Vascular and renal telomere shortening in mice exposed to chronic intermittent hypoxia.

Obstructive sleep apnea (OSA) is a chronic condition characterized by chronic intermittent hypoxia (IH) and is associated with cardiovascular (CVD) and chronic kidney diseases (CKD). Patients with OSA have increased biomarkers of aging such as telomere shortening. We used PCR to report shortened telomere lengths in aortic and renal tissues from mice exposed to 8 weeks of IH.

Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts.

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 (FEV and FEV/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta.

Phenotypic and functional translation of IL1RL1 locus polymorphisms in lung tissue and asthmatic airway epithelium.

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.

The pharmacogenomics of inhaled corticosteroids and lung function decline in COPD.

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 (FEV) 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.

IL-22 and its receptors are increased in human and experimental COPD and contribute to pathogenesis.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of morbidity and death globally. The lack of effective treatments results from an incomplete understanding of the underlying mechanisms driving COPD pathogenesis.Interleukin (IL)-22 has been implicated in airway inflammation and is increased in COPD patients.

Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations.

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.

The Overlap of Lung Tissue Transcriptome of Smoke Exposed Mice with Human Smoking and COPD.

Genome-wide mRNA profiling in lung tissue from human and animal models can provide novel insights into the pathogenesis of chronic obstructive pulmonary disease (COPD). While 6 months of smoke exposure are widely used, shorter durations were also reported. The overlap of short term and long-term smoke exposure in mice is currently not well understood, and their representation of the human condition is uncertain.

Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function.

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.

The genetics of smoking in individuals with chronic obstructive pulmonary disease.

Background: Smoking is the principal modifiable environmental risk factor for chronic obstructive pulmonary disease (COPD) which affects 300 million people and is the 3rd leading cause of death worldwide. Most of the genetic studies of smoking have relied on self-reported smoking status which is vulnerable to reporting and recall bias. Using data from the Lung Health Study (LHS), we sought to identify genetic variants associated with quantitative smoking and cessation in individuals with mild to moderate COPD.

Surfactant protein D is a causal risk factor for COPD: results of Mendelian randomisation.

Surfactant protein D (SP-D) is produced primarily in the lung and is involved in regulating pulmonary surfactants, lipid homeostasis and innate immunity. Circulating SP-D levels in blood are associated with chronic obstructive pulmonary disease (COPD), although causality remains elusive.In 4061 subjects with COPD, we identified genetic variants associated with serum SP-D levels.

The actin regulator zyxin reinforces airway smooth muscle and accumulates in airways of fatal asthmatics.

Bronchospasm induced in non-asthmatic human subjects can be easily reversed by a deep inspiration (DI) whereas bronchospasm that occurs spontaneously in asthmatic subjects cannot. This physiological effect of a DI has been attributed to the manner in which a DI causes airway smooth muscle (ASM) cells to stretch, but underlying molecular mechanisms-and their failure in asthma-remain obscure. Using cells and tissues from wild type and zyxin-/- mice we report responses to a transient stretch of physiologic magnitude and duration.

Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis.

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) 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.

Total particulate matter concentration skews cigarette smoke's gene expression profile.

Exposure of small animals to cigarette smoke is widely used as a model to study the pathogenesis of chronic obstructive pulmonary disease. However, protocols and exposure systems utilised vary substantially and it is unclear how these different systems compare. We analysed the gene expression profile of six publically available murine datasets from different cigarette smoke-exposure systems and related the gene signatures to three clinical cohorts.

Human Lung Tissue Transcriptome: Influence of Sex and Age.

Background: Sex and age strongly influence the pathophysiology of human lungs, but scarce information is available about their effects on pulmonary gene expression.

Methods: We followed a discovery-validation strategy to identify sex- and age-related transcriptional differences in lung.

Results: We identified transcriptional profiles significantly associated with sex (215 genes; FDR < 0.

Influence of SIGLEC9 polymorphisms on COPD phenotypes including exacerbation frequency.

Background And Objective: The exacerbation-prone phenotype of COPD is particularly important, as exacerbations lead to poor quality of life and disease progression. We previously found that COPD patients who lack Siglec-14, a myeloid cell protein that recognizes bacteria and triggers inflammatory responses, are less prone to exacerbation. We hypothesized that the variations in other SIGLEC genes could also influence COPD exacerbation frequency, and investigated the association between SIGLEC9 polymorphisms and the exacerbation-prone phenotype of COPD.

