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Rationale: The definition of the lower limit of normal (LLN) of spirometric variables is not well established. Objectives: To investigate the relationship between spirometric abnormalities defined with different thresholds of the LLN and clinical outcomes and to explore the possibility of using different LLN thresholds according to the pretest probability of disease. Methods: We studied the associations between prebronchodilator spirometric abnormalities (forced expiratory volume in the first second [FEV1] < LLN, forced vital capacity [FVC] < LLN, airflow obstruction, spirometric restriction) defined with different thresholds of the LLN (10th, 5th, 2.5th, 1st percentile) and multiple outcomes (prevalence of spirometric abnormalities, respiratory symptoms, all-cause and respiratory mortality) in 26,091 30- to 46-year-old men who participated in a general population survey in Norway in 1988–1990 and were followed for 26 years. Analyses were performed with both local and Global Lung Function Initiative (GLI)-2012 reference equations, stratified by pretest risk (presence or absence of respiratory symptoms), and adjusted for age, body mass index, smoking, and education. Results: In the total population, the prevalence of airflow obstruction was 11.6% with GLI-LLN10, 11.0% with Local-LLN5, 6.1% with GLI-LLN5, 7.6% with Local-LLN2.5, and 3.5% with GLI-LLN2.5. The prevalence of spirometric restriction was 5.9% with GLI-LLN10, 5.2% with Local-LLN5, and 2.8% with GLI-LLN5. Increasingly lower thresholds of the LLN were associated with increasingly higher odds of respiratory symptoms and hazard of mortality for all spirometric abnormalities with both reference equations. Spirometric abnormalities defined with Local-LLN2.5 in asymptomatic subjects were associated with lower hazard of all-cause mortality (hazard ratio [HR], 1.50; 95% confidence interval [CI], 1.15–1.95 for FEV1 < LLN) than those defined with Local-LLN5 in the general population (HR, 1.67; 95% CI, 1.50–1.87 for FEV1 < LLN) and symptomatic subjects (HR, 1.67; 95% CI, 1.46–1.91 for FEV1 < LLN). Overall, the prevalence of spirometric abnormalities and associations with outcomes obtained with Local-LLN5 were comparable to those obtained with GLI-LLN10 and those obtained with Local-LLN2.5 to GLI-LLN5. Conclusions: There is a relationship between statistically based thresholds of the LLN of spirometric variables and clinical outcomes. Different thresholds of the LLN may be used in different risk subgroups of subjects, but the choice of the threshold needs to be evaluated together with the choice of reference equations. [ABSTRACT FROM AUTHOR]

Background: Atrial fibrillation (AF) detection and treatment are key elements to reduce recurrence risk in cryptogenic stroke (CS) with underlying arrhythmia. The purpose of the present study was to assess the predictors of AF in CS and the utility of existing AF-predicting scores in The Nordic Atrial Fibrillation and Stroke (NOR-FIB) Study. Method: The NOR-FIB study was an international prospective observational multicenter study designed to detect and quantify AF in CS and cryptogenic transient ischaemic attack (TIA) patients monitored by the insertable cardiac monitor (ICM), and to identify AF-predicting biomarkers. The utility of the following AF-predicting scores was tested: AS5F, Brown ESUS-AF, CHA2DS2-VASc, CHASE-LESS, HATCH, HAVOC, STAF and SURF. Results: In univariate analyses increasing age, hypertension, left ventricle hypertrophy, dyslipidaemia, antiarrhythmic drugs usage, valvular heart disease, and neuroimaging findings of stroke due to intracranial vessel occlusions and previous ischemic lesions were associated with a higher likelihood of detected AF. In multivariate analysis, age was the only independent predictor of AF. All the AF-predicting scores showed significantly higher score levels for AF than non-AF patients. The STAF and the SURF scores provided the highest sensitivity and negative predictive values, while the AS5F and SURF reached an area under the receiver operating curve (AUC) > 0.7. Conclusion: Clinical risk scores may guide a personalized evaluation approach in CS patients. Increasing awareness of the usage of available AF-predicting scores may optimize the arrhythmia detection pathway in stroke units. [ABSTRACT FROM AUTHOR]

Background and purpose: There are currently no biomarkers to select cryptogenic stroke (CS) patients for monitoring with insertable cardiac monitors (ICMs), the most effective tool for diagnosing atrial fibrillation (AF) in CS. The purpose of this study was to assess clinically available biomarkers as predictors of AF. Methods: Eligible CS and cryptogenic transient ischaemic attack patients underwent 12‐month monitoring with ICMs, clinical follow‐up and biomarker sampling. Levels of cardiac and thromboembolic biomarkers, taken within 14 days from symptom onset, were compared between patients diagnosed with AF (n = 74) during monitoring and those without AF (n = 185). Receiver operating characteristic curves were created. Biomarkers reaching area under the receiver operating characteristic curve ≥ 0.7 were dichotomized by finding optimal cut‐off values and were used in logistic regression establishing their predictive value for increased risk of AF in unadjusted and adjusted models. Results: B‐type natriuretic peptide (BNP), N‐terminal pro‐brain natriuretic peptide (NT‐proBNP), creatine kinase, D‐dimer and high‐sensitivity cardiac troponin I and T were significantly higher in the AF than non‐AF group. BNP and NT‐proBNP reached the predefined area under the curve level, 0.755 and 0.725 respectively. Optimal cut‐off values were 33.5 ng/l for BNP and 87 ng/l for NT‐proBNP. Regression analysis showed that NT‐proBNP was a predictor of AF in both unadjusted (odds ratio 7.72, 95% confidence interval 3.16–18.87) and age‐ and sex‐adjusted models (odds ratio 4.82, 95% confidence interval 1.79–12.96). Conclusion: Several clinically established biomarkers were associated with AF. NT‐proBNP performed best as AF predictor and could be used for selecting patients for long‐term monitoring with ICMs. [ABSTRACT FROM AUTHOR]

Background: Cryptogenic stroke is a heterogeneous condition, with a wide spectrum of possible underlying causes for which the optimal secondary prevention may differ substantially. Attempting a correct etiological diagnosis to reduce the stroke recurrence should be the fundamental goal of modern stroke management. Methods: Prospective observational international multicenter study of cryptogenic stroke and cryptogenic transient ischemic attack (TIA) patients clinically monitored for 12 months to assign the underlying etiology. For atrial fibrillation (AF) detection continuous cardiac rhythm monitoring with insertable cardiac monitor (Reveal LINQ, Medtronic) was performed. The 12-month follow-up data for 250 of 259 initially included NOR-FIB patients were available for analysis. Results: After 12 months follow-up probable stroke causes were revealed in 43% patients, while 57% still remained cryptogenic. AF and atrial flutter was most prevalent (29%). In 14% patients other possible causes were revealed (small vessel disease, large-artery atherosclerosis, hypercoagulable states, other cardioembolism). Patients remaining cryptogenic were younger (p < 0.001), had lower CHA2DS2-VASc score (p < 0.001) on admission, and lower NIHSS score (p = 0.031) and mRS (p = 0.016) at discharge. Smoking was more prevalent in patients that were still cryptogenic (p = 0.014), while dyslipidaemia was less prevalent (p = 0.044). Stroke recurrence rate was higher in the cryptogenic group compared to the group where the etiology was revealed, 7.7% vs. 2.8%, (p = 0.091). Conclusion: Cryptogenic stroke often indicates the inability to identify the cause in the acute phase and should be considered as a working diagnosis until efforts of diagnostic work up succeed in identifying a specific underlying etiology. Timeframe of 6-12-month follow-up may be considered as optimal. Trial registration: ClinicalTrials.gov Identifier NCT02937077, EudraCT 2018-002298-23. [ABSTRACT FROM AUTHOR]

