risk for moderate-to-severe COPD, emphysema subtypes associated with cigarette smoking, and patterns of reduced lung growth. FUNDING: US National Institutes of Health, Wellcome Trust.


Assuntos
Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/genética , Adulto , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Volume Expiratório Forçado , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Fatores de Risco , Capacidade Vital
5.
Artigo em Inglês | MEDLINE | ID: mdl-32442646

RESUMO

BACKGROUND: Asthma is a complex disease with multiple phenotypes that may differ in disease pathobiology and treatment response. IL33 single nucleotide polymorphisms (SNPs) have been reproducibly associated with asthma. IL33 levels are elevated in sputum and bronchial biopsies of patients with asthma. The functional consequences of IL33 asthma SNPs remain unknown. OBJECTIVE: This study sought to determine whether IL33 SNPs associate with asthma-related phenotypes and with IL33 expression in lung or bronchial epithelium. This study investigated the effect of increased IL33 expression on human bronchial epithelial cell (HBEC) function. METHODS: Association between IL33 SNPs (Chr9: 5,815,786-6,657,983) and asthma phenotypes (Lifelines/DAG [Dutch Asthma GWAS]/GASP [Genetics of Asthma Severity & Phenotypes] cohorts) and between SNPs and expression (lung tissue, bronchial brushes, HBECs) was done using regression modeling. Lentiviral overexpression was used to study IL33 effects on HBECs. RESULTS: We found that 161 SNPs spanning the IL33 region associated with 1 or more asthma phenotypes after correction for multiple testing. We report a main independent signal tagged by rs992969 associating with blood eosinophil levels, asthma, and eosinophilic asthma. A second, independent signal tagged by rs4008366 presented modest association with eosinophilic asthma. Neither signal associated with FEV1, FEV1/forced vital capacity, atopy, and age of asthma onset. The 2 IL33 signals are expression quantitative loci in bronchial brushes and cultured HBECs, but not in lung tissue. IL33 overexpression in vitro resulted in reduced viability and reactive oxygen species-capturing of HBECs, without influencing epithelial cell count, metabolic activity, or barrier function. CONCLUSIONS: We identify IL33 as an epithelial susceptibility gene for eosinophilia and asthma, provide mechanistic insight, and implicate targeting of the IL33 pathway specifically in eosinophilic asthma.

6.
JCI Insight ; 5(8)2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32324168

RESUMO

The IL1RL1 (ST2) gene locus is robustly associated with asthma; however, the contribution of single nucleotide polymorphisms (SNPs) in this locus to specific asthma subtypes and the functional mechanisms underlying these associations remain to be defined. We tested for association between IL1RL1 region SNPs and characteristics of asthma as defined by clinical and immunological measures and addressed functional effects of these genetic variants in lung tissue and airway epithelium. Utilizing 4 independent cohorts (Lifelines, Dutch Asthma GWAS [DAG], Genetics of Asthma Severity and Phenotypes [GASP], and Manchester Asthma and Allergy Study [MAAS]) and resequencing data, we identified 3 key signals associated with asthma features. Investigations in lung tissue and primary bronchial epithelial cells identified context-dependent relationships between the signals and IL1RL1 mRNA and soluble protein expression. This was also observed for asthma-associated IL1RL1 nonsynonymous coding TIR domain SNPs. Bronchial epithelial cell cultures from asthma patients, exposed to exacerbation-relevant stimulations, revealed modulatory effects for all 4 signals on IL1RL1 mRNA and/or protein expression, suggesting SNP-environment interactions. The IL1RL1 TIR signaling domain haplotype affected IL-33-driven NF-κB signaling, while not interfering with TLR signaling. In summary, we identify that IL1RL1 genetic signals potentially contribute to severe and eosinophilic phenotypes in asthma, as well as provide initial mechanistic insight, including genetic regulation of IL1RL1 isoform expression and receptor signaling.

