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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

Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. of the risk score (similar to 6 alleles) (95% confidence interval) = 1.24 (1.20-1.27), P = 5.05 x 10(-49)), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications.

Lan Ai Kieu Le,1 Ane Johannessen,2,3Jon Andrew Hardie,2 Odd Erik Johansen,4,5Amund Gulsvik,2 Bjørn Egil Vikse,1,2Per Bakke21Department of Medicine, Haugesund Hospital, Haugesund, Norway; 2Department of Clinical Medicine, University of Bergen, Bergen, Norway; 3Centre for International Health, Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway; 4Department of Medicine, Bærum Hospital, Gjettum, Norway; 5Boehringer Ingelheim Norway KS, Asker, NorwayRationale: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 is based on an ABCD assessment tool of symptoms and exacerbation history and grade 1–4 of airflow limitation severity, facilitating classification either into 4 groups (ABCD) or 16 groups (1A-4D). We aimed to compare the GOLD 2011, GOLD 2017 ABCD, and GOLD 2017 1A-4D classifications in terms of their distribution and prediction of mortality and hospitalizations.Methods: In the GenKOLS study, 912 COPD patients with FEV1 less than 80% of the predicted answered questionnaires and performed lung function testing in 2003–2005. The patients were recruited from a hospital patient registry (n=662) and from the general population (n=250), followed up until 2011 with respect to all-cause and respiratory mortality, and all-cause and respiratory hospitalizations. We performed logistic regression and receiver operating curve (ROC) analyses for the different classifications with estimations of area under the curve (AUC) for comparisons.Results: Mean age at baseline was 60 years (SD 11), 55% were male. Mean duration of follow-up was 91 months. By GOLD 2011, 21% were classified as group A, 29% group B, 6% group C, and 43% as group D, corresponding percentages for GOLD 2017 were: 25%, 52%, 3%, and 20%. The GOLD 2011 classification had higher AUC values than the GOLD 2017 group ABCD classification for respiratory mortality and hospitalization, but after inclusion of airflow limitation severity in GOLD 2017 groups 2A–4D, AUC values were significantly higher with GOLD 2017.Conclusion: In a clinically relevant sample of COPD patients, the GOLD 2017 classification doubles the prevalence of group B and halves the prevalence of groups C and D as compared to the GOLD 2011 classification. The prediction of respiratory mortality and respiratory hospitalization was better for GOLD 2017 2A–4D taking airflow limitation severity into account, as compared to GOLD 2017 ABCD and GOLD 2011.Keywords: respiratory, hospitalization, mortality, Cox regression, ABCD classification, airflow limitation

Background There are several reports on underdiagnosis of COPD, while little is known about COPD overdiagnosis and overtreatment. We describe the overdiagnosis and the prevalence of spirometrically defined false positive COPD, as well as their relationship with overtreatment across 23 population samples in 20 countries participating in the BOLD Study between 2003 and 2012. Methods A false positive diagnosis of COPD was considered when participants reported a doctor’s diagnosis of COPD, but postbronchodilator spirometry was unobstructed (FEV1/FVC > LLN). Additional analyses were performed using the fixed ratio criterion (FEV1/FVC < 0.7). Results Among 16,177 participants, 919 (5.7%) reported a previous medical diagnosis of COPD. Postbronchodilator spirometry was unobstructed in 569 subjects (61.9%): false positive COPD. A similar rate of overdiagnosis was seen when using the fixed ratio criterion (55.3%). In a subgroup analysis excluding participants who reported a diagnosis of “chronic bronchitis” or “emphysema” (n = 220), 37.7% had no airflow limitation. The site-specific prevalence of false positive COPD varied greatly, from 1.9% in low- to middle-income countries to 4.9% in high-income countries. In multivariate analysis, overdiagnosis was more common among women, and was associated with higher education; former and current smoking; the presence of wheeze, cough, and phlegm; and concomitant medical diagnosis of asthma or heart disease. Among the subjects with false positive COPD, 45.7% reported current use of respiratory medication. Excluding patients with reported asthma, 34.4% of those with normal spirometry still used a respiratory medication. Conclusions False positive COPD is frequent. This might expose nonobstructed subjects to possible adverse effects of respiratory medication.

Dl(CO) is a widely used pulmonary function test in clinical practice and a particularly useful measure for assessing patients with chronic obstructive pulmonary disease (COPD). We hypothesized that elucidating genetic determinants of Dl(CO) could lead to better understanding of the genetic architecture of COPD. We estimated the heritability of Dl(CO) using common genetic variants and performed genome-wide association analyses in four cohorts enriched for subjects with COPD (COPDGene [Genetic Epidemiology of COPD], NETT [National Emphysema Treatment Trial], GenKOLS [Genetics of Chronic Obstructive Lung Disease study], and TESRA [Treatment of Emphysema With a Gamma-Selective Retinoid Agonist study]) using a combined European ancestry white dataset and a COPDGene African American dataset. We assessed our genome-wide significant and suggestive associations for Dl(CO) in previously reported genome-wide association studies of COPD and related traits. We also characterized associations of known COPD-associated variants and Dl(CO). We estimated the SNP-based heritability of Dl(CO) in the European ancestry white population to be 22% (P = 0.0004). We identified three genome-wide significant associations with Dl(CO): variants near TGFB2, CHRNA3, and PDE11A loci (P

Purpose: Paroxysmal atrial fibrillation is often suspected as a probable cause of cryptogenic stroke. Continuous long-term ECG monitoring using insertable cardiac monitors is a clinically effective technique to screen for atrial fibrillation and superior to conventional follow-up in cryptogenic stroke. However, more studies are needed to identify factors which can help selecting patients with the highest possibility of detecting atrial fibrillation with prolonged rhythm monitoring. The clinical relevance of short-term atrial fibrillation, the need for medical intervention and the evaluation as to whether intervention results in improved clinical outcomes should be assessed. Method: The Nordic Atrial Fibrillation and Stroke Study is an international, multicentre, prospective, observational trial evaluating the occurrence of occult atrial fibrillation in cryptogenic stroke and transient ischaemic attack. Patients with cryptogenic stroke or transient ischaemic attack from the Nordic countries are included and will have the Reveal LINQ® Insertable cardiac monitor system implanted for 12 months for atrial fibrillation detection. Biomarkers which can be used as predictors for atrial fibrillation and may identify patients, who could derive the most clinical benefit from the detection of atrial fibrillation by prolonged monitoring, are being studied. Conclusion: The primary endpoint is atrial fibrillation burden within 12 months of continuous rhythm monitoring. Secondary endpoints are atrial fibrillation burden within six months, levels of biomarkers predicting atrial fibrillation, CHA2DS2-VASc score, incidence of recurrent stroke or transient ischaemic attack, use of anticoagulation and antiarrhythmic drugs, and quality of life measurements. The clinical follow-up period is 12 months. The study started in 2017 and the completion is expected at the end of 2020. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: NOR-FIB is an investigator driven academic study. Of the 500 devices, 400 are supported by Medtronic. The study is supported by the research infrastructure of the European Cerebrovascular Research Infrastructure (ECRI).