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PURPOSE: Over 550 loci have been associated with human pulmonary function in genome-wide association studies (GWAS); however, the causal role of most remains uncertain. Single nucleotide polymorphisms in a disintegrin and metalloprotease domain 19 (ADAM19) are consistently related to pulmonary function in GWAS. Thus, we used a mouse model to investigate the causal link between Adam19 and pulmonary function. METHODS: We created an Adam19 knockout (KO) mouse model and validated the gene targeting using RNA-Seq and RT-qPCR. Mouse body composition was assessed using dual-energy X-ray absorptiometry. Mouse lung function was measured using flexiVent. RESULTS: Contrary to prior publications, the KO was not neonatal lethal. KO mice had lower body weight and shorter tibial length than wild-type (WT) mice. Their body composition revealed lower soft weight, fat weight, and bone mineral content. Adam19 KO had decreased baseline respiratory system elastance, minute work of breathing, tissue damping, tissue elastance, and forced expiratory flow at 50% forced vital capacity but higher FEV0.1 and FVC. Adam19 KO had attenuated tissue damping and tissue elastance in response to methacholine following LPS exposure. Adam19 KO also exhibited attenuated neutrophil extravasation into the airway after LPS administration compared to WT. RNA-Seq analysis of KO and WT lungs identified several differentially expressed genes (Cd300lg, Kpna2, and Pttg1) implicated in lung biology and pathogenesis. Gene set enrichment analysis identified negative enrichment for TNF pathways. CONCLUSION: Our murine findings support a causal role of ADAM19, implicated in human GWAS, in regulating pulmonary function.
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BACKGROUND: Adult asthma is complex and incompletely understood. Plasma proteomics is an evolving technique that can both generate biomarkers and provide insights into disease mechanisms. We aimed to identify plasma proteomic signatures of adult asthma. METHODS: Protein abundance in plasma was measured in individuals from the Agricultural Lung Health Study (ALHS) (761 asthma, 1095 non-case) and the Atherosclerosis Risk in Communities study (470 asthma, 10,669 non-case) using the SOMAScan 5K array. Associations with asthma were estimated using covariate adjusted logistic regression and meta-analyzed using inverse-variance weighting. Additionally, in ALHS, we examined phenotypes based on both asthma and seroatopy (asthma with atopy (n = 207), asthma without atopy (n = 554), atopy without asthma (n = 147), compared to neither (n = 948)). RESULTS: Meta-analysis of 4860 proteins identified 115 significantly (FDR<0.05) associated with asthma. Multiple signaling pathways related to airway inflammation and pulmonary injury were enriched (FDR<0.05) among these proteins. A proteomic score generated using machine learning provided predictive value for asthma (AUC = 0.77, 95% CI = 0.75-0.79 in training set; AUC = 0.72, 95% CI = 0.69-0.75 in validation set). Twenty proteins are targeted by approved or investigational drugs for asthma or other conditions, suggesting potential drug repurposing. The combined asthma-atopy phenotype showed significant associations with 20 proteins, including five not identified in the overall asthma analysis. CONCLUSION: This first large-scale proteomics study identified over 100 plasma proteins associated with current asthma in adults. In addition to validating previous associations, we identified many novel proteins that could inform development of diagnostic biomarkers and therapeutic targets in asthma management.