7.
Nat Commun ; 11(1): 27, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31911640

RESUMO

Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of these phenotypes in the UK Biobank and International Lung Cancer Consortium (29,266 cases, 56,450 controls) shows that lung cancer is genetically correlated with reduced forced expiratory volume in one second (FEV1: rg = 0.098, p = 2.3 × 10-8) and the ratio of FEV1 to forced vital capacity (FEV1/FVC: rg = 0.137, p = 2.0 × 10-12). Mendelian randomization analyses demonstrate that reduced FEV1 increases squamous cell carcinoma risk (odds ratio (OR) = 1.51, 95% confidence intervals: 1.21-1.88), while reduced FEV1/FVC increases the risk of adenocarcinoma (OR = 1.17, 1.01-1.35) and lung cancer in never smokers (OR = 1.56, 1.05-2.30). These findings support a causal role of pulmonary impairment in lung cancer etiology. Integrative analyses reveal that pulmonary function instruments, including 73 novel variants, influence lung tissue gene expression and implicate immune-related pathways in mediating the observed effects on lung carcinogenesis.


Assuntos
Neoplasias Pulmonares/genética , Pulmão/fisiopatologia , Adulto , Idoso , Feminino , Volume Expiratório Forçado , Predisposição Genética para Doença , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/fisiopatologia , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Testes de Função Respiratória , Capacidade Vital
8.
Int J Cancer ; 146(7): 1862-1878, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31696517

RESUMO

We have recently completed the largest GWAS on lung cancer including 29,266 cases and 56,450 controls of European descent. The goal of our study has been to integrate the complete GWAS results with a large-scale expression quantitative trait loci (eQTL) mapping study in human lung tissues (n = 1,038) to identify candidate causal genes for lung cancer. We performed transcriptome-wide association study (TWAS) for lung cancer overall, by histology (adenocarcinoma, squamous cell carcinoma and small cell lung cancer) and smoking subgroups (never- and ever-smokers). We performed replication analysis using lung data from the Genotype-Tissue Expression (GTEx) project. DNA damage assays were performed in human lung fibroblasts for selected TWAS genes. As expected, the main TWAS signal for all histological subtypes and ever-smokers was on chromosome 15q25. The gene most strongly associated with lung cancer at this locus using the TWAS approach was IREB2 (pTWAS = 1.09E-99), where lower predicted expression increased lung cancer risk. A new lung adenocarcinoma susceptibility locus was revealed on 9p13.3 and associated with higher predicted expression of AQP3 (pTWAS = 3.72E-6). Among the 45 previously described lung cancer GWAS loci, we mapped candidate target gene for 17 of them. The association AQP3-adenocarcinoma on 9p13.3 was replicated using GTEx (pTWAS = 6.55E-5). Consistent with the effect of risk alleles on gene expression levels, IREB2 knockdown and AQP3 overproduction promote endogenous DNA damage. These findings indicate genes whose expression in lung tissue directly influences lung cancer risk.


Assuntos
Biomarcadores Tumorais , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias Pulmonares/genética , Transcriptoma , Linhagem Celular Tumoral , Humanos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
9.
Am J Respir Crit Care Med ; 201(5): 564-574, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31710517

RESUMO

Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease characterized by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. Genome-wide association studies have reported signals of association implicating multiple pathways including host defense, telomere maintenance, signaling, and cell-cell adhesion.Objectives: To improve our understanding of factors that increase IPF susceptibility by identifying previously unreported genetic associations.Methods: We conducted genome-wide analyses across three independent studies and meta-analyzed these results to generate the largest genome-wide association study of IPF to date (2,668 IPF cases and 8,591 controls). We performed replication in two independent studies (1,456 IPF cases and 11,874 controls) and functional analyses (including statistical fine-mapping, investigations into gene expression, and testing for enrichment of IPF susceptibility signals in regulatory regions) to determine putatively causal genes. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF.Measurements and Main Results: We identified and replicated three new genome-wide significant (P < 5 × 10-8) signals of association with IPF susceptibility (associated with altered gene expression of KIF15, MAD1L1, and DEPTOR) and confirmed associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as yet unreported IPF susceptibility variants contribute to IPF susceptibility.Conclusions: The observation that decreased DEPTOR expression associates with increased susceptibility to IPF supports recent studies demonstrating the importance of mTOR signaling in lung fibrosis. New signals of association implicating KIF15 and MAD1L1 suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.


