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1.
BMJ Open Respir Res ; 7(1)2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33239407

RESUMO

INTRODUCTION: Family history is a risk factor for chronic obstructive pulmonary disease (COPD). We previously developed a COPD risk score from genome-wide genetic markers (Polygenic Risk Score, PRS). Whether the PRS and family history provide complementary or redundant information for predicting COPD and related outcomes is unknown. METHODS: We assessed the predictive capacity of family history and PRS on COPD and COPD-related outcomes in non-Hispanic white (NHW) and African American (AA) subjects from COPDGene and ECLIPSE studies. We also performed interaction and mediation analyses. RESULTS: In COPDGene, family history and PRS were significantly associated with COPD in a single model (PFamHx <0.0001; PPRS<0.0001). Similar trends were seen in ECLIPSE. The area under the receiver operator characteristic curve for a model containing family history and PRS was significantly higher than a model with PRS (p=0.00035) in NHWs and a model with family history (p<0.0001) alone in NHWs and AAs. Both family history and PRS were significantly associated with measures of quantitative emphysema and airway thickness. There was a weakly positive interaction between family history and the PRS under the additive, but not multiplicative scale in NHWs (relative excess risk due to interaction=0.48, p=0.04). Mediation analyses found that a significant proportion of the effect of family history on COPD was mediated through PRS in NHWs (16.5%, 95% CI 9.4% to 24.3%), but not AAs. CONCLUSION: Family history and the PRS provide complementary information for predicting COPD and related outcomes. Future studies can address the impact of obtaining both measures in clinical practice.

2.
Am J Epidemiol ; 2020 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-33106845

RESUMO

Risk for Chronic Obstructive Pulmonary Disease (COPD) is determined by both cigarette smoking and genetic susceptibility, but little is known about gene-by-smoking interactions. We performed a genome-wide association analysis of 179,689 controls and 21,077 COPD cases from UK Biobank subjects of European ancestry recruited from 2006 to 2010, considering genetic main effects and gene-by-smoking interaction effects simultaneously (2-degree-of-freedom test) as well as interaction effects alone (1-degree-of-freedom interaction test). We sought to replicate significant results in the COPDGene study and SpiroMeta Consortium. We considered two smoking variables: (1) ever/never and (2) current/non-current. In the 1-degree-of-freedom interaction test, we identified one genome-wide significant locus on 15q25.1 (CHRNB4) for ever- and current-smoking and identified PI*Z allele (rs28929474) of SERPINA1 for ever-smoking and 3q26.2 (MECOM) for current-smoking in an analysis of previously reported COPD loci. In the 2-degree-of-freedom test, most of the significant signals were also significant for genetic marginal effects, aside from 16q22.1 (SMPD3) and 19q13.2 (EGLN2). The significant effects at 15q25.1 and 19q13.2 loci, both previously described in prior genome-wide association studies of COPD or smoking, were replicated in the COPDGene and SpiroMeta. We identified interaction effects at previously reported COPD loci, however, we failed to identify novel susceptibility loci.

3.
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
4.
Respir Res ; 21(1): 183, 2020 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-32664956

RESUMO

BACKGROUND: Airway bacterial dysbiosis is a feature of chronic obstructive pulmonary disease (COPD). However, there is limited comparative data of the lung microbiome between healthy smokers, non-smokers and COPD. METHODS: We compared the 16S rRNA gene-based sputum microbiome generated from pair-ended Illumina sequencing of 124 healthy subjects (28 smokers and 96 non-smokers with normal lung function), with single stable samples from 218 COPD subjects collected from three UK clinical centres as part of the COPDMAP consortium. RESULTS: In healthy subjects Firmicutes, Bacteroidetes and Actinobacteria were the major phyla constituting 88% of the total reads, and Streptococcus, Veillonella, Prevotella, Actinomyces and Rothia were the dominant genera. Haemophilus formed only 3% of the healthy microbiome. In contrast, Proteobacteria was the most dominant phylum accounting for 50% of the microbiome in COPD subjects, with Haemophilus and Moraxella at genus level contributing 25 and 3% respectively. There were no differences in the microbiome profile within healthy and COPD subgroups when stratified based on smoking history. Principal coordinate analysis on operational taxonomic units showed two distinct clusters, representative of healthy and COPD subjects (PERMANOVA, p = 0·001). CONCLUSION: The healthy and COPD sputum microbiomes are distinct and independent of smoking history. Our results underline the important role for Gammaproteobacteria in COPD.