Background: The association between genetic variants on the X chromosome to risk of COPD has not been fully explored. We hypothesize that the X chromosome harbors variants important in determining risk of COPD related phenotypes and may drive sex differences in COPD manifestations. Methods: Using X chromosome data from three COPD-enriched cohorts of adult smokers, we performed X chromosome specific quality control, imputation, and testing for association with COPD case–control status, lung function, and quantitative emphysema. Analyses were performed among all subjects, then stratified by sex, and subsequently combined in meta-analyses. Results: Among 10,193 subjects of non-Hispanic white or European ancestry, a variant near TMSB4X, rs5979771, reached genome-wide significance for association with lung function measured by FEV1/FVC (β 0.020, SE 0.004, p 4.97 × 10–08), with suggestive evidence of association with FEV1 (β 0.092, SE 0.018, p 3.40 × 10–07). Sex-stratified analyses revealed X chromosome variants that were differentially trending in one sex, with significantly different effect sizes or directions. Conclusions: This investigation identified loci influencing lung function, COPD, and emphysema in a comprehensive genetic association meta-analysis of X chromosome genetic markers from multiple COPD-related datasets. Sex differences play an important role in the pathobiology of complex lung disease, including X chromosome variants that demonstrate differential effects by sex and variants that may be relevant through escape from X chromosome inactivation. Comprehensive interrogation of the X chromosome to better understand genetic control of COPD and lung function is important to further understanding of disease pathology. Trial registration Genetic Epidemiology of COPD Study (COPDGene) is registered at ClinicalTrials.gov, NCT00608764 (Active since January 28, 2008). Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints Study (ECLIPSE), GlaxoSmithKline study code SCO104960, is registered at ClinicalTrials.gov, NCT00292552 (Active since February 16, 2006). Genetics of COPD in Norway Study (GenKOLS) holds GlaxoSmithKline study code RES11080, Genetics of Chronic Obstructive Lung Disease. [ABSTRACT FROM AUTHOR]

This study determined the association between respiratory symptoms and death from cardiovascular (CV) diseases during 45 years in a pooled sample of four cohorts of random samples of the Norwegian population with 95,704 participants. Respiratory symptoms were assessed using a modification of the MRC questionnaire on chronic bronchitis. We analyzed the association between respiratory symptoms and specific cardiovascular deaths by using Cox regression analysis with age as the time variable, accounting for cluster-specific random effects using shared frailty for study cohort. Hazard ratios (HR) for death were adjusted for sex, highest attained education, smoking habits, occupational air pollution, and birth cohort. Overall, 12,491 (13%) of participants died from CV diseases: 4,123 (33%) acute myocardial infarction, 2,326 (18%) other ischemic heart disease, 2,246 (18%) other heart diseases, 2,553 (20%) cerebrovascular diseases, and 1,120 (9%) other vascular diseases. The adjusted HR (95% confidence interval) for CV deaths was 1.9 (1.7–2.1) in men and 1.5 (1.2–1.9) in women for "yes" to the question "Are you breathless when you walk on level ground at an ordinary pace?". The same item response showed an adjusted HR for death from acute myocardial infarction of 1.8 (1.5–2.1), other ischemic heart disease 2.2 (1.8–2.7), other heart diseases 1.5 (1.1–1.9), cerebrovascular disease 1.8 (1.5–2.3), and other circulatory diseases 1.7 (1.2–2.4). The adjusted HR for CV death was 1.3 (1.2–1.4) when answering positive to the question" Are you more breathless than people of your own age when walking uphill?". However, positive answers to questions on cough, phlegm, wheezing and attacks of breathlessness were after adjustments not associated with early CV deaths. The associations between CV deaths and breathlessness were also present in never smokers. Self-reported breathlessness was associated with CV deaths and could be an early marker of CV deaths. [ABSTRACT FROM AUTHOR]

This study determined the association between respiratory symptoms and death from respiratory causes over a period of 45 years. In four cohorts of random samples of Norwegian populations with 103,881 participants, 43,731 persons had died per 31 December 2016. In total, 5,949 (14%) had died from respiratory diseases; 2,442 (41%) from lung cancer, 1,717 (29%) chronic obstructive pulmonary disease (COPD), 1,348 (23%) pneumonia, 119 (2%) asthma, 147 (2%) interstitial lung disease and 176 (3%) other pulmonary diseases. Compared with persons without respiratory symptoms the multivariable adjusted hazard ratio (HR) for lung cancer deaths increased with score of breathlessness on effort and cough and phlegm, being 2.6 (95% CI 2.1–3.2) for breathlessness score 3 and 2.1 (95% CI 1.7–2.5) for cough and phlegm score 5. The HR of COPD death was 6.4 (95% CI 5.4–7.7) for breathlessness score 3 and 3.0 (2.4–3.6) for cough and phlegm score 5. Attacks of breathlessness and wheeze score 2 had a HR of 1.6 (1.4–1.9) for COPD death. The risk of pneumonia deaths increased also with higher breathlessness on effort score, but not with higher cough and phlegm score, except for score 2 with HR 1.5 (1.2–1.8). In this study with >2.4 million person-years at risk, a positive association was observed between scores of respiratory symptoms and deaths due to COPD and lung cancer. Respiratory symptoms are thus important risk factors, which should be followed thoroughly by health care practitioners for the benefit of public health. [ABSTRACT FROM AUTHOR]