Assuntos
Fibrose Pulmonar Idiopática/genética , Idoso , Estudos de Casos e Controles , Proteínas de Ciclo Celular/genética , Feminino , Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Cinesina/genética , Masculino , Pessoa de Meia-Idade , Medição de Risco , Transdução de Sinais , Fuso Acromático , Serina-Treonina Quinases TOR/metabolismo
10.
Sci Rep ; 9(1): 17600, 2019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31772224

RESUMO

Epidemiological studies have shown that female smokers are at higher risk of chronic obstructive pulmonary disease (COPD). Female patients have worse symptoms and health status and increased risk of exacerbations. We determined the differences in the transcriptome of the airway epithelium between males and females, as well the sex-by-smoking interaction. We processed public gene expression data of human airway epithelium into a discovery cohort of 211 subjects (never smokers n = 68; current smokers n = 143) and two replication cohorts of 104 subjects (21 never, 52 current, and 31 former smokers) and 238 subjects (99 current and 139 former smokers. We analyzed gene differential expression with smoking status, sex, and smoking-by-sex interaction and used network approaches for modules' level analyses. We identified and replicated two differentially expressed modules between the sexes in response to smoking with genes located throughout the autosomes and not restricted to sex chromosomes. The two modules were enriched in autophagy (up-regulated in female smokers) and response to virus and type 1 interferon signaling pathways which were down-regulated in female smokers compared to males. The results offer insights into the molecular mechanisms of the sexually dimorphic effect of smoking, potentially enabling a precision medicine approach to smoking related lung diseases.


Assuntos
Caracteres Sexuais , Fumar Tabaco/genética , Transcriptoma , Adulto , Autofagia/genética , Mineração de Dados , Células Epiteliais/metabolismo , Feminino , Perfilação da Expressão Gênica , Ontologia Genética , Humanos , Interferon Tipo I/biossíntese , Interferon Tipo I/genética , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , não Fumantes , Medicina de Precisão , Doença Pulmonar Obstrutiva Crônica/etiologia , Transdução de Sinais/genética , Fumantes , Abandono do Hábito de Fumar
11.
Respir Res ; 20(1): 236, 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31665000

RESUMO

BACKGROUND: There is considerable heterogeneity in the rate of lung function decline in chronic obstructive pulmonary disease (COPD), the determinants of which are largely unknown. Observational studies in COPD indicate that low body mass index (BMI) is associated with worse outcomes, and overweight/obesity has a protective effect - the so-called "obesity paradox". We aimed to determine the relationship between BMI and the rate of FEV1 decline in data from published clinical trials in COPD. METHODS: We performed a systematic review of the literature, and identified 5 randomized controlled trials reporting the association between BMI and FEV1 decline. Four of these were included in the meta-analyses. We analyzed BMI in 4 categories: BMI-I (< 18.5 or <  20 kg/m2), BMI-II (18.5 or 20 to < 25 kg/m2), BMI-III (25 to < 29 or < 30 kg/m2) and BMI-IV (≥29 or ≥ 30 kg/m2). We then performed a meta-regression of all the estimates against the BMI category. RESULTS: The estimated rate of FEV1 decline decreased with increasing BMI. Meta-regression of the estimates showed that BMI was significantly associated with the rate of FEV1 decline (linear trend p = 1.21 × 10- 5). CONCLUSIONS: These novel findings support the obesity paradox in COPD: compared to normal BMI, low BMI is a risk factor for accelerated lung function decline, whilst high BMI has a protective effect. The relationship may be due to common but as-of-yet unknown causative factors; further investigation into which may reveal novel endotypes or targets for therapeutic intervention.


Assuntos
Índice de Massa Corporal , Volume Expiratório Forçado/fisiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Humanos , Obesidade/diagnóstico , Obesidade/epidemiologia , Obesidade/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Testes de Função Respiratória/tendências
12.
Eur Respir J ; 54(6)2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31537701

