Expression of asthma susceptibility genes in bronchial epithelial cells and bronchial alveolar lavage in the Severe Asthma Research Program (SARP) cohort

<p><i>Objective</i>: Genome-wide association studies (GWASs) have identified genes associated with asthma, however expression of these genes in asthma-relevant tissues has not been studied. This study tested expression and correlation between GWAS-identified asthma genes and asthma or asthma severity. <i>Methods</i>: Correlation analyses of expression levels of GWAS-identified asthma genes and asthma-related biomarkers were performed in cells from human bronchial epithelial biopsy (BEC, <i>n</i> = 107) and bronchial alveolar lavage (BAL, <i>n</i> = 94). <i>Results</i>: Expression levels of asthma genes between BEC and BAL and with asthma or asthma severity were weakly correlated. The expression levels of <i>IL18R1</i> were consistently higher in asthma than controls or in severe asthma than mild/moderate asthma in BEC and BAL (<i>p</i> < 0.05). In <i>RAD50-IL13</i> region, the expression levels of <i>RAD50</i>, not <i>IL4, IL5</i>, or <i>IL13</i>, were positively correlated between BEC and BAL (ρ = 0.53, <i>P</i> = 4.5 × 10⁻⁶). The expression levels of <i>IL13</i> were positively correlated with <i>IL5</i> in BEC (ρ = 0.35, <i>P</i> = 1.9 × 10⁻⁴) and <i>IL4</i> in BAL (ρ = 0.42, <i>P</i> = 2.5 × 10⁻⁵), respectively. rs3798134 in <i>RAD50</i>, a GWAS-identified SNP, was correlated with <i>IL13</i> expression and the expression levels of <i>IL13</i> were correlated with asthma (<i>P</i> = 0.03). rs17772583 in <i>RAD50</i> was significantly correlated with <i>RAD50</i> expression in BAL and BEC (<i>P</i> = 7.4 × 10⁻⁷ and 0.04) but was not associated with asthma. <i>Conclusions</i>: This is the first report studying the expression of GWAS-identified asthma genes in BEC and BAL. <i>IL13</i>, rather than <i>RAD50, IL4</i>, or <i>IL5</i>, is more likely to be the asthma susceptibility gene. Our study illustrates tissue-specific expression of asthma-related genes. Therefore, whenever possible, disease-relevant tissues should be used for transcription analysis.</p

Additional file 2: of The value of blood cytokines and chemokines in assessing COPD

Cross Sectional Associations by Subgroup Heat Map. (PDF 156 kb

Additional file 1: of Genome-wide association study of lung function and clinical implication in heavy smokers

Table S1. Association Results of the Top SNPs (P < 10− 4) with Post-bronchodilator FEV1/FVC. Table S2. Association Results of the Top SNPs (P < 10− 4) with Post-bronchodilator % Predicted FEV1.Table S3. Genotype Frequency of rs28929474 in SERPINA1 Stratified by GOLD Stages. Table S4. Prediction Models for Post-bronchodilator Lung Function Using Top 10 SNPs for Post-bronchodilator % Predicted FEV1.Figure S1. Joint analysis of the top10 SNPs for post-bronchodilator % predicted FEV1 in 1075 SPIROMICS non-Hispanic White smokers with COPD. (DOCX 141 kb

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 (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 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.</div

Genetic Associations and Architecture of Asthma-COPD Overlap

Background Some people have characteristics of both asthma and COPD (asthma-COPD overlap), and evidence suggests they experience worse outcomes than those with either condition alone. Research Question What is the genetic architecture of asthma-COPD overlap, and do the determinants of risk for asthma-COPD overlap differ from those for COPD or asthma? Study Design and Methods We conducted a genome-wide association study in 8,068 asthma-COPD overlap case subjects and 40,360 control subjects without asthma or COPD of European ancestry in UK Biobank (stage 1). We followed up promising signals (P Results We selected 31 independent variants for further investigation in stage 2, and discovered eight novel signals (P Interpretation We identified eight signals for asthma-COPD overlap, which may represent loci that predispose to type 2 inflammation, and serious long-term consequences of asthma.</p