Pulmonary ORMDL3 is critical for induction of Alternaria -induced allergic airways disease

Genome-wide association studies have identified the ORM (yeast)-like protein isoform 3 (ORMDL3) gene locus on human chromosome 17q to be a highly significant risk factor for childhood-onset asthma. Objective We sought to investigate in vivo the functional role of ORMDL3 in disease inception. Methods An Ormdl3-deficient mouse was generated and the role of ORMDL3 in the generation of allergic airways disease to the fungal aeroallergen Alternaria alternata was determined. An adeno-associated viral vector was also used to reconstitute ORMDL3 expression in airway epithelial cells of Ormdl3 knockout mice. Results Ormdl3 knockout mice were found to be protected from developing allergic airways disease and showed a marked decrease in pathophysiology, including lung function and airway eosinophilia induced by Alternaria. Alternaria is a potent inducer of cellular stress and the unfolded protein response, and ORMDL3 was found to play a critical role in driving the activating transcription factor 6–mediated arm of this response through Xbp1 and downstream activation of the endoplasmic reticulum–associated degradation pathway. In addition, ORMDL3 mediated uric acid release, another marker of cellular stress. In the knockout mice, reconstitution of Ormdl3 transcript levels specifically in the bronchial epithelium resulted in reinstatement of susceptibility to fungal allergen–induced allergic airways disease. Conclusions This study demonstrates that ORMDL3, an asthma susceptibility gene identified by genome-wide association studies, contributes to key pathways that promote changes in airway physiology during allergic immune responses

Whole-blood gene expression in pulmonary nontuberculous mycobacterial infection

The factors predisposing toward the development of pulmonary nontuberculous mycobacterial (pNTM) disease and influencing disease progression remain unclear. Impaired immune responses have been reported in individuals with pNTM disease, but data are limited and inconsistent. In this study, we sought to use gene expression profiling to examine the host response to pNTM disease. Microarray analysis of whole-blood gene expression was performed on 25 subjects with pNTM disease and 27 uninfected control subjects with respiratory disease. Gene expression results were compared with phenotypic variables and survival data. Compared with uninfected control subjects, pNTM disease was associated with downregulation of 213 transcripts enriched for terms related to T cell signaling, including IFNG. Reduced IFNG expression was associated with more severe computed tomography changes and impaired lung function. Mortality was associated with the expression of transcripts related to the innate immune response and inflammation, whereas transcripts related to T and B cell function were associated with improved survival. These findings suggest that pNTM disease is associated with an aberrant immune response, which may reflect an underlying propensity to infection or result from NTM infection itself. There were important differences in the immune response associated with survival and mortality in pNTM disease

The role of bacteria in the pathogenesis and progression of idiopathic pulmonary fibrosis

Rationale:Idiopathic pulmonaryfibrosis (IPF)isa progressivelung disease of unknown cause that leads to respiratory failure and death within 5 years of diagnosis. Overt respiratory infection and immunosuppression carry a high morbidity and mortality, and polymorphisms in genes related to epithelial integrity and host defense predispose to IPF. Objectives: To investigate the role of bacteria in the pathogenesis and progression of IPF. Methods: We prospectively enrolled patients diagnosed with IPF according to international criteria together with healthy smokers, nonsmokers, and subjectswithmoderate chronic obstructive pulmonary disease as control subjects. Subjects underwent bronchoalveolar lavage (BAL), from which genomic DNA was isolated. The V3–V5 region of the bacterial 16S rRNA gene was amplified, allowing quantification of bacterial load and identification of communities by 16S rRNA quantitative polymerase chain reaction and pyrosequencing. Measurements and Main Results: Sixty-five patients with IPF had double the burden of bacteria in BAL fluid compared with 44 control subjects. Baseline bacterial burden predicted the rate of decline in lung volume and risk of death and associated independently with the rs35705950 polymorphism of the MUC5B mucin gene, a proven host susceptibilityfactorfor IPF. Sequencing yielded912,883 high-quality reads from all subjects.WeidentifiedHaemophilus, Streptococcus,Neisseria, and Veillonella spp. to be more abundant in cases than control subjects. Regression analyses indicated that these specific operational taxonomic units as well as bacterial burden associated independently with IPF. Conclusions: IPF is characterized by an increased bacterial burden in BAL that predicts decline in lung function and death. Trials of antimicrobial therapy are needed to determine if microbial burden is pathogenic in the disease

A large-scale genome-wide association analysis of lung function in the Chinese population identifies novel loci and highlights shared genetic aetiology with obesity

