Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide(1). We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 x 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(2-7), while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis(8,9) (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(10). 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

BackgroundCigarette smoking is the leading modifiable risk factor for disease and death worldwide. Previous studies quantifying gene-level expression have documented the effect of smoking on mRNA levels. Using RNA sequencing, it is possible to analyze the impact of smoking on complex regulatory phenomena (e.g. alternative splicing, differential isoform usage) leading to a more detailed understanding of the biology underlying smoking-related disease.MethodsWe used whole-blood RNA sequencing to describe gene and exon-level expression differences between 229 current and 286 former smokers in the COPDGene study. We performed differential gene expression and differential exon usage analyses using the voom/limma and DEXseq R packages. Samples from current and former smokers were compared while controlling for age, gender, race, lifetime smoke exposure, cell counts, and technical covariates.ResultsAt an adjusted p-value <0.05, 171 genes were differentially expressed between current and former smokers. Differentially expressed genes included 7 long non-coding RNAs that have not been previously associated with smoking: LINC00599, LINC01362, LINC00824, LINC01624, RP11-563D10.1, RP11-98G13.1, AC004791.2. Secondary analysis of acute smoking (having smoked within 2-h) revealed 5 of the 171 smoking genes demonstrated an acute response above the baseline effect of chronic smoking. Exon-level analyses identified 9 exons from 8 genes with significant differential usage by smoking status, suggesting smoking-induced changes in isoform expression.ConclusionsTranscriptomic changes at the gene and exon levels from whole blood can refine our understanding of the molecular mechanisms underlying the response to smoking.Electronic supplementary materialThe online version of this article (10.1186/s12920-017-0295-9) contains supplementary material, which is available to authorized users.

The dependence of plasma energy confinement on minor radius, density and plasma current is described for Ohmically heated near-circular plasmas in Doublet III. A wide range of parameters is used for the study of scaling laws; the plasma minor radius defined by the flux surface in contact with limiter is varied by a factor of 2 (a = 44, 32 and 23 cm) , the line average plasma density, n̄e, is varied by a factor of 20 from 0.5 to 10 × 1013 cm−3 (n̄e R0/BT = 0.3 to 6 × 1014 cm−2·kG−1) and the plasma current, I, is varied by a factor of 6 from 120 to 718 kA. The range of the limiter safety factor, qL, is from 2 to 12. – For plasmas with a = 23 and 32 cm, the scaling law at low n̄e for the gross electron energy confinement time can be written as (s, cm) where qc = 2πa2BT/μ0IR0. For the 44-cm plasmas, is about 1.8 times less than predicted by this scaling, possibly owing to the change in limiter configuration and small plasma-wall separation and/or the aspect ratio change. At high n̄e, saturates and in many cases decreases with n̄e but increases with I in a classical-like manner. The dependence of on a is considerably weakened. The confinement behaviour can be explained by taking an ion thermal conductivity 2 to 7 times that given by Hinton-Hazeltine's neoclassical theory with a lumped-Zeff impurity model. Within this range the enhancement factor increases with a or a/R0. The electron thermal conductivity evaluated at half-temperature radius where most of the thermal insulation occurs sharply increases with average current density within that radius, but does not depend on a within the uncertainties of the measurements.

BACKGROUND Asthma exacerbations are a major cause of morbidity and medical cost. OBJECTIVE The objective of this study was to identify genetic predictors of exacerbations in subjects with asthma. METHODS We performed GWAS meta analysis of acute asthma exacerbation in two pediatric clinical trials: Childhood Asthma Management Program (CAMP, n=581) and Childhood Asthma Research and Education (CARE, n=205) network trials. Acute asthma exacerbations was defined as treatment with a five-day course of oral steroids. We obtained a replication cohort from BioVU (n=786), the Vanderbilt University electronic medical record-linked DNA biobank. We used CD4+ lymphocyte genome-wide mRNA expression profiling to identify associations of top SNPs with mRNA abundance of nearby genes. RESULTS A locus in CTNNA3 reached genome-wide significance (rs7915695, p=2.19*10-8, mean exacerbations 6.05 for minor alleles vs. 3.71 for homozygous major). Among four top SNPs replicated in BioVU, rs993312 in SEMA3D was significant (p=0.0083), and displayed stronger association among African Americans (p=0.0004 in BioVU, mean exacerbations 3.91 vs. 1.53; p=0.0089 in CAMP, mean exacerbations 6.0 vs. 3.25). CTNNA3 variants did not replicate in BioVU. A regulatory variant in the CTNNA3 locus was associated with CTNNA3 mRNA expression in CD4+ cells from asthmatics (p=0.00079). CTNNA3 appears to be active in immune response, and SEMA3D has a plausible role in airway remodeling. We also provide a replication of a previous association of P2RX7 with asthma exacerbation. CONCLUSIONS We identified two loci associated with exacerbations through GWAS. CTNNA3 met genome-wide significance thresholds and SEMA3D replicated in a clinical Biobank database.

Background Multiple gene expression studies have been performed separately in peripheral blood, lung, and airway tissues to study COPD. We performed RNA-sequencing gene expression profiling of large-airway epithelium, alveolar macrophage and peripheral blood samples from the same subset of COPD cases and controls from the COPDGene study who underwent bronchoscopy at a single center. Using statistical and gene set enrichment approaches, we sought to improve the understanding of COPD by studying gene sets and pathways across these tissues, beyond the individual genomic determinants. Methods We performed differential expression analysis using RNA-seq data obtained from 63 samples from 21 COPD cases and controls (includes four non-smokers) via the R package DESeq2. We tested associations between gene expression and variables related to lung function, smoking history, and CT scan measures of emphysema and airway disease. We examined the correlation of differential gene expression across the tissues and phenotypes, hypothesizing that this would reveal preserved and private gene expression signatures. We performed gene set enrichment analyses using curated databases and findings from prior COPD studies to provide biological and disease relevance. Results The known smoking-related genes CYP1B1 and AHRR were among the top differential expression results for smoking status in the large-airway epithelium data. We observed a significant overlap of genes primarily across large-airway and macrophage results for smoking and airway disease phenotypes. We did not observe specific genes differentially expressed in all three tissues for any of the phenotypes. However, we did observe hemostasis and immune signaling pathways in the overlaps across all three tissues for emphysema, and amyloid and telomere-related pathways for smoking. In peripheral blood, the emphysema results were enriched for B cell related genes previously identified in lung tissue studies. Conclusions Our integrative analyses across COPD-relevant tissues and prior studies revealed shared and tissue-specific disease biology. These replicated and novel findings in the airway and peripheral blood have highlighted candidate genes and pathways for COPD pathogenesis. Electronic supplementary material The online version of this article (10.1186/s12931-019-1032-z) contains supplementary material, which is available to authorized users.