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.
BMC Med ; 18(1): 71, 2020 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-32200763

RESUMO

BACKGROUND: Age at menarche has been associated with various health outcomes. We aimed to identify potential causal effects of age at menarche on health-related traits in a hypothesis-free manner. METHODS: We conducted a Mendelian randomization phenome-wide association study (MR-pheWAS) of age at menarche with 17,893 health-related traits in UK Biobank (n = 181,318) using PHESANT. The exposure of interest was the genetic risk score for age at menarche. We conducted a second MR-pheWAS after excluding SNPs associated with BMI from the genetic risk score, to examine whether results might be due to the genetic overlap between age at menarche and BMI. We followed up a subset of health-related traits to investigate MR assumptions and seek replication in independent study populations. RESULTS: Of the 17,893 tests performed in our MR-pheWAS, we identified 619 associations with the genetic risk score for age at menarche at a 5% false discovery rate threshold, of which 295 were below a Bonferroni-corrected P value threshold. These included potential effects of younger age at menarche on lower lung function, higher heel bone-mineral density, greater burden of psychosocial/mental health problems, younger age at first birth, higher risk of childhood sexual abuse, poorer cardiometabolic health, and lower physical activity. After exclusion of variants associated with BMI, the genetic risk score for age at menarche was related to 37 traits at a 5% false discovery rate, of which 29 were below a Bonferroni-corrected P value threshold. We attempted to replicate findings for bone-mineral density, lung function, neuroticism, and childhood sexual abuse using 5 independent cohorts/consortia. While estimates for lung function, higher bone-mineral density, neuroticism, and childhood sexual abuse in replication cohorts were consistent with UK Biobank estimates, confidence intervals were wide and often included the null. CONCLUSIONS: The genetic risk score for age at menarche was related to a broad range of health-related traits. Follow-up analyses indicated imprecise evidence of an effect of younger age at menarche on greater bone-mineral density, lower lung function, higher neuroticism score, and greater risk of childhood sexual abuse in the smaller replication samples available; hence, these findings need further exploration when larger independent samples become available.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Menarca/fisiologia , Análise da Randomização Mendeliana/métodos , Fatores Etários , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
8.
Am J Hum Genet ; 106(3): 315-326, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32084330

RESUMO

Whether smoking-associated DNA methylation has a causal effect on lung function has not been thoroughly evaluated. We first investigated the causal effects of 474 smoking-associated CpGs on forced expiratory volume in 1 s (FEV1) in UK Biobank (n = 321,047) by using two-sample Mendelian randomization (MR) and then replicated this investigation in the SpiroMeta Consortium (n = 79,055). Second, we used two-step MR to investigate whether DNA methylation mediates the effect of smoking on FEV1. Lastly, we evaluated the presence of horizontal pleiotropy and assessed whether there is any evidence for shared causal genetic variants between lung function, DNA methylation, and gene expression by using a multiple-trait colocalization ("moloc") framework. We found evidence of a possible causal effect for DNA methylation on FEV1 at 18 CpGs (p < 1.2 × 10-4). Replication analysis supported a causal effect at three CpGs (cg21201401 [LIME1 and ZGPAT], cg19758448 [PGAP3], and cg12616487 [EML3 and AHNAK] [p < 0.0028]). DNA methylation did not clearly mediate the effect of smoking on FEV1, although DNA methylation at some sites might influence lung function via effects on smoking. By using "moloc", we found evidence of shared causal variants between lung function, gene expression, and DNA methylation. These findings highlight potential therapeutic targets for improving lung function and possibly smoking cessation, although larger, tissue-specific datasets are required to confirm these results.