Background: Penicillin allergy prevalence is internationally reported to be around 10%. However, the majority of patients who report a penicillin allergy do not have a clinically significant hypersensitivity. Few patients undergo evaluation, which leads to overuse of broad-spectrum antibiotics. The objective of this study was to monitor prevalence and implement screening and testing of hospitalized patients.Methods: All patients admitted to the medical department in a local hospital in Oslo, Norway, with a self-reported penicillin allergy were screened using an interview algorithm to categorize the reported allergy as high-risk or low-risk. Patients with a history of low-risk allergy underwent a direct graded oral amoxicillin challenge to verify absence of a true IgE-type allergy.Results: 257 of 5529 inpatients (4.6%) reported a penicillin allergy. 191 (74%) of these patients underwent screening, of which 86 (45%) had an allergy categorized as low-risk. 54 (63%) of the low-risk patients consented to an oral test. 98% of these did not have an immediate reaction to the amoxicillin challenge, and their penicillin allergy label could thus be removed. 42% of the patients under treatment with antibiotics during inclusion could switch to treatment with penicillins immediately after testing, in line with the national recommendations for antibiotic use.Conclusions: The prevalence of self-reported penicillin allergy was lower in this Norwegian population, than reported in other studies. Screening and testing of hospitalized patients with self-reported penicillin allergy is a feasible and easy measure to de-label a large proportion of patients, resulting in immediate clinical and environmental benefit. Our findings suggest that non-allergist physicians can safely undertake clinically impactful allergy evaluations. [ABSTRACT FROM AUTHOR]

Rationale: The Global Burden of Disease program identified smoking and ambient and household air pollution as the main drivers of death and disability from chronic obstructive pulmonary disease (COPD). Objectives: To estimate the attributable risk of chronic airflow obstruction (CAO), a quantifiable characteristic of COPD, due to several risk factors. Methods: The Burden of Obstructive Lung Disease study is a cross-sectional study of adults, aged ≥40, in a globally distributed sample of 41 urban and rural sites. Based on data from 28,459 participants, we estimated the prevalence of CAO, defined as a postbronchodilator FEV1-to-FVC ratio less than the lower limit of normal, and the relative risks associated with different risk factors. Local relative risks were estimated using a Bayesian hierarchical model borrowing information from across sites. From these relative risks and the prevalence of risk factors, we estimated local population attributable risks. Measurements and Main Results: The mean prevalence of CAO was 11.2% in men and 8.6% in women. The mean population attributable risk for smoking was 5.1% in men and 2.2% in women. The next most influential risk factors were poor education levels, working in a dusty job for ≥10 years, low body mass index, and a history of tuberculosis. The risk of CAO attributable to the different risk factors varied across sites. Conclusions: Although smoking remains the most important risk factor for CAO, in some areas, poor education, low body mass index, and passive smoking are of greater importance. Dusty occupations and tuberculosis are important risk factors at some sites. [ABSTRACT FROM AUTHOR]

Introduction: Cigarette smoking is a major environmental risk factor for many diseases, including chronic obstructive pulmonary disease (COPD). There are shared genetic influences on cigarette smoking and COPD. Genetic risk factors for cigarette smoking in cohorts enriched for COPD are largely unknown.Methods: We performed genome-wide association analyses for average cigarettes per day (CPD) across the Genetic Epidemiology of COPD (COPDGene) non-Hispanic white (NHW) (n = 6659) and African American (AA) (n = 3260), GenKOLS (the Genetics of Chronic Obstructive Lung Disease) (n = 1671), and ECLIPSE (the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) (n = 1942) cohorts. In addition, we performed exome array association analyses across the COPDGene NHW and AA cohorts. We considered analyses across the entire cohort and stratified by COPD case-control status.Results: We identified genome-wide significant associations for CPD on chromosome 15q25 across all cohorts (lowest p = 1.78 × 10-15), except in the COPDGene AA cohort alone. Previously reported associations on chromosome 19 had suggestive and directionally consistent associations (RAB4, p = 1.95 × 10-6; CYP2A7, p = 7.50 × 10-5; CYP2B6, p = 4.04 × 10-4). When we stratified by COPD case-control status, single nucleotide polymorphisms on chromosome 15q25 were nominally associated with both NHW COPD cases (β = 0.11, p = 5.58 × 10-4) and controls (β = 0.12, p = 3.86 × 10-5) For the gene-based exome array association analysis of rare variants, there were no exome-wide significant associations. For these previously replicated associations, the most significant results were among COPDGene NHW subjects for CYP2A7 (p = 5.2 × 10-4).Conclusions: In a large genome-wide association study of both common variants and a gene-based association of rare coding variants in ever-smokers, we found genome-wide significant associations on chromosome 15q25 with CPD for common variants, but not for rare coding variants. These results were directionally consistent among COPD cases and controls.Implications: We examined both common and rare coding variants associated with CPD in a large population of heavy smokers with and without COPD of NHW and AA descent. We replicated genome-wide significant associations on chromosome 15q25 with CPD for common variants among NHW subjects, but not for rare variants. We demonstrated for the first time that common variants on chromosome 15q25 associated with CPD are similar among COPD cases and controls. Previously reported associations on chromosome 19 showed suggestive and directionally consistent associations among common variants (RAB4, CYP2A7, and CYP2B6) and for rare variants (CYP2A7) among COPDGene NHW subjects. Although the genetic effect sizes for these single nucleotide polymorphisms on chromosome 15q25 are modest, we show that this creates a substantial smoking burden over the lifetime of a smoker. [ABSTRACT FROM AUTHOR]

Introduction: Based on the National Lung Cancer Screening Trial (NLST), guidelines on screening programs for lung cancer have recommended low‐dose computed tomography (LDCT). De Torres et al made a score for COPD patients (COPD‐LUCSS) to improve their selection criteria. Objective: To examine and compare the discriminating value of both scores in a community‐based cohort of COPD patients. Methods: Four hundred and twenty‐two ever‐smokers with COPD from the GenKOLS study in Bergen were merged with the Cancer Registry of Norway. We divided the patients into groups of high and low risk according to the COPD‐LUCSS and the NLST criteria. Cox regression and logistic regression were used to analyse the associations between the scores and lung cancer. We used Harrell's C and area under the curve (AUC) to estimate discriminating values and to compare the models. Results: Hazard ratio for the high risk vs the low risk in the COPD‐LUCSS was 3.0 (1.4‐6.5 95% CI), P < 0.01. Hazard ratio for the NLST criteria was 2.2 (95% CI 1.1‐4.5), P < 0.05. Harrell's C was 0.63 for the COPD‐LUCSS and 0.59 for the NLST selection criteria. AUC was 0.61 for COPD‐LUCSS and 0.59 for NLST criteria. Comparing tests showed no differences (P = 0.76). Conclusion: Although the COPD‐LUCSS and the NLST criteria were associated with increased risk of lung cancer, the AUC and Harrell's C values showed that these models have poor discriminating abilities in our cohort of COPD patients. The COPD‐LUCSS was not significantly better than the NLST criteria. [ABSTRACT FROM AUTHOR]