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Asma , Hipersensibilidad Inmediata , Adulto , Humanos , Proteómica/métodos , Asma/metabolismo , Biomarcadores , Fenotipo , Proteínas Sanguíneas/genéticaRESUMEN
BACKGROUND: Preserved ratio impaired spirometry (PRISm) is defined as a forced expiratory volume in 1â s (FEV1) <80% predicted and FEV1/forced vital capacity ≥0.70. PRISm is associated with respiratory symptoms and comorbidities. Our objective was to discover novel genetic signals for PRISm and see if they provide insight into the pathogenesis of PRISm and associated comorbidities. METHODS: We undertook a genome-wide association study (GWAS) of PRISm in UK Biobank participants (Stage 1), and selected single nucleotide polymorphisms (SNPs) reaching genome-wide significance for replication in 13 cohorts (Stage 2). A combined meta-analysis of Stage 1 and Stage 2 was done to determine top SNPs. We used cross-trait linkage disequilibrium score regression to estimate genome-wide genetic correlation between PRISm and pulmonary and extrapulmonary traits. Phenome-wide association studies of top SNPs were performed. RESULTS: 22 signals reached significance in the joint meta-analysis, including four signals novel for lung function. A strong genome-wide genetic correlation (rg) between PRISm and spirometric COPD (rg=0.62, p<0.001) was observed, and genetic correlation with type 2 diabetes (rg=0.12, p=0.007). Phenome-wide association studies showed that 18 of 22 signals were associated with diabetic traits and seven with blood pressure traits. CONCLUSION: This is the first GWAS to successfully identify SNPs associated with PRISm. Four of the signals, rs7652391 (nearest gene MECOM), rs9431040 (HLX), rs62018863 (TMEM114) and rs185937162 (HLA-B), have not been described in association with lung function before, demonstrating the utility of using different lung function phenotypes in GWAS. Genetic factors associated with PRISm are strongly correlated with risk of both other lung diseases and extrapulmonary comorbidity.
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Diabetes Mellitus Tipo 2 , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Estudio de Asociación del Genoma Completo , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/genética , Diabetes Mellitus Tipo 2/genética , Pulmón , Volumen Espiratorio Forzado/genética , Espirometría , Capacidad VitalRESUMEN
Background: Several studies conducted in Europe have suggested a protective association between early-life farming exposures and childhood eczema or atopic dermatitis; few studies have examined associations in adults. Objectives: To investigate associations between early-life exposures and eczema among 3217 adult farmers and farm spouses (mean age 62.8 years) in a case-control study nested within an US agricultural cohort. Methods: We used sampling-weighted logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (95%CIs) for associations between early-life exposures and self-reported doctor-diagnosed eczema (273 cases) and polytomous logistic regression to estimate ORs (95%CIs) for a 4-level outcome combining information on eczema and atopy (specific IgE≥0.35). Additionally, we explored genetic and gene-environment associations with eczema. Results: Although early-life farming exposures were not associated with eczema overall, several early-life exposures were associated with a reduced risk of having both eczema and atopy. Notably, results suggest stronger protective associations among individuals with both eczema and atopy than among those with either atopy alone or eczema alone. For example, ORs (95%CIs) for having a mother who did farm work while pregnant were 1.01 (0.60-1.69) for eczema alone and 0.80 (0.65-0.99) for atopy alone, but 0.54 (0.33-0.80) for having both eczema and atopy. A genetic risk score based on previously identified atopic dermatitis variants was strongly positively associated with eczema, and interaction testing suggested protective effects of several early-life farming exposures only in individuals at lower genetic risk. Conclusions: In utero and childhood farming exposures are associated with decreased odds of having eczema with atopy in adults.