Assuntos
Metilação de DNA , Pulmão/fisiologia , Análise da Randomização Mendeliana/métodos , Fumar , Ilhas de CpG , Volume Expiratório Forçado , Pleiotropia Genética , Humanos
9.
Allergy ; 75(2): 370-380, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31506971

RESUMO

BACKGROUND: Whether the clinical or pathophysiologic significance of the "treatable trait" high blood eosinophil count in COPD is the same as for asthma remains controversial. We sought to determine the relationship between the blood eosinophil count, clinical characteristics and gene expression from bronchial brushings in COPD and asthma. METHODS: Subjects were recruited into a COPD (emphysema versus airway disease [EvA]) or asthma cohort (Unbiased BIOmarkers in PREDiction of respiratory disease outcomes, U-BIOPRED). We determined gene expression using RNAseq in EvA (n = 283) and Affymetrix microarrays in U-BIOPRED (n = 85). We ran linear regression analysis of the bronchial brushings transcriptional signal versus blood eosinophil counts as well as differential expression using a blood eosinophil > 200 cells/µL as a cut-off. The false discovery rate was controlled at 1% (with continuous values) and 5% (with dichotomized values). RESULTS: There were no differences in age, gender, lung function, exercise capacity and quantitative computed tomography between eosinophilic versus noneosinophilic COPD cases. Total serum IgE was increased in eosinophilic asthma and COPD. In EvA, there were 12 genes with a statistically significant positive association with the linear blood eosinophil count, whereas in U-BIOPRED, 1197 genes showed significant associations (266 positive and 931 negative). The transcriptome showed little overlap between genes and pathways associated with blood eosinophil counts in asthma versus COPD. Only CST1 was common to eosinophilic asthma and COPD and was replicated in independent cohorts. CONCLUSION: Despite shared "treatable traits" between asthma and COPD, the molecular mechanisms underlying these clinical entities are predominately different.

10.
Thorax ; 75(1): 8-16, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31699806

RESUMO

BACKGROUND: Antibiotic resistance is a major global threat. We hypothesised that the chronic obstructive pulmonary disease (COPD) airway is a reservoir of antimicrobial resistance genes (ARGs) that associate with microbiome-specific COPD subgroups. OBJECTIVE: To determine the resistance gene profiles in respiratory samples from COPD patients and healthy volunteers. METHODS: Quantitative PCR targeting 279 specific ARGs was used to profile the resistomes in sputum from subjects with COPD at stable, exacerbation and recovery visits (n=55; COPD-BEAT study), healthy controls with (n=7) or without (n=22) exposure to antibiotics in the preceding 12 months (EXCEED study) and in bronchial brush samples from COPD (n=8) and healthy controls (n=7) (EvA study). RESULTS: ARG mean (SEM) prevalence was greater in stable COPD samples (35.2 (1.6)) than in healthy controls (27.6 (1.7); p=0.004) and correlated with total bacterial abundance (r2=0.23; p<0.001). Prevalence of ARG positive signals in individuals was not related to COPD symptoms, lung function or their changes at exacerbation. In the COPD subgroups designated High γProteobacteria and High Firmicutes, ARG prevalence was not different at stable state but significantly declined from stable through exacerbation to recovery in the former (p=0.011) without changes in total bacterial abundance. The ARG patterns were similar in COPD versus health, COPD microbiome-subgroups and between sputum and bronchoscopic samples independent of antibiotic exposure in the last 12 months. CONCLUSIONS: ARGs are highly prevalent in sputum, broadly in proportion to bacterial abundance in both healthy and COPD subjects. Thus, COPD appears to be an ARG reservoir due to high levels of bacterial colonisation.