Objective: There are some indications of increasing incidence of amyotrophic lateral sclerosis (ALS). Awareness of cognitive impairment in ALS has increased in recent years. We describe the epidemiology and clinical features of ALS in a county in northern Norway over a period of 15 years. Methods: All patients with motor neuron disease (MND) living in Nordland County in the period 2000-2015 were identified and the medical records were scrutinized. The average annual incidence was calculated for the whole period and for five-year periods. Prevalence point was 1 January 2015. Results: We identified 74 cases with MND. The crude point prevalence was 4.1 per 100,000. The average annual incidence was 2.1 per 100,000 for the whole period, 2.0 in the period 2000-2004, 2.3 in 2005-2009, and 2.0 in 2010-2014. All except one of the 22 patients with other forms of MND developed ALS during the course of the disease. The mean survival time was 38 months, patients with bulbar symptoms at diagnosis had a mean survival time of 29 months and those with solely spinal symptoms had a mean survival time of 50 months. Seven patients were diagnosed with frontotemporal dementia (FTD). Conclusion: The incidence was stable during the study period. Other forms of MND converts to clinical ALS given time. Survival time is almost two years shorter in patients with bulbar symptoms at the first examination, compared to those with solely symptoms from spinal muscles. FTD was found in 9% of the patients. [ABSTRACT FROM AUTHOR]

Rationale: Emphysema has considerable variability in the severity and distribution of parenchymal destruction throughout the lungs. Upper lobe-predominant emphysema has emerged as an important predictor of response to lung volume reduction surgery. Yet, aside from alpha-1 antitrypsin deficiency, the genetic determinants of emphysema distribution remain largely unknown.Objectives: To identify the genetic influences of emphysema distribution in non-alpha-1 antitrypsin-deficient smokers.Methods: A total of 11,532 subjects with complete genotype and computed tomography densitometry data in the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD]; non-Hispanic white and African American), ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints), and GenKOLS (Genetics of Chronic Obstructive Lung Disease) studies were analyzed. Two computed tomography scan emphysema distribution measures (difference between upper-third and lower-third emphysema; ratio of upper-third to lower-third emphysema) were tested for genetic associations in all study subjects. Separate analyses in each study population were followed by a fixed effect metaanalysis. Single-nucleotide polymorphism-, gene-, and pathway-based approaches were used. In silico functional evaluation was also performed.Measurements and Main Results: We identified five loci associated with emphysema distribution at genome-wide significance. These loci included two previously reported associations with COPD susceptibility (4q31 near HHIP and 15q25 near CHRNA5) and three new associations near SOWAHB, TRAPPC9, and KIAA1462. Gene set analysis and in silico functional evaluation revealed pathways and cell types that may potentially contribute to the pathogenesis of emphysema distribution.Conclusions: This multicohort genome-wide association study identified new genomic loci associated with differential emphysematous destruction throughout the lungs. These findings may point to new biologic pathways on which to expand diagnostic and therapeutic approaches in chronic obstructive pulmonary disease. Clinical trial registered with www.clinicaltrials.gov (NCT 00608764). [ABSTRACT FROM AUTHOR]

Background: Previous studies, all of <20 years of followup, have suggested an association between lung function and the risk of fatal stroke. This study investigates the stability of this association in a cohort followed for 4 decades. Methods: The Bergen Clinical Blood Pressure Survey was conducted in Norway in 1964--1971. The risk of fatal stroke associated with forced expiratory volume after one second (FEV1) was estimated with Cox proportional hazards regression, making progressive adjustment for potential confounders. Results: Of 5617 (84%) participants with recorded baseline FEV1, 462 died from stroke over 152 786 subsequent person-years of follow-up according to mortality statistics of 2005; mean (SD) follow-up was 27 (12) years. An association between baseline FEV1 (L) and fatal stroke was observed; HR=1.38 (95% CI 1.11 to 1.71) and HR=1.62 (95% CI 1.22 to 2.15) for men and women, respectively (adjusted for age and height). The findings were not explained by smoking, hypertension, diabetes, atherosclerosis, socioeconomic status, obstructive lung disease, physical inactivity, cholesterol or body mass index and persisted in subgroups of never-smokers, subgroups without respiratory symptoms and survivors of the first 20 years of follow-up. For male survivors with a valid FEV1 at follow-up (1988--1990) (n=953), baseline FEV1 (L) indicated a possible strong and independent association to the risk of fatal stroke after adjustments for individual changes in FEV1 (ml/year) (HR 1.95 (95% CI 0.98 to 3.86)). Conclusion: There is a consistent, independent and long-lasting association between lung function and fatal stroke, probably irrespective of changes during adult life. [ABSTRACT FROM AUTHOR]

Background Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease (COPD) and COPD severity. Previous genome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) associated with the number of cigarettes smoked per day (CPD) and a dopamine beta-hydroxylase (DBH) locus associated with smoking cessation in multiple populations. Objective To identify SNPs associated with lifetime average and current CPD, age at smoking initiation, and smoking cessation in patients with COPD. Methods GWAS were conducted in four independent cohorts encompassing 3441 ever-smoking patients with COPD (Global Initiative for Obstructive Lung Disease stage II or higher). Untyped SNPs were imputed using the HapMap (phase II) panel. Results from all cohorts were meta-analysed. Results Several SNPs near the HLA region on chromosome 6p21 and in an intergenic region on chromosome 2q21 showed associations with age at smoking initiation, both with the lowest p=2×10(-7). No SNPs were associated with lifetime average CPD, current CPD or smoking cessation with p<10(-6). Nominally significant associations with candidate SNPs within cholinergic receptors, nicotinic, alpha 3/5 (CHRNA3/CHRNA5; eg, p=0.00011 for SNP rs1051730) and cytochrome P450, family 2, subfamily A, polypeptide 6 (CYP2A6; eg, p=2.78×10(-5) for a non-synonymous SNP rs1801272) regions were observed for lifetime average CPD, however only CYP2A6 showed evidence of significant association with current CPD. A candidate SNP (rs3025343) in DBH was significantly (p=0.015) associated with smoking cessation. Conclusion The authors identified two candidate regions associated with age at smoking initiation in patients with COPD. Associations of CHRNA3/CHRNA5 and CYP2A6 loci with CPD and DBH with smoking cessation are also likely of importance in the smoking behaviours of patients with COPD. [ABSTRACT FROM AUTHOR]

Background: The identification of gene-by-environment interactions is important for understanding the genetic basis of chronic obstructive pulmonary disease (COPD). Many COPD genetic association analyses assume a linear relationship between pack-years of smoking exposure and forced expiratory volume in 1 s (FEV(1)); however, this assumption has not been evaluated empirically in cohorts with a wide spectrum of COPD severity.Methods: The relationship between FEV(1) and pack-years of smoking exposure was examined in four large cohorts assembled for the purpose of identifying genetic associations with COPD. Using data from the Alpha-1 Antitrypsin Genetic Modifiers Study, the accuracy and power of two different approaches to model smoking were compared by performing a simulation study of a genetic variant with a range of gene-by-smoking interaction effects.Results: Non-linear relationships between smoking and FEV(1) were identified in the four cohorts. It was found that, in most situations where the relationship between pack-years and FEV(1) is non-linear, a piecewise linear approach to model smoking and gene-by-smoking interactions is preferable to the commonly used total pack-years approach. The piecewise linear approach was applied to a genetic association analysis of the PI*Z allele in the Norway Case-Control cohort and a potential PI*Z-by-smoking interaction was identified (p=0.03 for FEV(1) analysis, p=0.01 for COPD susceptibility analysis).Conclusion: In study samples of subjects with a wide range of COPD severity, a non-linear relationship between pack-years of smoking and FEV(1) is likely. In this setting, approaches that account for this non-linearity can be more powerful and less biased than the more common approach of using total pack-years to model the smoking effect. [ABSTRACT FROM AUTHOR]