Targeted high-throughput sequencing of candidate genes for chronic obstructive pulmonary disease.

Background: Reduced lung function in patients with chronic obstructive pulmonary disease (COPD) is likely due to both environmental and genetic factors. We report here a targeted high-throughput DNA sequencing approach to identify new and previously known genetic variants in a set of candidate genes for COPD.

Methods: Exons in 22 genes implicated in lung development as well as 61 genes and 10 genomic regions previously associated with COPD were sequenced using individual DNA samples from 68 cases with moderate or severe COPD and 66 controls matched for age, gender and smoking.

Genome-wide association study on the FEV/FVC ratio in never-smokers identifies HHIP and FAM13A.

Background: Although a striking proportion (25% to 45%) of patients with chronic obstructive pulmonary disease are never-smokers, most genetic susceptibility studies have not focused on this group exclusively.

Objective: The aim of this study was to identify common genetic variants associated with FEV and its ratio to forced vital capacity (FVC) in never-smokers.

Methods: Genome-wide association studies were performed in 5070 never-smokers of the identification cohort LifeLines, and results (P < 10) were verified by using a meta-analysis of the Vlagtwedde-Vlaardingen study and the Rotterdam Study I-III (total n = 1966).

Identification of Susceptibility Genes of Adult Asthma in French Canadian Women.

Susceptibility genes of asthma may be more successfully identified by studying subgroups of phenotypically similar asthma patients. This study aims to identify single nucleotide polymorphisms (SNPs) associated with asthma in French Canadian adult women. A pooling-based genome-wide association study was performed in 240 allergic asthmatic and 120 allergic nonasthmatic women.

Increased Epicardial Adipose Tissue Is Associated with the Airway Dominant Phenotype of Chronic Obstructive Pulmonary Disease.

Background: Epicardial adipose tissue (EAT) has been shown to be a non-invasive marker that predicts the progression of cardiovascular disease (CVD). It has been reported that the EAT volume is increased in patients with chronic obstructive pulmonary disease (COPD). However, little is known about which phenotypes of COPD are associated with increased EAT.

Association of Forced Vital Capacity with the Developmental Gene NCOR2.

Background: Forced Vital Capacity (FVC) is an important predictor of all-cause mortality in the absence of chronic respiratory conditions. Epidemiological evidence highlights the role of early life factors on adult FVC, pointing to environmental exposures and genes affecting lung development as risk factors for low FVC later in life. Although highly heritable, a small number of genes have been found associated with FVC, and we aimed at identifying further genetic variants by focusing on lung development genes.

Molecular mechanisms underlying variations in lung function: a systems genetics analysis.

Background: Lung function measures reflect the physiological state of the lung, and are essential to the diagnosis of chronic obstructive pulmonary disease (COPD). The SpiroMeta-CHARGE consortium undertook the largest genome-wide association study (GWAS) so far (n=48,201) for forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FEV1/FVC) in the general population. The lung expression quantitative trait loci (eQTLs) study mapped the genetic architecture of gene expression in lung tissue from 1111 individuals.

Airway Epithelial Expression Quantitative Trait Loci Reveal Genes Underlying Asthma and Other Airway Diseases.

Genome-wide association studies (GWASs) have identified loci that are robustly associated with asthma and related phenotypes; however, the molecular mechanisms underlying these associations need to be explored. The most relevant tissues to study the functional consequences of asthma are the airways. We used publically available data to derive expression quantitative trait loci (eQTLs) for human epithelial cells from small and large airways and applied the eQTLs in the interpretation of GWAS results of asthma and related phenotypes.

Identification of TMPRSS2 as a Susceptibility Gene for Severe 2009 Pandemic A(H1N1) Influenza and A(H7N9) Influenza.

The genetic predisposition to severe A(H1N1)2009 (A[H1N1]pdm09) influenza was evaluated in 409 patients, including 162 cases with severe infection and 247 controls with mild infection. We prioritized candidate variants based on the result of a pilot genome-wide association study and a lung expression quantitative trait locus data set. The GG genotype of rs2070788, a higher-expression variant of TMPRSS2, was a risk variant (odds ratio, 2.