Assuntos
Farmacorresistência Bacteriana/genética , Doença Pulmonar Obstrutiva Crônica/microbiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Escarro/microbiologia , Idoso , Carga Bacteriana , Feminino , Genes Bacterianos , Humanos , Masculino , Microbiota , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase
12.
Eur Respir J ; 54(1)2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31073081

RESUMO

Previous reports link differential DNA methylation (DNAme) to environmental exposures that are associated with lung function. Direct evidence on lung function DNAme is, however, limited. We undertook an agnostic epigenome-wide association study (EWAS) on pre-bronchodilation lung function and its change in adults.In a discovery-replication EWAS design, DNAme in blood and spirometry were measured twice, 6-15 years apart, in the same participants of three adult population-based discovery cohorts (n=2043). Associated DNAme markers (p<5×10-7) were tested in seven replication cohorts (adult: n=3327; childhood: n=420). Technical bias-adjusted residuals of a regression of the normalised absolute ß-values on control probe-derived principle components were regressed on level and change of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and their ratio (FEV1/FVC) in the covariate-adjusted discovery EWAS. Inverse-variance-weighted meta-analyses were performed on results from discovery and replication samples in all participants and never-smokers.EWAS signals were enriched for smoking-related DNAme. We replicated 57 lung function DNAme markers in adult, but not childhood samples, all previously associated with smoking. Markers not previously associated with smoking failed replication. cg05575921 (AHRR (aryl hydrocarbon receptor repressor)) showed the statistically most significant association with cross-sectional lung function (FEV1/FVC: pdiscovery=3.96×10-21 and pcombined=7.22×10-50). A score combining 10 DNAme markers previously reported to mediate the effect of smoking on lung function was associated with lung function (FEV1/FVC: p=2.65×10-20).Our results reveal that lung function-associated methylation signals in adults are predominantly smoking related, and possibly of clinical utility in identifying poor lung function and accelerated decline. Larger studies with more repeat time-points are needed to identify lung function DNAme in never-smokers and in children.


Assuntos
Metilação de DNA , Epigênese Genética , Estudo de Associação Genômica Ampla , Fumar/genética , Adulto , Idoso , Ilhas de CpG , Feminino , Volume Expiratório Forçado , Humanos , Modelos Lineares , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Valores de Referência , Fumar/fisiopatologia , Espirometria
14.
Lancet Respir Med ; 7(1): 20-34, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30552067

RESUMO

BACKGROUND: Few genetic studies that focus on moderate-to-severe asthma exist. We aimed to identity novel genetic variants associated with moderate-to-severe asthma, see whether previously identified genetic variants for all types of asthma contribute to moderate-to-severe asthma, and provide novel mechanistic insights using expression analyses in patients with asthma. METHODS: In this genome-wide association study, we used a two-stage case-control design. In stage 1, we genotyped patient-level data from two UK cohorts (the Genetics of Asthma Severity and Phenotypes [GASP] initiative and the Unbiased BIOmarkers in PREDiction of respiratory disease outcomes [U-BIOPRED] project) and used data from the UK Biobank to collect patient-level genomic data for cases and controls of European ancestry in a 1:5 ratio. Cases were defined as having moderate-to-severe asthma if they were taking appropriate medication or had been diagnosed by a doctor. Controls were defined as not having asthma, rhinitis, eczema, allergy, emphysema, or chronic bronchitis as diagnosed by a doctor. For stage 2, an independent cohort of cases and controls (1:5) was selected from the UK Biobank only, with no overlap with stage 1 samples. In stage 1 we undertook a genome-wide association study of moderate-to-severe asthma, and in stage 2 we followed up independent variants that reached the significance threshold of p less than 1 × 10-6 in stage 1. We set genome-wide significance at p less than 5 × 10-8. For novel signals, we investigated their effect on all types of asthma (mild, moderate, and severe). For all signals meeting genome-wide significance, we investigated their effect on gene expression in patients with asthma and controls. FINDINGS: We included 5135 cases and 25 675 controls for stage 1, and 5414 cases and 21 471 controls for stage 2. We identified 24 genome-wide significant signals of association with moderate-to-severe asthma, including several signals in innate or adaptive immune-response genes. Three novel signals were identified: rs10905284 in GATA3 (coded allele A, odds ratio [OR] 0·90, 95% CI 0·88-0·93; p=1·76 × 10-10), rs11603634 in the MUC5AC region (coded allele G, OR 1·09, 1·06-1·12; p=2·32 × 10-8), and rs560026225 near KIAA1109 (coded allele GATT, OR 1·12, 1·08-1·16; p=3·06 × 10-9). The MUC5AC signal was not associated with asthma when analyses included mild asthma. The rs11603634 G allele was associated with increased expression of MUC5AC mRNA in bronchial epithelial brush samples via proxy SNP rs11602802; (p=2·50 × 10-5) and MUC5AC mRNA was increased in bronchial epithelial samples from patients with severe asthma (in two independent analyses, p=0·039 and p=0·022). INTERPRETATION: We found substantial shared genetic architecture between mild and moderate-to-severe asthma. We also report for the first time genetic variants associated with the risk of developing moderate-to-severe asthma that regulate mucin production. Finally, we identify candidate causal genes in these loci and provide increased insight into this difficult to treat population. FUNDING: Asthma UK, AirPROM, U-BIOPRED, UK Medical Research Council, and Rosetrees Trust.