Mortality statistics represent important endpoints in epidemiological studies. The diagnostic validity of cerebral stroke and ischemic heart disease recorded as the underlying cause of death in Norwegian mortality statistics was assessed by using mortality data of participants in the Bergen Clinical Blood Pressure Study in Norway and autopsy records from the Gade Institute in Bergen. In the 41 years of the study (1965-2005) 4,387 subjects had died and 1,140 (26%) had undergone a post mortem examination; 548 (12%) died from cerebral stroke and 1,120 (24%) from ischemic heart disease according to the mortality statistics, compared to 113 (10%) strokes and 323 (28%) coronary events registered in the autopsy records. The sensitivity and positive predictive value of fatal cerebral strokes in the mortality statistics were 0.75, 95% confidence interval (CI) [0.66, 0.83] and 0.86 [0.77, 0.92], respectively, whereas those of coronary deaths were 0.87 [0.84, 0.91] and 0.85 [0.81, 0.89] respectively. Cohen's Kappa coefficients were 0.78 [0.72, 0.84] for stroke and 0.80 [0.76, 0.84] for coronary deaths. In addition to female gender and increasing age at death, cerebral stroke was a negative predictor of an autopsy being carried out (odds ratio (OR) 0.69, 95% CI [0.54, 0.87]), whereas death from coronary heart disease was not (OR 1.14, 95% CI [0.97, 1,33]), both adjusted for gender and age at death. There was substantial agreement between mortality statistics and autopsy findings for both fatal strokes and coronary deaths. Selection for post mortem examinations was associated with age, gender and cause of death. [ABSTRACT FROM AUTHOR]

Rationale: There is limited knowledge about the relationship between respiratory symptoms and quantitative high-resolution computed tomography measures of emphysema and airway wall thickness. Objectives: To describe the ability of these measures of emphysema and airway wall thickness to predict respiratory symptoms in subjects with and without chronic obstructive pulmonary disease (COPD). Methods: We included 463 subjects with chronic obstructive pulmonary disease (COPD) (65% men) and 488 subjects without COPD (53% men). All subjects were current or ex-smokers older than 40 years. They underwent spirometry and high-resolution computed tomography examination, and completed an American Thoracic Society questionnaire on respiratory symptoms. Measurements and Main Results: Median (25th percentile, 75th percentile) percent low-attenuation areas less than -950 Hounsfield units (%LAA) was 7.0 (2.2, 17.8) in subjects with COPD and 0.5 (0.2, 1.3) in subjects without COPD. Mean (SD) standardized airway wall thickness (AWT) at an internal perimeter of 10 mm (AWT-Pi10) was 4.94 (0.33) mm in subjects with COPD and 4.77 (0.29) in subjects without COPD. Both %LAA and AWT-Pi10 were independently and significantly related to the level of dyspnea among subjects with COPD, even after adjustments for percent predicted FEV(1). AWT-Pi10 was significantly related to cough and wheezing in subjects with COPD, and to wheezing in subjects without COPD. Odds ratios (95% confidence intervals) for increased dyspnea in subjects with COPD and in subjects without COPD were 1.9 (1.5-2.3) and 1.9 (0.6-6.6) per 10% increase in %LAA, and 1.07 (1.01-1.14) and 1.11 (0.99-1.24) per 0.1-mm increase in AWT-Pi10, respectively. Conclusions: Quantitative computed tomography assessment of the lung parenchyma and airways may be used to explain the presence of respiratory symptoms beyond the information offered by spirometry. [ABSTRACT FROM AUTHOR]

Introduction There are few data available on the optimal number of lung cancer patients needed to generate and compare estimates of quality between units managing lung cancer. The number of lung cancer patients per management unit varies considerably in Norway, where there are 42 hospitals that treated between 1 and 454 lung cancer patients in 2011. Aims To estimate the differences in quality indicators that are of sufficient importance to change a pulmonary physician's lung cancer management program, and to estimate the size of the patient samples necessary to detect such differences. Method Twenty-six physicians were asked about the relative differences from a national average of quality indicators that would change their own lung cancer management program. Sample sizes were calculated to give valid estimates of quality of a management unit based on prevalence of quality indicators and minimally important differences ( MID). Results The average MID in quality indicators that would cause a change in management varied from 18% to 24% among 26 chest physicians, depending on the indicator. Conclusions To generate precise estimates for quality control of lung cancer care in Norway, the number of management units must be reduced. Given the present willingness of chest physicians to change their procedures for management of lung cancer according to the results of quality control indicators, we recommend a maximum of 10 units with a minimum of 200 incident lung cancer patients per year for each management center. [ABSTRACT FROM AUTHOR]

Background: Amplifications of the transcription factor, SRY (sex determining region Y)-box 2 (SOX2), are common in non-small cell lung cancer (NSCLC). SOX2 signaling is important in maintaining the stem cell-like phenotype of cancer cells and contributes to the pathogenesis of lung cancer. TP53 is known to inhibit gene amplifications and to repress many stem cell-associated genes following DNA damage. The aim of this study was to investigate if TP53 mutational status affected SOX2 copy number variation and gene expression in early-stage NSCLC patients; moreover, to assess if TP53 regulates SOX2 expression in human lung cancer cells.Methods: 258 early-stage lung cancer patients were included in the study. Exons 4-9 in the TP53 gene were sequenced for mutations in tumor tissues. SOX2 copy number as well as TP53 and SOX2 gene expression were analyzed in tumor and in adjacent non-tumorous tissues by qPCR. TP53 and SOX2 were silenced using gene-specific siRNAs in human lung adenocarcinoma A427 cells, and the expression of TP53, SOX2 and subset of selected miRNAs was analyzed by qPCR. The odds ratios (ORs) for associations between copy number variation and lung cancer were estimated by conditional logistic regression, and the correlation between gene status and clinicopathological characteristics was assessed by Chi-square or Fisher's exact test. Gene expression data was analyzed using nonparametric Mann-Whitney test.Results: TP53 mutations were associated with an increased risk of acquiring a SOX2 copy number alteration (OR = 2.08, 95% CI: 1.14-3.79, p = 0.017), which was more frequently occurring in tumor tissues (34%) than in adjacent non-tumorous tissues (3%). Moreover, SOX2 and TP53 expression levels were strongly correlated in tumor tissues. In vitro studies showed that a reduction in TP53 was associated with decreased SOX2 expression in A427 cells. Furthermore, TP53 knockdown reduced the miRNA hsa-miR-145, which has previously been shown to regulate SOX2 expression.Conclusions: TP53 signaling may be important in the regulation of SOX2 copy number and expression in NSCLC tumors, and the miRNA hsa-miR-145-5p may be one potential driver. This prompts for further studies on the mechanisms behind the TP53-induced regulation of SOX2 expression and the possible importance of hsa-miR-145 in lung cancer. [ABSTRACT FROM AUTHOR]