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BACKGROUND: In low- and middle-income countries, burning biomass indoors for cooking or heating has been associated with poorer lung function. In high-income countries, wood, a form of biomass, is commonly used for heating in rural areas with increasing prevalence. However, in these settings the potential impact of chronic indoor woodsmoke exposure on pulmonary function is little studied. OBJECTIVE: We evaluated the association of residential wood burning with pulmonary function in case-control study of asthma nested within a U.S. rural cohort. METHODS: Using sample weighted multivariable linear regression, we estimated associations between some and frequent wood burning, both relative to no exposure, in relation to forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), their ratio (FEV1/FVC), and fractional exhaled nitric oxide (FeNO). We examined effect modification by smoking or asthma status. RESULTS: Among all participants and within smoking groups, wood burning was not appreciably related to pulmonary function. However, in individuals with asthma (n=1,083), frequent wood burning was significantly associated with lower FEV1 [ß: -164mL; 95% confidence interval (CI): -261, -66mL], FVC (ß: -125mL; 95% CI: -230, -20mL), and FEV1/FVC (ß: -2%; 95% CI: -4, -0.4%), whereas no appreciable association was seen in individuals without asthma (n=1,732). These differences in association by asthma were statistically significant for FEV1 (pinteraction=0.0044) and FEV1/FVC (pinteraction=0.049). Frequent wood burning was also associated with higher FeNO levels in all individuals (n=2,598; ß: 0.1 ln(ppb); 95% CI: 0.02, 0.2), but associations did not differ by asthma or smoking status. DISCUSSION: Frequent exposure to residential wood burning was associated with a measure of airway inflammation (FeNO) among all individuals and with lower pulmonary function among individuals with asthma. This group may wish to reduce wood burning or consider using air filtration devices. https://doi.org/10.1289/EHP10734.
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Asma , Madera , Asma/epidemiología , Volumen Espiratorio Forzado , Humanos , Pulmón , Capacidad VitalRESUMEN
Aim: To identify differential methylation related to prescribed opioid use. Methods: This study examined whether blood DNA methylation, measured using Illumina arrays, differs by recent opioid medication use in four population-based cohorts. We meta-analyzed results (282 users; 10,560 nonusers) using inverse-variance weighting. Results: Differential methylation (false discovery rate <0.05) was observed at six CpGs annotated to the following genes: KIAA0226, CPLX2, TDRP, RNF38, TTC23 and GPR179. Integrative epigenomic analyses linked implicated loci to regulatory elements in blood and/or brain. Additionally, 74 CpGs were differentially methylated in males or females. Methylation at significant CpGs correlated with gene expression in blood and/or brain. Conclusion: This study identified DNA methylation related to opioid medication use in general populations. The results could inform the development of blood methylation biomarkers of opioid use.
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Analgésicos Opioides , Metilación de ADN , Epigenoma , Femenino , Humanos , Masculino , Islas de CpG , Epigénesis Genética , Estudio de Asociación del Genoma CompletoRESUMEN
RATIONALE: Genome-wide association studies (GWASs) have identified numerous loci associated with lower pulmonary function. Pulmonary function is strongly related to smoking and has also been associated with asthma and dust endotoxin. At the individual SNP level, genome-wide analyses of pulmonary function have not identified appreciable evidence for gene by environment interactions. Genetic Risk Scores (GRSs) may enhance power to identify gene-environment interactions, but studies are few. METHODS: We analysed 2844 individuals of European ancestry with 1000 Genomes imputed GWAS data from a case-control study of adult asthma nested within a US agricultural cohort. Pulmonary function traits were FEV1, FVC and FEV1/FVC. Using data from a recent large meta-analysis of GWAS, we constructed a weighted GRS for each trait by combining the top (p value<5×10-9) genetic variants, after clumping based on distance (±250 kb) and linkage disequilibrium (r2=0.5). We used linear regression, adjusting for relevant covariates, to estimate associations of each trait with its GRS and to assess interactions. RESULTS: Each trait was highly significantly associated with its GRS (all three p values<8.9×10-8). The inverse association of the GRS with FEV1/FVC was stronger for current smokers (pinteraction=0.017) or former smokers (pinteraction=0.064) when compared with never smokers and among asthmatics compared with non-asthmatics (pinteraction=0.053). No significant interactions were observed between any GRS and house dust endotoxin. CONCLUSIONS: Evaluation of interactions using GRSs supports a greater impact of increased genetic susceptibility on reduced pulmonary function in the presence of smoking or asthma.
