Publications by authors named "Arnulf Langhammer"

138 Publications

Changes in lung function in European adults born between 1884 and 1996 and implications for the diagnosis of lung disease: a cross-sectional analysis of ten population-based studies.

Lancet Respir Med 2021 Oct 4. Epub 2021 Oct 4.

Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; COPD Centre, Department of Respiratory Medicine and Allergology, Sahlgrenska University Hospital, Gothenburg, Sweden.

Background: During the past century, socioeconomic and scientific advances have resulted in changes in the health and physique of European populations. Accompanying improvements in lung function, if unrecognised, could result in the misclassification of lung function measurements and misdiagnosis of lung diseases. We therefore investigated changes in population lung function with birth year across the past century, accounting for increasing population height, and examined how such changes might influence the interpretation of lung function measurements.

Methods: In our analyses of cross-sectional data from ten European population-based studies, we included individuals aged 20-94 years who were born between 1884 and 1996, regardless of previous respiratory diagnoses or symptoms. FEV, forced vital capacity (FVC), height, weight, and smoking behaviour were measured between 1965 and 2016. We used meta-regression to investigate how FEV and FVC (adjusting for age, study, height, sex, smoking status, smoking pack-years, and weight) and the FEV/FVC ratio (adjusting for age, study, sex, and smoking status) changed with birth year. Using estimates from these models, we graphically explored how mean lung function values would be expected to progressively deviate from predicted values. To substantiate our findings, we used linear regression to investigate how the FEV and FVC values predicted by 32 reference equations published between 1961 and 2015 changed with estimated birth year.

Findings: Across the ten included studies, we included 243 465 European participants (mean age 51·4 years, 95% CI 51·4-51·5) in our analysis, of whom 136 275 (56·0%) were female and 107 190 (44·0%) were male. After full adjustment, FEV increased by 4·8 mL/birth year (95% CI 2·6-7·0; p<0·0001) and FVC increased by 8·8 mL/birth year (5·7-12·0; p<0·0001). Birth year-related increases in the FEV and FVC values predicted by published reference equations corroborated these findings. This height-independent increase in FEV and FVC across the last century will have caused mean population values to progressively exceed previously predicted values. However, the population mean adjusted FEV/FVC ratio decreased by 0·11 per 100 birth years (95% CI 0·09-0·14; p<0·0001).

Interpretation: If current diagnostic criteria remain unchanged, the identified shifts in European values will allow the easier fulfilment of diagnostic criteria for lung diseases such as chronic obstructive pulmonary disease, but the systematic underestimation of lung disease severity.

Funding: The European Respiratory Society, AstraZeneca, Chiesi Farmaceutici, GlaxoSmithKline, Menarini, and Sanofi-Genzyme.
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http://dx.doi.org/10.1016/S2213-2600(21)00313-1DOI Listing
October 2021

The blood metabolome of incident kidney cancer: A case-control study nested within the MetKid consortium.

PLoS Med 2021 09 20;18(9):e1003786. Epub 2021 Sep 20.

Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France.

Background: Excess bodyweight and related metabolic perturbations have been implicated in kidney cancer aetiology, but the specific molecular mechanisms underlying these relationships are poorly understood. In this study, we sought to identify circulating metabolites that predispose kidney cancer and to evaluate the extent to which they are influenced by body mass index (BMI).

Methods And Findings: We assessed the association between circulating levels of 1,416 metabolites and incident kidney cancer using pre-diagnostic blood samples from up to 1,305 kidney cancer case-control pairs from 5 prospective cohort studies. Cases were diagnosed on average 8 years after blood collection. We found 25 metabolites robustly associated with kidney cancer risk. In particular, 14 glycerophospholipids (GPLs) were inversely associated with risk, including 8 phosphatidylcholines (PCs) and 2 plasmalogens. The PC with the strongest association was PC ae C34:3 with an odds ratio (OR) for 1 standard deviation (SD) increment of 0.75 (95% confidence interval [CI]: 0.68 to 0.83, p = 2.6 × 10-8). In contrast, 4 amino acids, including glutamate (OR for 1 SD = 1.39, 95% CI: 1.20 to 1.60, p = 1.6 × 10-5), were positively associated with risk. Adjusting for BMI partly attenuated the risk association for some-but not all-metabolites, whereas other known risk factors of kidney cancer, such as smoking and alcohol consumption, had minimal impact on the observed associations. A mendelian randomisation (MR) analysis of the influence of BMI on the blood metabolome highlighted that some metabolites associated with kidney cancer risk are influenced by BMI. Specifically, elevated BMI appeared to decrease levels of several GPLs that were also found inversely associated with kidney cancer risk (e.g., -0.17 SD change [ßBMI] in 1-(1-enyl-palmitoyl)-2-linoleoyl-GPC (P-16:0/18:2) levels per SD change in BMI, p = 3.4 × 10-5). BMI was also associated with increased levels of glutamate (ßBMI: 0.12, p = 1.5 × 10-3). While our results were robust across the participating studies, they were limited to study participants of European descent, and it will, therefore, be important to evaluate if our findings can be generalised to populations with different genetic backgrounds.