RESUMO

Inhaled corticosteroids (ICS) are widely prescribed for patients with chronic obstructive pulmonary disease (COPD), yet have variable outcomes and adverse reactions, which may be genetically determined. The primary aim of the study was to identify the genetic determinants for forced expiratory volume in 1 s (FEV1) changes related to ICS therapy.In the Lung Health Study (LHS)-2, 1116 COPD patients were randomised to the ICS triamcinolone acetonide (n=559) or placebo (n=557) with spirometry performed every 6 months for 3 years. We performed a pharmacogenomic genome-wide association study for the genotype-by-ICS treatment effect on 3 years of FEV1 changes (estimated as slope) in 802 genotyped LHS-2 participants. Replication was performed in 199 COPD patients randomised to the ICS, fluticasone or placebo.A total of five loci showed genotype-by-ICS interaction at p<5×10-6; of these, single nucleotide polymorphism (SNP) rs111720447 on chromosome 7 was replicated (discovery p=4.8×10-6, replication p=5.9×10-5) with the same direction of interaction effect. ENCODE (Encyclopedia of DNA Elements) data revealed that in glucocorticoid-treated (dexamethasone) A549 alveolar cell line, glucocorticoid receptor binding sites were located near SNP rs111720447. In stratified analyses of LHS-2, genotype at SNP rs111720447 was significantly associated with rate of FEV1 decline in patients taking ICS (C allele ß 56.36 mL·year-1, 95% CI 29.96-82.76 mL·year-1) and in patients who were assigned to placebo, although the relationship was weaker and in the opposite direction to that in the ICS group (C allele ß -27.57 mL·year-1, 95% CI -53.27- -1.87 mL·year-1).The study uncovered genetic factors associated with FEV1 changes related to ICS in COPD patients, which may provide new insight on the potential biology of steroid responsiveness in COPD.


Assuntos
Corticosteroides/uso terapêutico , Volume Expiratório Forçado/efeitos dos fármacos , Farmacogenética , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/genética , Células A549 , Administração por Inalação , Corticosteroides/administração & dosagem , Idoso , Progressão da Doença , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Qualidade de Vida
13.
Respir Res ; 20(1): 176, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31382977

RESUMO

BACKGROUND: Effects of systemic corticosteroids on blood gene expression are largely unknown. This study determined gene expression signature associated with short-term oral prednisone therapy in patients with chronic obstructive pulmonary disease (COPD) and its relationship to 1-year mortality following an acute exacerbation of COPD (AECOPD). METHODS: Gene expression in whole blood was profiled using the Affymetrix Human Gene 1.1 ST microarray chips from two cohorts: 1) a prednisone cohort with 37 stable COPD patients randomly assigned to prednisone 30 mg/d + standard therapy for 4 days or standard therapy alone and 2) the Rapid Transition Program (RTP) cohort with 218 COPD patients who experienced AECOPD and were treated with systemic corticosteroids. All gene expression data were adjusted for the total number of white blood cells and their differential cell counts. RESULTS: In the prednisone cohort, 51 genes were differentially expressed between prednisone and standard therapy group at a false discovery rate of < 0.05. The top 3 genes with the largest fold-changes were KLRF1, GZMH and ADGRG1; and 21 genes were significantly enriched in immune system pathways including the natural killer cell mediated cytotoxicity. In the RTP cohort, 27 patients (12.4%) died within 1 year after hospitalisation of AECOPD; 32 of 51 genes differentially expressed in the prednisone cohort significantly changed from AECOPD to the convalescent state and were enriched in similar cellular immune pathways to that in the prednisone cohort. Of these, 10 genes including CX3CR1, KLRD1, S1PR5 and PRF1 were significantly associated with 1-year mortality. CONCLUSIONS: Short-term daily prednisone therapy produces a distinct blood gene signature that may be used to determine and monitor treatment responses to prednisone in COPD patients during AECOPD. TRIAL REGISTRATION: The prednisone cohort was registered at clinicalTrials.gov ( NCT02534402 ) and the RTP cohort was registered at ClinicalTrials.gov ( NCT02050022 ).


Assuntos
Glucocorticoides/administração & dosagem , Prednisona/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/genética , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Esquema de Medicação , Feminino , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico
16.
Med J Aust ; 210(9): 424-428, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30977152