Background: Pulmonary function decline is a major contributor to morbidity and mortality among smokers. Post bronchodilator FEV1 and FEV1/FVC ratio are considered the standard assessment of airflow obstruction. We performed a genome-wide association study (GWAS) in 9919 current and former smokers in the COPDGene study (6659 non-Hispanic Whites [NHW] and 3260 African Americans [AA]) to identify associations with spirometric measures (post-bronchodilator FEV1 and FEV1/FVC). We also conducted meta-analysis of FEV1 and FEV1/FVC GWAS in the COPDGene, ECLIPSE, and GenKOLS cohorts (total n = 13,532). Results: Among NHW in the COPDGene cohort, both measures of pulmonary function were significantly associated with SNPs at the 15q25 locus [containing CHRNA3/5, AGPHD1, IREB2, CHRNB4] (lowest p-value = 2.17 × 10-11), and FEV1/FVC was associated with a genomic region on chromosome 4 [upstream of HHIP] (lowest p-value = 5.94 × 10-10); both regions have been previously associated with COPD. For the meta-analysis, in addition to confirming associations to the regions near CHRNA3/5 and HHIP, genome-wide significant associations were identified for FEV1 on chromosome 1 [TGFB2] (p-value = 8.99 × 10-9), 9 [DBH] (p-value = 9.69 × 10-9) and 19 [CYP2A6/7] (p-value = 3.49 × 10-8) and for FEV1/FVC on chromosome 1 [TGFB2] (p-value = 8.99 × 10-9), 4 [FAM13A] (p-value = 3.88 × 10-12), 11 [MMP3/12] (p-value = 3.29 × 10-10) and 14 [RIN3] (p-value = 5.64 × 10-9). Conclusions: In a large genome-wide association study of lung function in smokers, we found genome-wide significant associations at several previously described loci with lung function or COPD. We additionally identified a novel genome-wide significant locus with FEV1 on chromosome 9 [DBH] in a meta-analysis of three study populations. [ABSTRACT FROM AUTHOR]

Objectives: To use a systems biology approach to integrate genotype and protein-protein interaction (PPI) data to identify disease network modules associated with chronic obstructive pulmonary disease (COPD) and to perform traditional pathway analysis. Methods: We utilized a standard gene-set association approach (FORGE) using gene-based association analysis and gene-set definitions from the molecular signatures database (MSigDB). As a discovery step, we analyzed GWAS results from 2 well-characterized COPD cohorts: COPDGene and GenKOLS. We used a third well-characterized COPD case-control cohort for replication: ECLIPSE. Next, we used dmGWAS, a method that integrates GWAS results with PPI, to identify COPD disease modules. Results: No gene-sets reached experiment-wide significance in either discovery population. We identified a consensus network of 10 genes identified in modules by integrating GWAS results with PPI that replicated in COPDGene, GenKOLS, and ECLIPSE. Members of 4 gene-sets were enriched among these 10 genes: (i) lung adenocarcinoma tumor-sequencing genes, (ii) IL-7 pathway genes, (iii) kidney cell response to arsenic, and (iv) CD4 T-cell responses. Further, several genes have also been associated with pathophysiology relevant to COPD including KCNK3, NEDD4L, and RIN3. In particular, KCNK3 has been associated with pulmonary arterial hypertension, a common complication in advanced COPD. Conclusion: We report a set of new genes that may influence the etiology of COPD that would not have been identified using traditional GWAS and pathway analyses alone. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: The purpose of this cross-sectional study was to investigate whether the presence of serum complement antibodies was associated with reduced one-second forced expiratory volume (FEV1) in adults.Methods: From a stratified random sample of 18-73 year old adults, we performed measurements of serum complement fixing virus antibodies against influenza type A and B, parainfluenza type 1, 2, and 3, respiratory syncytial virus and adenovirus on 82% (n = 1239).Results: In the crude data, subjects having five of the seven virus antibodies had significantly lower lung function, given as sex-, age- and height-standardized residuals of FEV1 (SFEV1), compared with those without. After adjusting in addition for smoking habits, lifetime smoking consumption and season, the lung function levels were significantly lower in subjects with influenza type B and respiratory syncytial virus antibodies compared to those without (P < 0.01). Increasing influenza and respiratory syncytial virus antibody titres and increasing numbers of virus antibodies, respectively, were related to progressively lower lung function. Subjects with respiratory symptoms but without obstructive lung disease had lower antibody levels than subjects with obstructive lung disease, but higher levels than asymptomatic subjects. In a final multiple linear regression analysis adjusting in addition for respiratory symptom and disease status as well as for the other respiratory virus antibodies, the presence of respiratory syncytial virus antibodies was a significant predictor for reduced SFEV1 (regression coefficient: -0.226; SE = 0.112; P = 0.04). The magnitude of the effect on lung function remained after excluding subjects reporting symptoms of respiratory infection within 3 weeks prior to the examination (regression coefficient: -0.252; SE = -0.218; P = 0.25).Conclusions: This cross-sectional community study indicates that respiratory syncytial virus infection or re-infection is an independent predictor for reduced lung function in adults of a wide age range. [ABSTRACT FROM AUTHOR]

Background: The aims were to examine prevalences as well as demographic and environmental predictors of respiratory virus antibodies in serum.Methods: In a cross-sectional study of 18-73 year old Norwegian adults a random stratified sample (n = 1512) was invited to attend an examination at an outpatient clinic. Seven respiratory virus antibodies were assessed by the complement fixation test.Results: The attendance rate was 84%. The most frequent virus antibodies with titre of > or = 1:8 were influenza virus type A with a population standardized prevalence of 44%, adenovirus 25% and influenza virus type B 22%. The prevalences of antibodies against parainfluenza virus type 1, 2 and 3 increased with age. Smokers compared to non-smokers had an adjusted odds ratio (OR) of 1.7 (95% confidence interval [CI]: 1.3-2.4) for having one or more of the seven examined virus antibodies. The presence of one or more of the virus antibodies increased from summer to winter months (adjusted OR = 1.3 per month; 95% CI: 1.2-1.4) and it was higher in occupational dust or gas exposed smokers (adjusted OR = 2.0; 95% CI: 1.1-3.7) compared with unexposed smokers.Conclusions: Ageing, smoking, occupational dust or gas exposure as well as season of the year may thus be predictors for levels of respiratory virus antibodies in adults. These observations should be taken into account when comparing prevalences of virus antibodies in various communities as well as when examining the relationship between presence of virus antibodies and airway disease. [ABSTRACT FROM AUTHOR]