Assuntos
Asma/genética , Fator de Transcrição GATA3/genética , Predisposição Genética para Doença , Mucina-5AC , Proteínas , Adulto , Idoso , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença
15.
Ann Am Thorac Soc ; 16(1): 1-16, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30592451

RESUMO

High-throughput, "next-generation" sequencing methods are now being broadly applied across all fields of biomedical research, including respiratory disease, critical care, and sleep medicine. Although there are numerous review articles and best practice guidelines related to sequencing methods and data analysis, there are fewer resources summarizing issues related to study design and interpretation, especially as applied to common, complex, nonmalignant diseases. To address these gaps, a single-day workshop was held at the American Thoracic Society meeting in May 2017, led by the American Thoracic Society Section on Genetics and Genomics. The aim of this workshop was to review the design, analysis, interpretation, and functional follow-up of high-throughput sequencing studies in respiratory, critical care, and sleep medicine research. This workshop brought together experts in multiple fields, including genetic epidemiology, biobanking, bioinformatics, and research ethics, along with physician-scientists with expertise in a range of relevant diseases. The workshop focused on application of DNA and RNA sequencing research in common chronic diseases and did not cover sequencing studies in lung cancer, monogenic diseases (e.g., cystic fibrosis), or microbiome sequencing. Participants reviewed and discussed study design, data analysis and presentation, interpretation, functional follow-up, and reporting of results. This report summarizes the main conclusions of the workshop, specifically addressing the application of these methods in respiratory, critical care, and sleep medicine research. This workshop report may serve as a resource for our research community as well as for journal editors and reviewers of sequencing-based manuscript submissions in our research field.


Assuntos
Cuidados Críticos , Sequenciamento de Nucleotídeos em Larga Escala , Pneumologia , Medicina do Sono , Humanos , Sociedades Médicas , Estados Unidos , Sequenciamento Completo do Genoma
16.
Eur Respir J ; 52(5)2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30093573