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Asma , Estudio de Asociación del Genoma Completo , Adulto , Asma/genética , Estudios de Casos y Controles , Endotoxinas/toxicidad , Predisposición Genética a la Enfermedad , Humanos , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Fumar/efectos adversosRESUMEN
BACKGROUND: Bacterial exposure from house dust has been associated with asthma and atopy in children but whether these relationships are present in adults remains unclear. OBJECTIVE: We sought to examine associations of house dust microbiota with adult asthma, atopy, and hay fever. METHODS: Vacuumed bedroom dust samples from the homes of 879 participants (average age, 62 years) in the Agricultural Lung Health Study, a case-control study of asthma nested within a farming cohort, were subjected to 16S rRNA amplicon sequencing to characterize bacterial communities. We defined current asthma and hay fever using questionnaires and current atopy by blood specific IgE level > 0.70 IU/mL to 1 or more of 10 common allergens. We used linear regression to examine whether overall within-sample bacterial diversity differed by outcome, microbiome regression-based kernel association test to evaluate whether between-sample bacterial community compositions differed by outcome, and analysis of composition of microbiomes to identify differentially abundant bacterial taxa. RESULTS: Overall diversity of bacterial communities in house dust was similar by asthma status but was lower (P < .05) with atopy or hay fever. Many individual bacterial taxa were differentially abundant (false-discovery rate, <0.05) by asthma, atopy, or hay fever. Several taxa from Cyanobacteria, Bacteroidetes, and Fusobacteria were more abundant with asthma, atopy, or hay fever. In contrast, several taxa from Firmicutes were more abundant in homes of individuals with adequately controlled asthma (vs inadequately controlled asthma), individuals without atopy, or individuals without hay fever. CONCLUSIONS: Microbial composition of house dust may influence allergic outcomes in adults.
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Asma/microbiología , Bacteroidetes/fisiología , Cianobacterias/fisiología , Polvo/análisis , Fusobacterias/fisiología , Hipersensibilidad Inmediata/microbiología , Microbiota/inmunología , ARN Ribosómico 16S/genética , Rinitis Alérgica Estacional/microbiología , Anciano , Agricultura , Asma/inmunología , Estudios de Casos y Controles , Polvo/inmunología , Femenino , Interacciones Microbiota-Huesped , Humanos , Hipersensibilidad Inmediata/inmunología , Inmunoglobulina E/metabolismo , Masculino , Microbiota/genética , Persona de Mediana Edad , Grupos de Población , Rinitis Alérgica Estacional/inmunología , Estados UnidosRESUMEN
Epigenome-wide studies of methylation in children support a role for epigenetic mechanisms in asthma; however, studies in adults are rare and few have examined non-atopic asthma. We conducted the largest epigenome-wide association study (EWAS) of blood DNA methylation in adults in relation to non-atopic and atopic asthma.We measured DNA methylation in blood using the Illumina MethylationEPIC array among 2286 participants in a case-control study of current adult asthma nested within a United States agricultural cohort. Atopy was defined by serum specific immunoglobulin E (IgE). Participants were categorised as atopy without asthma (n=185), non-atopic asthma (n=673), atopic asthma (n=271), or a reference group of neither atopy nor asthma (n=1157). Analyses were conducted using logistic regression.No associations were observed with atopy without asthma. Numerous cytosine-phosphate-guanine (CpG) sites were differentially methylated in non-atopic asthma (eight at family-wise error rate (FWER) p<9×10-8, 524 at false discovery rate (FDR) less than 0.05) and implicated 382 novel genes. More CpG sites were identified in atopic asthma (181 at FWER, 1086 at FDR) and implicated 569 novel genes. 104 FDR CpG sites overlapped. 35% of CpG sites in non-atopic asthma and 91% in atopic asthma replicated in studies of whole blood, eosinophils, airway epithelium, or nasal epithelium. Implicated genes were enriched in pathways related to the nervous system or inflammation.We identified numerous, distinct differentially methylated CpG sites in non-atopic and atopic asthma. Many CpG sites from blood replicated in asthma-relevant tissues. These circulating biomarkers reflect risk and sequelae of disease, as well as implicate novel genes associated with non-atopic and atopic asthma.