Background: The association between occupational quartz exposure and ventilatory function was investigated in men in a general population after adjusting for other potential determinants of outcome.Methods: All eligible men aged 30-46 years living in western Norway (n = 45,380) were invited to a cross sectional community survey. This included a self administered questionnaire (with respiratory symptoms, smoking habits and occupational exposures), spirometric recordings (using dry wedge below spirometers), and a chest radiograph (65% attendance). Measurements of forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were obtained in 91% (n = 26,803) of those who participated, 26,106 of whom performed successful spirometric tests and had normal chest radiographs and remained for further analysis. Age, body mass index, and technician standardised residuals ((observed minus predicted value)/residual standard error) of maximum FEV1/height2 and FVC/height2 were used as outcome variables for adjusted lung function levels, respectively.Results: Occupational quartz exposure was reported by 13% (n = 3445) of those who participated in the survey, with a mean duration of seven years. Among those exposed to quartz, significant inverse linear relationships were observed between years of exposure and FEV1 level and the ratio of FEV1/FVC, independent of host characteristics. Multiple linear regression analyses showed that the difference in FEV1 associated with each year of quartz exposure was -4.3 ml (95% CI -1.1 to -7.5 ml; p = 0.01) compared with -6.9 ml (95% CI -4.7 to -9.1 ml; p < 0.01) from smoking 20 cigarettes/day for one year after adjusting for age, atopy, asthma, wheezing, marital status, and other occupational exposures.Conclusion: In men aged 30-46 years with occupational quartz exposure and normal chest radiographs the duration of occupational quartz exposure was an independent predictor for spirometric airflow limitation. [ABSTRACT FROM AUTHOR]

Background: Chronic bronchitis (CB) is one of the classic phenotypes of COPD. The aims of our study were to investigate genetic variants associated with COPD subjects with CB relative to smokers with normal spirometry, and to assess for genetic differences between subjects with CB and without CB within the COPD population. Methods: We analyzed data from current and former smokers from three cohorts: the COPDGene Study; GenKOLS (Bergen, Norway); and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE). CB was defined as having a cough productive of phlegm on most days for at least 3 consecutive months per year for at least 2 consecutive years. CB COPD cases were defined as having both CB and at least moderate COPD based on spirometry. Our primary analysis used smokers with normal spirometry as controls; secondary analysis was performed using COPD subjects without CB as controls. Genotyping was performed on Illumina platforms; results were summarized using fixed-effect meta-analysis. Results: For CB COPD relative to smoking controls, we identified a new genome-wide significant locus on chromosome 11p15.5 (rs34391416, OR = 1.93, P=4.99× 10-8) as well as significant associations of known COPD SNPs within FAM13A. In addition, a GWAS of CB relative to those without CB within COPD subjects showed suggestive evidence for association on 1q23.3 (rs114931935, OR = 1.88, P= 4.99 ×10-7). Conclusions: We found genome-wide significant associations with CB COPD on 4q22.1 (FAM13A) and 11p15.5 (EFCAB4A, CHID1 and AP2A2), and a locus associated with CB within COPD subjects on 1q23.3 (RPL31P11 and ATF6). This study provides further evidence that genetic variants may contribute to phenotypic heterogeneity of COPD. [ABSTRACT FROM AUTHOR]

Atrial fibrillation ( AF) is the most common cardiac arrhythmia. The prevalence increases with increasing age. In middle-aged men, endurance sport practice is associated with increased risk of AF but there are few studies among elderly people. The aim of this study was to investigate the role of long-term endurance sport practice as a risk factor for AF in elderly men. A cross-sectional study compared 509 men aged 65-90 years who participated in a long-distance cross-country ski race with 1768 men aged 65-87 years from the general population. Long-term endurance sport practice was the main exposure. Self-reported AF and covariates were assessed by questionnaires. Risk differences ( RDs) for AF were estimated by using a linear regression model. After multivariable adjustment, a history of endurance sport practice gave an added risk for AF of 6.0 percent points (pp) (95% confidence interval 0.8-11.1). Light and moderate leisure-time physical activity during the last 12 months reduced the risk with 3.7 and 4.3 pp, respectively, but the RDs were not statistically significant. This study suggests that elderly men with a history of long-term endurance sport practice have an increased risk of AF compared with elderly men in the general population. [ABSTRACT FROM AUTHOR]

Motivation: For samples of unrelated individuals, we propose a general analysis framework in which hundred thousands of genetic loci can be tested simultaneously for association with complex phenotypes. The approach is built on spatial-clustering methodology, assuming that genetic loci that are associated with the target phenotype cluster in certain genomic regions. In contrast to standard methodology for multilocus analysis, which has focused on the dimension reduction of the data, our multilocus association-clustering test profits from the availability of large numbers of genetic loci by detecting clusters of loci that are associated with the phenotype.Results: The approach is computationally fast and powerful, enabling the simultaneous association testing of large genomic regions. Even the entire genome or certain chromosomes can be tested simultaneously. Using simulation studies, the properties of the approach are evaluated. In an application to a genome-wide association study for chronic obstructive pulmonary disease, we illustrate the practical relevance of the proposed method by simultaneously testing all genotyped loci of the genome-wide association study and by testing each chromosome individually. Our findings suggest that statistical methodology that incorporates spatial-clustering information will be especially useful in whole-genome sequencing studies in which millions or billions of base pairs are recorded and grouped by genomic regions or genes, and are tested jointly for association.Availability and implementation: Implementation of the approach is available upon request.Contact: daq412@mail.harvard.eduSupplementary information: Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Background Due to the pleiotropic effects of nitric oxide (NO) within the lungs, it is likely that NO is a significant factor in the pathogenesis of chronic obstructive pulmonary disease (COPD). The aim of this study was to test for association between single nucleotide polymorphisms (SNPs) in three NO synthase (NOS) genes and lung function, as well as to examine gene expression and protein levels in relation to the genetic variation. Methods One SNP in each NOS gene (neuronal NOS (NOS1), inducible NOS (NOS2), and endothelial NOS (NOS3)) was genotyped in the Lung Health Study (LHS) and correlated with lung function. One SNP (rs1800779) was also analyzed for association with COPD and lung function in four COPD case-control populations. Lung tissue expression of NOS3 mRNA and protein was tested in individuals of known genotype for rs1800779. Immunohistochemistry of lung tissue was used to localize NOS3 expression. Results For the NOS3 rs1800779 SNP, the baseline forced expiratory volume in one second in the LHS was significantly higher in the combined AG + GG genotypic groups compared with the AA genotypic group. Gene expression and protein levels in lung tissue were significantly lower in subjects with the AG + GG genotypes than in AA subjects. NOS3 protein was expressed in the airway epithelium and subjects with the AA genotype demonstrated higher NOS3 expression compared with AG and GG individuals. However, we were not able to replicate the associations with COPD or lung function in the other COPD study groups. Conclusions Variants in the NOS genes were not associated with lung function or COPD status. However, the G allele of rs1800779 resulted in a decrease of NOS3 gene expression and protein levels and this has implications for the numerous disease states that have been associated with this polymorphism. [ABSTRACT FROM AUTHOR]