RESUMO

Lymphangioleiomyomatosis (LAM) is a rare disease of women. Decline in lung function is variable, making appropriate targeting of therapy difficult. We used unbiased serum proteomics to identify markers associated with outcome in LAM.101 women with LAM and 22 healthy controls were recruited from the National Centre for LAM in the UK. 152 DNA and serum samples with linked lung function and outcome data were obtained from patients in the National Heart, Lung and Blood Institute LAM Registry in the USA. Proteomic analysis was performed on a discovery cohort of 50 LAM and 20 control serum samples using a SCIEX SWATH mass spectrometric workflow. Protein levels were quantitated by ELISA and single nucleotide polymorphisms in GC (group-specific component) encoding vitamin D binding protein (VTDB) were genotyped.Proteomic analysis showed VTDB was 2.6-fold lower in LAM than controls. Serum VTDB was lower in progressive compared with stable LAM (p=0.001) and correlated with diffusing capacity of the lung for carbon monoxide (p=0.01). Median time to death or lung transplant was reduced by 46 months in those with CC genotypes at rs4588 and 38 months in those with non-A-containing haplotypes at rs7041/4588 (p=0.014 and 0.008, respectively).The VTDB axis is associated with disease severity and outcome, and GC genotype could help predict transplant-free survival in LAM.


Assuntos
Neoplasias Pulmonares/genética , Pulmão/fisiopatologia , Linfangioleiomiomatose/genética , Polimorfismo de Nucleotídeo Único , Proteína de Ligação a Vitamina D/genética , Adulto , Estudos de Casos e Controles , Feminino , Haplótipos , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/mortalidade , Transplante de Pulmão , Linfangioleiomiomatose/sangue , Linfangioleiomiomatose/mortalidade , Pessoa de Meia-Idade , Proteômica , Análise de Sobrevida , Tomografia Computadorizada por Raios X , Reino Unido , Estados Unidos , Proteína de Ligação a Vitamina D/sangue
17.
Circ Genom Precis Med ; 11(1): e001758, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29874175

RESUMO

BACKGROUND: QT interval, measured through a standard ECG, captures the time it takes for the cardiac ventricles to depolarize and repolarize. JT interval is the component of the QT interval that reflects ventricular repolarization alone. Prolonged QT interval has been linked to higher risk of sudden cardiac arrest. METHODS AND RESULTS: We performed an ExomeChip-wide analysis for both QT and JT intervals, including 209 449 variants, both common and rare, in 17 341 genes from the Illumina Infinium HumanExome BeadChip. We identified 10 loci that modulate QT and JT interval duration that have not been previously reported in the literature using single-variant statistical models in a meta-analysis of 95 626 individuals from 23 cohorts (comprised 83 884 European ancestry individuals, 9610 blacks, 1382 Hispanics, and 750 Asians). This brings the total number of ventricular repolarization associated loci to 45. In addition, our approach of using coding variants has highlighted the role of 17 specific genes for involvement in ventricular repolarization, 7 of which are in novel loci. CONCLUSIONS: Our analyses show a role for myocyte internal structure and interconnections in modulating QT interval duration, adding to previous known roles of potassium, sodium, and calcium ion regulation, as well as autonomic control. We anticipate that these discoveries will open new paths to the goal of making novel remedies for the prevention of lethal ventricular arrhythmias and sudden cardiac arrest.


Assuntos
Exoma/genética , Síndrome do QT Longo/diagnóstico , Locos de Características Quantitativas , Antiporters/genética , Proteínas de Ligação a DNA/genética , Eletrocardiografia , Estudo de Associação Genômica Ampla , Humanos , Síndrome do QT Longo/etnologia , Síndrome do QT Longo/genética , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Receptores de Detecção de Cálcio/genética , Fatores de Transcrição/genética
18.
Wellcome Open Res ; 3: 13, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29682616