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Asma , Epigenoma , Adulto , Asma/genética , Estudios de Casos y Controles , Niño , Islas de CpG , Metilación de ADN , Epigénesis Genética , Estudio de Asociación del Genoma Completo , Humanos , Pulmón , Estados UnidosRESUMEN
Rationale: Poor lung health in adult life may occur partly through suboptimal growth and development, as suggested by epidemiological evidence pointing to early life risk factors.Objectives: To systematically investigate the effects of lung development genes on adult lung function.Methods: Using UK Biobank data, we tested the association of 391 genes known to influence lung development with FVC and FEV1/FVC. We split the dataset into two random subsets of 207,616 and 138,411 individuals, using the larger subset to select the most promising signals and the smaller subset for replication.Measurements and Main Results: We identified 55 genes, of which 36 (16 for FVC, 19 for FEV1/FVC, and one for both) had not been identified in the largest, most recent genome-wide study of lung function. Most of these 36 signals were intronic variants; expression data from blood and lung tissue showed that the majority affect the expression of the genes they lie within. Further testing of 34 of these 36 signals in the CHARGE and SpiroMeta consortia showed that 16 replicated after Bonferroni correction and another 12 replicated at nominal significance level. Of the 55 genes, 53 fell into four biological categories whose function is to regulate organ size and cell integrity (growth factors; transcriptional regulators; cell-to-cell adhesion; extracellular matrix), suggesting that these specific processes are important for adult lung health.Conclusions: Our study demonstrates the importance of lung development genes in regulating adult lung function and influencing both restrictive and obstructive patterns. Further investigation of these developmental pathways could lead to druggable targets.
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Biología Evolutiva , Predisposición Genética a la Enfermedad , Crecimiento y Desarrollo/genética , Pulmón/crecimiento & desarrollo , Fenómenos Fisiológicos Respiratorios/genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Pruebas de Función Respiratoria , Factores de Riesgo , Reino UnidoRESUMEN
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.
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Estudio de Asociación del Genoma Completo/métodos , Menarquia/fisiología , Análisis de la Aleatorización Mendeliana/métodos , Factores de Edad , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
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.
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Predisposición Genética a la Enfermedad/genética , Enfermedad Pulmonar Obstructiva Crónica/genética , Adulto , Anciano , Asma/genética , Estudios de Casos y Controles , Femenino , Expresión Génica/genética , Sitios Genéticos/genética , Estudio de Asociación del Genoma Completo/métodos , Humanos , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Fibrosis Pulmonar/genética , Fumar/genéticaRESUMEN
Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci.
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Estudio de Asociación del Genoma Completo , Desequilibrio de Ligamiento , Enfermedades Pulmonares/etnología , Enfermedades Pulmonares/genética , Pulmón/fisiología , Polimorfismo de Nucleótido Simple , Asiático , Población Negra/genética , Femenino , Volumen Espiratorio Forzado , Predisposición Genética a la Enfermedad , Genómica , Hispánicos o Latinos , Humanos , Masculino , Enfermedad Pulmonar Obstructiva Crónica , Sitios de Carácter Cuantitativo , Análisis de Regresión , Tamaño de la Muestra , Fumar , Capacidad Vital , Población Blanca/genéticaRESUMEN
Literature suggests that early exposure to the farming environment protects against atopy and asthma; few studies have examined pulmonary function. We evaluated associations between early-life farming exposures and pulmonary function in 3061 adults (mean age=63) from a US farming population using linear regression. Childhood raw milk consumption was associated with higher FEV1 (ß=49.5 mL, 95% CI 2.8 to 96.1 mL, p=0.04) and FVC (ß=66.2 mL, 95% CI 13.2 to 119.1 mL, p=0.01). We did not find appreciable associations with other early-life farming exposures. We report a novel association between raw milk consumption and higher pulmonary function that lasts into older adulthood.