Background Lung function is a heritable complex phenotype with obesity being one of its important risk factors. However, knowledge of their shared genetic basis is limited. Most genome-wide association studies (GWASs) for lung function have been based on European populations, limiting the generalisability across populations. Large-scale lung function GWASs in other populations are lacking. Methods We included 100 285 subjects from the China Kadoorie Biobank (CKB). To identify novel loci for lung function, single-trait GWAS analyses were performed on forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC in the CKB. We then performed genome-wide cross-trait analysis between lung function and obesity traits (body mass index (BMI), BMI-adjusted waist-to-hip ratio and BMI-adjusted waist circumference) to investigate the shared genetic effects in the CKB. Finally, polygenic risk scores (PRSs) of lung function were developed in the CKB and their interaction with BMI's association on lung function were examined. We also conducted cross-trait analysis in parallel with the CKB using up to 457 756 subjects from the UK Biobank (UKB) for replication and investigation of ancestry-specific effects. Results We identified nine genome-wide significant novel loci for FEV1, six for FVC and three for FEV1/FVC in the CKB. FEV1 and FVC showed significant negative genetic correlation with obesity traits in both the CKB and UKB. Genetic loci shared between lung function and obesity traits highlighted important biological pathways, including cell proliferation, embryo, skeletal and tissue development, and regulation of gene expression. Mendelian randomisation analysis suggested significant negative causal effects of BMI on FEV1 and on FVC in both the CKB and UKB. Lung function PRSs significantly modified the effect of change in BMI on change in lung function during an average follow-up of 8 years. Conclusion This large-scale GWAS of lung function identified novel loci and shared genetic aetiology between lung function and obesity. Change in BMI might affect change in lung function differently according to a subject's polygenic background. These findings may open new avenues for the development of molecular-targeted therapies for obesity and lung function improvement

Idiopathic pulmonary fibrosis is strongly associated with productive infection by herpesvirus saimiri

Idiopathic pulmonary fibrosis is a fatal disease without effective therapy or diagnostic test. To investigate a potential role for c�herpesviruses in this disease, 21 paraffin-embedded lung biopsies from patients diagnosed with idiopathic pulmonary fibrosis and 21 lung biopsies from age-matched controls with pulmonary fibrosis of known etiology were examined for a series of c�herpesviruses’ DNA/RNA and related proteins using in situ hybridization and reverse transcriptase-polymerase chain reaction (RT-PCR)-based methods. We detected four proteins known to be in the genome of several c�herpesviruses (cyclin D, thymidylate synthase, dihydrofolate reductase, and interleukin-17) that were strongly co-expressed in the regenerating epithelial cells of each of the 21 idiopathic pulmonary fibrosis cases and not in the benign epithelia of the controls. Among the c� herpesviruses, only herpesvirus saimiri expresses all four of these ‘pirated’ mammalian proteins. We found herpesvirus saimiri DNA in the regenerating epithelial cells of 21/21 idiopathic pulmonary fibrosis cases using four separate probe sets but not in the 21 controls. RT-PCR showed that the source of the cyclin D RNA in active idiopathic pulmonary fibrosis was herpesvirus saimiri and not human. We cloned and sequenced part of genome corresponding to the DNA polymerase herpesvirus saimiri gene from an idiopathic pulmonary fibrosis sample and it matched 100% with the published viral sequence. These data are consistent with idiopathic pulmonary fibrosis representing herpesvirus saimiri-induced pulmonary fibrosis. Thus, treatment directed against viral proliferation and/or viral-associated proteins may halt disease progression. Further, demonstration of the viral nucleic acids or proteins may help diagnose the disease

Genetic and genomic approaches to asthma: new insights for the origins

Purpose of review: The aim is to update current understanding of the genes identified by the recent genome-wide association studies (GWASs) of asthma and its associated traits. The review also discusses how to dissect the functional roles of novel genes in future research. Recent findings: More than 10 GWAS aimed at identifying the genes underlying asthma and relevant traits have been published in the past 3 years. The largest of these was from the GABRIEL consortium, which discovered that the IL18R1, IL33, SMAD3, ORMDL3, HLA-DQ and IL2RB loci were all significantly associated with asthma. Many novel asthma genes, including those previously identified by positional cloning, are expressed within the respiratory epithelium, emphasizing the importance of epithelial barriers in causing asthma . The genes controlling IgE levels have surprisingly little overlap with the genes mediating asthma susceptibility, suggesting that atopy is secondary to asthma rather than a primary driver of the disease. The next challenge will be the systematic analysis of the precise functions of these genes in the pathogenesis of asthma. Summary: GWAS have uncovered many novel genes underlying asthma and detailed functional dissection of their roles in asthma will point the way to new therapies for the disease

GRR: Graphical representation of relationship errors

Summary: A graphical tool for verifying assumed relationships between individuals in genetic studies is described. GRR can detect many common errors using genotypes from many markers.link_to_subscribed_fulltex