RESUMO

Background: The CCL3L1-CCR5 signaling axis is important in a number of inflammatory responses, including macrophage function, and T-cell-dependent immune responses. Small molecule CCR5 antagonists exist, including the approved antiretroviral drug maraviroc, and therapeutic monoclonal antibodies are in development. Repositioning of drugs and targets into new disease areas can accelerate the availability of new therapies and substantially reduce costs. As it has been shown that drug targets with genetic evidence supporting their involvement in the disease are more likely to be successful in clinical development, using genetic association studies to identify new target repurposing opportunities could be fruitful. Here we investigate the potential of perturbation of the CCL3L1-CCR5 axis as treatment for respiratory disease. Europeans typically carry between 0 and 5 copies of CCL3L1 and this multi-allelic variation is not detected by widely used genome-wide single nucleotide polymorphism studies.  Methods: We directly measured the complex structural variation of CCL3L1 using the Paralogue Ratio Test and imputed (with validation) CCR5del32 genotypes in 5,000 individuals from UK Biobank, selected from the extremes of the lung function distribution, and analysed DNA and RNAseq data for CCL3L1 from the 1000 Genomes Project. Results: We confirmed the gene dosage effect of CCL3L1 copy number on CCL3L1 mRNA expression levels.  We found no evidence for association of CCL3L1 copy number or CCR5del32 genotype with lung function. Conclusions: These results suggest that repositioning CCR5 antagonists is unlikely to be successful for the treatment of airflow obstruction.

19.
Nat Commun ; 9(1): 711, 2018 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-29459775

RESUMO

Detailed phenotyping is required to deepen our understanding of the biological mechanisms behind genetic associations. In addition, the impact of potentially modifiable risk factors on disease requires analytical frameworks that allow causal inference. Here, we discuss the characteristics of Recall-by-Genotype (RbG) as a study design aimed at addressing both these needs. We describe two broad scenarios for the application of RbG: studies using single variants and those using multiple variants. We consider the efficacy and practicality of the RbG approach, provide a catalogue of UK-based resources for such studies and present an online RbG study planner.


Assuntos
Estudo de Associação Genômica Ampla , Genótipo , Fenótipo , Causalidade , Variação Genética , Estudo de Associação Genômica Ampla/métodos , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Estudo de Associação Genômica Ampla/tendências , Humanos , Epidemiologia Molecular , Fatores de Risco , Reino Unido
20.
Am J Respir Crit Care Med ; 198(2): 208-219, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29394082

RESUMO

RATIONALE: Lung function and chronic obstructive pulmonary disease (COPD) are heritable traits. Genome-wide association studies (GWAS) have identified numerous pulmonary function and COPD loci, primarily in cohorts of European ancestry. OBJECTIVES: Perform a GWAS of COPD phenotypes in Hispanic/Latino populations to identify loci not previously detected in European populations. METHODS: GWAS of lung function and COPD in Hispanic/Latino participants from a population-based cohort. We performed replication studies of novel loci in independent studies. MEASUREMENTS AND MAIN RESULTS: Among 11,822 Hispanic/Latino participants, we identified eight novel signals; three replicated in independent populations of European Ancestry. A novel locus for FEV1 in ZSWIM7 (rs4791658; P = 4.99 × 10-9) replicated. A rare variant (minor allele frequency = 0.002) in HAL (rs145174011) was associated with FEV1/FVC (P = 9.59 × 10-9) in a region previously identified for COPD-related phenotypes; it remained significant in conditional analyses but did not replicate. Admixture mapping identified a novel region, with a variant in AGMO (rs41331850), associated with Amerindian ancestry and FEV1, which replicated. A novel locus for FEV1 identified among ever smokers (rs291231; P = 1.92 × 10-8) approached statistical significance for replication in admixed populations of African ancestry, and a novel SNP for COPD in PDZD2 (rs7709630; P = 1.56 × 10-8) regionally replicated. In addition, loci previously identified for lung function in European samples were associated in Hispanic/Latino participants in the Hispanic Community Health Study/Study of Latinos at the genome-wide significance level. CONCLUSIONS: We identified novel signals for lung function and COPD in a Hispanic/Latino cohort. Including admixed populations when performing genetic studies may identify variants contributing to genetic etiologies of COPD.


Assuntos
Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hispano-Americanos/genética , Doença Pulmonar Obstrutiva Crônica/genética , Adolescente , Adulto , Idoso , Estudos de Coortes , Europa (Continente) , Feminino , Frequência do Gene , Loci Gênicos , Humanos , Masculino , Pessoa de Meia-Idade , Testes de Função Respiratória , Estados Unidos , Adulto Jovem
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