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Exposición a Riesgos Ambientales , Pulmón/fisiopatología , Leche/fisiología , Espirometría/métodos , Adulto , Anciano , Agricultura , Animales , Estudios de Casos y Controles , Niño , Preescolar , Granjas/estadística & datos numéricos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Fenómenos Fisiológicos Respiratorios , Estados UnidosRESUMEN
Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 × 10-6) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples, while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity. We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases.
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Sitios Genéticos/genética , Predisposición Genética a la Enfermedad/genética , Pulmón/fisiología , Enfermedad Pulmonar Obstructiva Crónica/genética , Fibrosis Pulmonar/genética , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Asma/genética , Femenino , Estudio de Asociación del Genoma Completo/métodos , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo , Fumar/genéticaRESUMEN
RATIONALE: Endotoxin initiates a proinflammatory response from the innate immune system. Studies in children suggest that endotoxin exposure from house dust may be an important risk factor for asthma, but few studies have been conducted in adult populations. OBJECTIVES: To investigate the association of house dust endotoxin levels with asthma and related phenotypes (wheeze, atopy, and pulmonary function) in a large U.S. farming population. METHODS: Dust was collected from the bedrooms (n = 2,485) of participants enrolled in a case-control study of current asthma (927 cases) nested within the Agricultural Health Study. Dust endotoxin was measured by Limulus amebocyte lysate assay. Outcomes were measured by questionnaire, spirometry, and blood draw. We evaluated associations using linear and logistic regression. MEASUREMENTS AND MAIN RESULTS: Endotoxin was significantly associated with current asthma (odds ratio [OR], 1.30; 95% confidence interval [CI], 1.14-1.47), and this relationship was modified by early-life farm exposure (born on a farm: OR, 1.18; 95% CI, 1.02-1.37; not born on a farm: OR, 1.67; 95% CI, 1.26-2.20; Interaction P = 0.05). Significant positive associations were seen with both atopic and nonatopic asthma. Endotoxin was not related to either atopy or wheeze. Higher endotoxin was related to lower FEV1/FVC in asthma cases only (Interaction P = 0.01). For asthma, there was suggestive evidence of a gene-by-environment interaction for the CD14 variant rs2569190 (Interaction P = 0.16) but not for the TLR4 variants rs4986790 and rs4986791. CONCLUSIONS: House dust endotoxin was associated with current atopic and nonatopic asthma in a U.S. farming population. The degree of the association with asthma depended on early-life farm exposures. Furthermore, endotoxin was associated with lower pulmonary function in patients with asthma.
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Agricultura/estadística & datos numéricos , Asma/epidemiología , Polvo/análisis , Endotoxinas/análisis , Exposición a Riesgos Ambientales/efectos adversos , Interacción Gen-Ambiente , Anciano , Asma/genética , Estudios de Casos y Controles , Femenino , Humanos , Receptores de Lipopolisacáridos/genética , Modelos Logísticos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Ruidos Respiratorios , Encuestas y Cuestionarios , Receptor Toll-Like 4/genética , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Previous studies, mostly from Europe, suggest that early-life farming exposures protect against childhood asthma and allergy; few data exist on asthma and allergy in adults. OBJECTIVE: We sought to examine associations between early-life farming exposures and current asthma and atopy in an older adult US farming population. METHODS: We analyzed data from 1746 farmers and 1555 spouses (mean age, 63) from a case-control study nested within the Agricultural Health Study. Current asthma and early-life farming exposures were assessed via questionnaires. We defined atopy based on specific IgE > 0.70 IU/mL to at least 1 of 10 allergens measured in blood. We used logistic regression, adjusted for age, sex, race, state (Iowa or North Carolina), and smoking (pack years), to estimate associations between early-life exposures and asthma (1198 cases and 2031 noncases) or atopy (578 cases and 2526 noncases). RESULTS: Exposure to the farming environment in utero and in early childhood had little or no association with asthma but was associated with reduced odds of atopy. The strongest association was seen for having a mother who performed farm activities while pregnant (odds ratio, 0.60; 95% CI, 0.48-0.74) and remained significant in models with correlated early-life exposures including early childhood farm animal contact and raw milk consumption. CONCLUSIONS: In a large US farming population, early-life farm exposures, particularly maternal farming activities while pregnant, were strongly associated with reduced risk of atopy in adults. These results extend previous work done primarily on childhood outcomes and suggest that protective associations of early-life farming exposures on atopy endure across the life course.