Conclusions: This study suggests a potentially important role of the blood metabolome in kidney cancer aetiology by highlighting a wide range of metabolites associated with the risk of developing kidney cancer and the extent to which changes in levels of these metabolites are driven by BMI-the principal modifiable risk factor of kidney cancer.
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http://dx.doi.org/10.1371/journal.pmed.1003786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8496779PMC
September 2021

Bone mineral density and risk of cardiovascular disease in men and women: the HUNT study.

Eur J Epidemiol 2021 Nov 13;36(11):1169-1177. Epub 2021 Sep 13.

K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.

The association between bone mineral density (BMD) and cardiovascular disease (CVD) is not fully understood. We evaluated BMD as a risk factor for cardiovascular disease and specifically atrial fibrillation (AF), acute myocardial infarction (AMI), ischemic (IS) and hemorrhagic stroke (HS) and heart failure (HF) in men and women. This prospective population cohort utilized data on 22 857 adults from the second and third surveys of the HUNT Study in Norway free from CVD at baseline. BMD was measured using single and dual-energy X-ray absorptiometry in the non-dominant distal forearm and T-score was calculated. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated from adjusted cox proportional hazards models. The analyses were sex-stratified, and models were adjusted for age, age-squared, BMI, physical activity, smoking status, alcohol use, and education level. Additionally, in women, we adjusted for estrogen use and postmenopause. During a mean follow-up of 13.6 ± 5.7 years, 2 928 individuals (12.8%) developed fatal or non-fatal CVD, 1 020 AF (4.5%), 1 172 AMI (5.1%), 1 389 IS (6.1%), 264 HS (1.1%), and 464 HF (2.0%). For every 1 unit decrease in BMD T-score the HR for any CVD was 1.01 (95% CI 0.98 to 1.04) in women and 0.99 (95% CI 0.94 to 1.03) in men. Point estimates for the four cardiovascular outcomes ranged from slightly protective (HR 0.95 for AF in men) to slightly deleterious (HR 1.12 for HS in men). We found no evidence of association of lower distal forearm BMD with CVD, AF, AMI, IS, HS, and HF.
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http://dx.doi.org/10.1007/s10654-021-00803-yDOI Listing
November 2021

Epidemiology of 40 blood biomarkers of one-carbon metabolism, vitamin status, inflammation, and renal and endothelial function among cancer-free older adults.

Sci Rep 2021 07 5;11(1):13805. Epub 2021 Jul 5.

Duke - NUS Medical School, Singapore, Singapore.

Imbalances of blood biomarkers are associated with disease, and biomarkers may also vary non-pathologically across population groups. We described variation in concentrations of biomarkers of one-carbon metabolism, vitamin status, inflammation including tryptophan metabolism, and endothelial and renal function among cancer-free older adults. We analyzed 5167 cancer-free controls aged 40-80 years from 20 cohorts in the Lung Cancer Cohort Consortium (LC3). Centralized biochemical analyses of 40 biomarkers in plasma or serum were performed. We fit multivariable linear mixed effects models to quantify variation in standardized biomarker log-concentrations across four factors: age, sex, smoking status, and body mass index (BMI). Differences in most biomarkers across most factors were small, with 93% (186/200) of analyses showing an estimated difference lower than 0.25 standard-deviations, although most were statistically significant due to large sample size. The largest difference was for creatinine by sex, which was - 0.91 standard-deviations lower in women than men (95%CI - 0.98; - 0.84). The largest difference by age was for total cysteine (0.40 standard-deviation increase per 10-year increase, 95%CI 0.36; 0.43), and by BMI was for C-reactive protein (0.38 standard-deviation increase per 5-kg/m increase, 95%CI 0.34; 0.41). For 31 of 40 markers, the mean difference between current and never smokers was larger than between former and never smokers. A statistically significant (p < 0.05) association with time since smoking cessation was observed for 8 markers, including C-reactive protein, kynurenine, choline, and total homocysteine. We conclude that most blood biomarkers show small variations across demographic characteristics. Patterns by smoking status point to normalization of multiple physiological processes after smoking cessation.
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http://dx.doi.org/10.1038/s41598-021-93214-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257595PMC
July 2021