Introduction Coexistent respiratory failure and metabolic alkalosis is a common finding. Acidotic diuretics cause a fall in pH that may stimulate respiration. Objective The purpose of the study was to evaluate the effectiveness of short-term treatment with acetazolamide for combined respiratory failure and metabolic alkalosis. Methods A randomised, placebo-controlled and double-blind parallel group trial where oral acetazolamide 250 mg three times a day for 5 days were administered to patients hospitalised for respiratory failure because of a pulmonary disease ( PaO2 ≤ 8 k Pa and/or PaCO2 ≥ 7 k Pa) who had concurrent metabolic alkalosis [base excess ( BE) ≥8 mmol/ L]. PaO2 after 5 days was the primary effect variable. Secondary effect variables were PaCO2, BE and pH on day 5, and the total number of days in hospital. Results Of 70 patients enrolled (35 in each group), data from 54 were analysed per protocol, while last observation carried forward was used for the remaining 16. During the 5-day treatment, PaO2 increased on average 0.81 k Pa in the placebo group and 1.41 k Pa in the acetazolamide group. After adjustment for baseline skewness, the difference was statistically significant (adjusted mean difference 0.55 k Pa, 95% confidence interval 0.03-1.06). PaCO2 decreased in both groups, but the difference was not statistically significant. As expected, pH and BE decreased markedly in the acetazolamide group. Conclusion Acetazolamide may constitute a useful adjuvant treatment mainly to be considered in selected patients with respiratory failure combined with prominent metabolic alkalosis or where non-invasive ventilation is insufficient or infeasible. [ABSTRACT FROM AUTHOR]

Rationale: The GOLD (Global Initiative for Chronic Obstructive Lung Disease) 2011 update on chronic obstructive pulmonary disease (COPD) bases disease classification on level of dyspnea, exacerbation history, and FEV1, whereas the previous GOLD categorized disease severity according to FEV1 only. Information on how the new classification predicts long-term hospitalizations and mortality is limited. Objectives: To examine how GOLD 2011 predicts hospitalizations and mortality over an 8-year period and to assess differences in predictive ability between GOLD 2011 and GOLD 2007. Methods: In the GenKOLS study, 912 patients with COPD (FEV1/FVC < 0.7 and FEV1 < 80% predicted) aged 40 to 91 years were clinically examined. Patients answered questionnaires and performed lung function testing in 2003-2005. The population was followed for 8 years regarding hospitalizations (all-cause, respiratory) and mortality (all-cause, respiratory, cardiovascular). We performed logistic regression and receiver operating curve analyses for GOLD 2007 and GOLD 2011 with estimations of area under the curve (AUC) to compare the different classifications. Measurements and Main Results: Twenty percent of patients were classified as GOLD 2011 group A (mild), 30% as group B, 6% group as C, and 44% as group D (very severe). Patients in GOLD 2011 group D had odds ratios of 4.1 (95% confidence interval [CI], 2.5-6.7), 9.6 (95% CI, 3.4-27.0), and 3.0 (95% CI, 0.7-13.2) relative to group A for all-cause, respiratory, and cardiovascular mortality, respectively, and 3.8 (95% CI, 2.4-5.9) and 13.0 (95% CI, 6.6-25.6) for all-cause and respiratory hospitalizations, respectively. Associations were similar also for GOLD 2007. The adjusted AUC values for GOLD 2011 and GOLD 2007 were 0.82/0.82 for respiratory mortality (P = 0.87) and 0.77/0.76 for respiratory hospitalizations (P = 0.51). Conclusions: The predictive ability of GOLD 2011 did not differ significantly from GOLD 2007 in terms of hospitalizations and mortality. [ABSTRACT FROM AUTHOR]

Genome-wide association studies have demonstrated that genetic polymorphisms influence the risk of developing lung cancer. Nicotinic acetylcholine receptor alpha3, alpha5 and beta4 genes ( CHRNA3, CHRNA5 and CHRNB4) cluster at the 15q25.1 lung cancer susceptibility locus. We genotyped 310 patients with non-small cell lung cancer and a control group of 348 cancer-free individuals for seven sequence variants located in CHRNA3 and CHRNA5 genes. Two of the polymorphisms (rs3829787 and rs3841324) statistically influenced the risk of developing lung cancer. We found that four of the variants (rs3829787, rs3841324, rs588765 and rs3743073) were associated with differential levels of genetic alterations measured as the levels of hydrophobic DNA adducts in the adjacent histologically normal tissue of the lung cancer patients and as TP53 mutations in their lung tumors. The seven sequence variants formed three haplotypes with a frequency above 5%. The two most frequent haplotypes were associated with the risk of developing lung cancer and with smoking-related DNA alterations. We also found an association between CHRNA5 mRNA levels and the sequence variants or haplotypes. In conclusion, our results showed that several of the polymorphisms and their haplotypes in CHRNA5/CHRNA3 genes may have functional effects on ( i) CHRNA5 mRNA levels, ( ii) polycyclic aromatic hydrocarbon-DNA adduct levels, ( iii) TP53 mutations and ( iv) susceptibility to lung cancer. [ABSTRACT FROM AUTHOR]

Cigarette smoking is the major environmental risk factor for chronic obstructive pulmonary disease (COPD). Genome-wide association studies have provided compelling associations for three loci with COPD. In this study, we aimed to estimate direct, i.e., independent from smoking, and indirect effects of those loci on COPD development using mediation analysis. We included a total of 3,424 COPD cases and 1,872 unaffected controls with data on two smoking-related phenotypes: lifetime average smoking intensity and cumulative exposure to tobacco smoke (pack years). Our analysis revealed that effects of two linked variants (rs1051730 and rs8034191) in the AGPHD1/ CHRNA3 cluster on COPD development are significantly, yet not entirely, mediated by the smoking-related phenotypes. Approximately 30 % of the total effect of variants in the AGPHD1/ CHRNA3 cluster on COPD development was mediated by pack years. Simultaneous analysis of modestly ( r = 0.21) linked markers in CHRNA3 and IREB2 revealed that an even larger (~42 %) proportion of the total effect of the CHRNA3 locus on COPD was mediated by pack years after adjustment for an IREB2 single nucleotide polymorphism. This study confirms the existence of direct effects of the AGPHD1/ CHRNA3, IREB2, FAM13A and HHIP loci on COPD development. While the association of the AGPHD1/ CHRNA3 locus with COPD is significantly mediated by smoking-related phenotypes, IREB2 appears to affect COPD independently of smoking. [ABSTRACT FROM AUTHOR]