RESUMO

Chronic obstructive pulmonary disease (COPD) is defined based on a reduced ratio of forced expiratory volume in one second (FEV1 ) to forced vital capacity (FVC) on spirometry. However, within this definition, there is significant heterogeneity of pathophysiological processes that lead to airflow obstruction and variation in phenotypic manifestations across patients. Current pharmacological treatments are based on large randomised clinical trials that apply to an "average" patient. Precision health enables tailoring of treatment for each individual patient by taking into account their unique characteristics. The number needed to treat (NNT) metric is often used to define implementation of precision health for specific interventions, with common endpoints requiring an NNT ≤ 5 to achieve precision therapy. Higher NNTs may be acceptable for rare but important endpoints such as mortality. Long-acting muscarinic antagonists and inhaled corticosteroids, which are commonly used in COPD, have 1-year treatment NNTs between 15 and 20 for exacerbation prevention in unselected patients with COPD. Subgroup identification using biomarkers or clinical traits may enable precision health. For example, NNT for inhaled corticosteroids is 9 in patients with a blood eosinophil count ≥ 300 cells/µL and 8 for long-acting muscarinic antagonists in patients with a body mass index ≤ 20 kg/m2 . Lung volume reduction surgery is associated with an NNT of 6 for survival over 5 years in patients with upper lobe-predominant disease and low exercise capacity (whereas the NNT is 245 when no bioimaging or exercise markers are used). Continuous domiciliary oxygen therapy (for at least 15 hours/day) has an NNT of 5 for survival over 5 years in patients with resting hypoxemia (PaO2  < 60 mmHg on room air). Emerging areas of precision health in COPD with potential for low NNTs in specific circumstances include anti-interleukin-5 therapy for eosinophilic COPD, and immunoglobulin replacement therapy for patients with severe immunoglobulin deficiency.


Assuntos
Biomarcadores , Números Necessários para Tratar , Medicina de Precisão , Doença Pulmonar Obstrutiva Crônica/terapia , Administração por Inalação , Corticosteroides/administração & dosagem , Broncodilatadores/administração & dosagem , Volume Expiratório Forçado , Humanos , Antagonistas Muscarínicos/administração & dosagem , Oxigenoterapia , Doença Pulmonar Obstrutiva Crônica/mortalidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Espirometria
17.
Nat Genet ; 51(3): 481-493, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804560

RESUMO

Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function-associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.


Assuntos
Predisposição Genética para Doença/genética , Pulmão/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Fumar/genética
18.
Nat Genet ; 51(3): 494-505, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804561

RESUMO

Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide new insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci associated with P < 5 × 10-8; 47 of these were previously described in association with either COPD or population-based measures of lung function. Of the remaining 35 new loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified functional enrichment of COPD risk loci in lung tissue, smooth muscle, and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups based on associations with quantitative imaging features and comorbidities. Our analyses provide further support for the genetic susceptibility and heterogeneity of COPD.


Assuntos
Predisposição Genética para Doença/genética , Doença Pulmonar Obstrutiva Crônica/genética , Adulto , Idoso , Asma/genética , Estudos de Casos e Controles , Feminino , Expressão Gênica/genética , Loci Gênicos/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fibrose Pulmonar/genética , Fumar/genética
19.
Eur Respir J ; 53(4)2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30679189

RESUMO

Although there has been tremendous growth in our understanding of chronic obstructive pulmonary disease (COPD) and its pathophysiology over the past few decades, the pace of therapeutic innovation has been extremely slow. COPD is now widely accepted as a heterogeneous condition with multiple phenotypes and endotypes. Thus, there is a pressing need for COPD care to move from the current "one-size-fits-all" approach to a precision medicine approach that takes into account individual patient variability in genes, environment and lifestyle. Precision medicine is enabled by biomarkers that can: 1) accurately identify subgroups of patients who are most likely to benefit from therapeutics and those who will only experience harm (predictive biomarkers); 2) predict therapeutic responses to drugs at an individual level (response biomarkers); and 3) segregate patients who are at risk of poor outcomes from those who have relatively stable disease (prognostic biomarkers). In this essay, we will discuss the current concept of precision medicine and its relevance for COPD and explore ways to implement precision medicine for millions of patients across the world with COPD.


Assuntos
Medicina de Precisão , Doença Pulmonar Obstrutiva Crônica/terapia , Humanos
20.
Wellcome Open Res ; 3: 4, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30175238

RESUMO

Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV 1), forced vital capacity (FVC) and the ratio of FEV 1 to FVC (FEV 1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P<2·8x10 -7) associations with six SNPs: a nonsynonymous variant in RPAP1, which is predicted to be damaging, three intronic SNPs ( SEC24C, CASC17 and UQCC1) and two intergenic SNPs near to LY86 and FGF10. Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including TYRO3 and PLAU. Conclusions: Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.

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