Variants associated with expression have sex-differential effects on lung function.

Wellcome Open Res 2020 24;5:111. Epub 2021 May 24.

Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, EH4 2XU, UK.

Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P<5x10 ) interactions with sex on lung function, and 21 showed suggestive interactions (P<1x10 ). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV ) (P=3.15x10 ), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV more in males (untransformed FEV β=0.028 [SE 0.0022] litres) than females (β=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein ( ) gene and was previously associated with lung function and lung expression. We found expression was significantly different between the sexes (P=6.90x10 ), but we could not detect sex differential effects of rs7697189 on expression. We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the gene. Establishing the mechanism by which SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.
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http://dx.doi.org/10.12688/wellcomeopenres.15846.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938335.2PMC
May 2021

Lung function and peak oxygen uptake in chronic obstructive pulmonary disease phenotypes with and without emphysema.

PLoS One 2021 27;16(5):e0252386. Epub 2021 May 27.

Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.

Previous studies of associations of forced expiratory lung volume in one second (FEV1) with peak oxygen uptake (VO2peak) in chronic obstructive pulmonary disease (COPD) have not taken sex, age and height related variance of dynamic lung volumes into account. Nor have such demographic spread of spirometric measures been considered in studies comparing VO2peak between COPD phenotypes characterized by degree of emphysema. We aimed to assess the association of FEV1Z-score with VO2peak in COPD (n = 186) and investigate whether this association differs between emphysema (E-COPD) and non-emphysema (NE-COPD) phenotypes. Corresponding assessments using standardized percent predicted FEV1 (ppFEV1) were performed for comparison. Additionally, phenotype related differences in VO2peak were compared using FEV1Z-score and ppFEV1 as alternative expressions of FEV1. E-COPD and NE-COPD were defined by transfer factor of the lung for carbon monoxide below and above lower limits of normal (LLN), respectively. The associations were assessed in linear regression models. One unit reduction in FEV1Z-score was associated with 1.9 (95% CI 1.4, 2.5) ml/kg/min lower VO2peak. In stratified analyses, corresponding estimates were 2.2 (95% CI 1.4, 2.9) and 1.2 (95% CI 0.2, 2.2) ml/kg/min lower VO2peak in E-COPD and NE-COPD, respectively. The association did not differ statistically by COPD phenotype (p-value for interaction = 0.153). Similar estimates were obtained in analyses using standardized ppFEV1. Compared to NE-COPD, VO2peak was 2.2 (95% CI 0.8, 3.6) and 2.1 (95% CI 0.8, 3.5) ml/kg/min lower in E-COPD when adjusted for FEV1Z-score and ppFEV1, respectively. In COPD, FEV1Z-score is positively associated with VO2peak. This association was stronger in E-COPD but did not differ statistically by phenotype. Both the association of FEV1 with VO2peak and the difference in VO2peak comparing COPD phenotypes seems independent of sex, age and height related variance in FEV1. Mechanisms leading to reduction in FEV1 may contribute to lower VO2peak in E-COPD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0252386PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158861PMC
October 2021

Multimorbidity in Finnish and Swedish speaking Finns; association with daily habits and socioeconomic status - Nordic EpiLung cross-sectional study.

Prev Med Rep 2021 Jun 23;22:101338. Epub 2021 Feb 23.

Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.