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Asma/epidemiología , Exposición a Riesgos Ambientales , Granjas , Hipersensibilidad Inmediata/epidemiología , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Hipersensibilidad Inmediata/sangre , Inmunoglobulina E/sangre , Iowa/epidemiología , Masculino , Persona de Mediana Edad , North Carolina/epidemiología , Oportunidad Relativa , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Fumar/epidemiologíaRESUMEN
Few studies have examined particulate matter (PM) exposure from self-reported use of wood stoves and other indoor combustion sources in urban settings in developed countries. We measured concentrations of indoor PM < 2.5 microns (PM2.5) for one week with the MicroPEM™ nephelometer in 36 households in the greater Oslo, Norway metropolitan area. We examined indoor PM2.5 levels in relation to use of wood stoves and other combustion sources during a 7 day monitoring period using mixed effects linear models with adjustment for ambient PM2.5 levels. Mean hourly indoor PM2.5 concentrations were higher (p = 0.04) for the 14 homes with wood stove use (15.6 µg/m3) than for the 22 homes without (12.6 µg/m3). Moreover, mean hourly PM2.5 was higher (p = 0.001) for use of wood stoves made before 1997 (6 homes, 20.2 µg/m3), when wood stove emission limits were instituted in Norway, compared to newer wood stoves (8 homes, 11.9 µg/m3) which had mean hourly values similar to control homes. Increased PM2.5 levels during diary-reported burning of candles was detected independently of concomitant wood stove use. These results suggest that self-reported use of wood stoves, particularly older stoves, and other combustion sources, such as candles, are associated with indoor PM2.5 measurements in an urban population from a high income country.
Asunto(s)
Contaminación del Aire Interior/análisis , Ciudades , Culinaria , Exposición a Riesgos Ambientales/análisis , Material Particulado/análisis , Autoinforme , Humo , Humanos , Modelos Lineales , Noruega , Factores de TiempoRESUMEN
Previous studies on smokeless tobacco use and head and neck cancer (HNC) have found inconsistent and often imprecise estimates, with limited control for cigarette smoking. Using pooled data from 11 US case-control studies (1981-2006) of oral, pharyngeal, and laryngeal cancers (6,772 cases and 8,375 controls) in the International Head and Neck Cancer Epidemiology (INHANCE) Consortium, we applied hierarchical logistic regression to estimate odds ratios and 95% confidence intervals for ever use, frequency of use, and duration of use of snuff and chewing tobacco separately for never and ever cigarette smokers. Ever use (versus never use) of snuff was strongly associated with HNC among never cigarette smokers (odds ratio (OR) = 1.71, 95% confidence interval (CI): 1.08, 2.70), particularly for oral cavity cancers (OR = 3.01, 95% CI: 1.63, 5.55). Although ever (versus never) tobacco chewing was weakly associated with HNC among never cigarette smokers (OR = 1.20, 95% CI: 0.81, 1.77), analyses restricted to cancers of the oral cavity showed a stronger association (OR = 1.81, 95% CI: 1.04, 3.17). Few or no associations between each type of smokeless tobacco and HNC were observed among ever cigarette smokers, possibly reflecting residual confounding by smoking. Smokeless tobacco use appears to be associated with HNC, especially oral cancers, with snuff being more strongly associated than chewing tobacco.