Multimorbidity is an emerging public health priority. This study aims to assess the role of lifestyle and socioeconomic status in the prevalence of multimorbidity and chronic diseases by using two language groups that are part of the same genetic subgroup but differ by daily habits. We conducted a cross-sectional survey in 2016 with randomly selected population sample with 4173 responders (52.3%) aged 20-69 years in Western Finland. We included 3864 Finnish participants with Swedish (28.1%) or Finnish (71.9%) as a native language. We used a questionnaire to assess participants' chronic diseases and lifestyle. We determined multimorbidity as a disease count ≥ 2. Finnish speakers were more likely to have a diagnosis of COPD, heart failure, diabetes, reflux disease, chronic kidney failure, and painful conditions than Swedish speakers. The prevalence of multimorbidity was higher for Finnish speakers in the age group of 60-69 years (41.0% vs. 32.0%, p = 0.018) than Swedish speakers. A higher proportion of Finnish speakers smoked, were obese, inactive, and had lower socioeconomic status compared to Swedish speakers. All these factors, in addition to age and female sex, were significant risk factors for multimorbidity. Prevalence of multimorbidity was different in two language groups living in the same area and was associated with differences in lifestyle factors such as smoking, physical inactivity and obesity.
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http://dx.doi.org/10.1016/j.pmedr.2021.101338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937573PMC
June 2021

Assessing the role of genome-wide DNA methylation between smoking and risk of lung cancer using repeated measurements: the HUNT study.

Int J Epidemiol 2021 11;50(5):1482-1497

Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Norway.

Background: It is unclear if smoking-related DNA methylation represents a causal pathway between smoking and risk of lung cancer. We sought to identify novel smoking-related DNA methylation sites in blood, with repeated measurements, and to appraise the putative role of DNA methylation in the pathway between smoking and lung cancer development.

Methods: We derived a nested case-control study from the Trøndelag Health Study (HUNT), including 140 incident patients who developed lung cancer during 2009-13 and 140 controls. We profiled 850 K DNA methylation sites (Illumina Infinium EPIC array) in DNA extracted from blood that was collected in HUNT2 (1995-97) and HUNT3 (2006-08) for the same individuals. Epigenome-wide association studies (EWAS) were performed for a detailed smoking phenotype and for lung cancer. Two-step Mendelian randomization (MR) analyses were performed to assess the potential causal effect of smoking on DNA methylation as well as of DNA methylation (13 sites as putative mediators) on risk of lung cancer.

Results: The EWAS for smoking in HUNT2 identified associations at 76 DNA methylation sites (P < 5 × 10-8), including 16 novel sites. Smoking was associated with DNA hypomethylation in a dose-response relationship among 83% of the 76 sites, which was confirmed by analyses using repeated measurements from blood that was collected at 11 years apart for the same individuals. Two-step MR analyses showed evidence for a causal effect of smoking on DNA methylation but no evidence for a causal link between DNA methylation and the risk of lung cancer.

Conclusions: DNA methylation modifications in blood did not seem to represent a causal pathway linking smoking and the lung cancer risk.
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http://dx.doi.org/10.1093/ije/dyab044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8580278PMC
November 2021

Asthma and asthma symptom control in relation to incidence of lung cancer in the HUNT study.

Sci Rep 2021 02 25;11(1):4539. Epub 2021 Feb 25.

Department of Public Health and Nursing, Faculty of Medicine and Health Science, Norwegian University of Science and Technology (NTNU), Postbox 8905, MTFS, N-7491, Trondheim, Norway.

Large prospective studies on asthma, especially asthma symptom control, as a potential risk factor for lung cancer are limited. We followed up 62,791 cancer-free Norwegian adults from 1995-1997 to 2017. Self-reported doctor-diagnosed asthma was categorized into active and non-active asthma. Levels of asthma symptom control were classified into controlled and partially controlled (including partly controlled and uncontrolled) according to the Global Initiative for Asthma guidelines. Incident lung cancer cases were ascertained from the Cancer Registry of Norway. Cox regression models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for possible associations. Totally, 984 participants developed lung cancer during a median follow-up of 21.1 years. After adjustment for smoking and other potential confounders, an increased incidence of lung cancer was found for adults with partially controlled asthma (HR 1.39, 95% CI 1.00-1.92) compared with those without asthma at baseline. Adults with active asthma had a tendency of increased lung cancer incidence (HR 1.29, 95% CI 0.95-1.75). Sensitivity analyses indicated that the observed associations were less likely resulted from reverse causation or residual confounding by smoking. Our findings suggested that proper control of asthma symptoms might contribute to a reduced incidence of lung cancer.
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http://dx.doi.org/10.1038/s41598-021-84012-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907333PMC
February 2021

Level of education and asthma control in adult-onset asthma.

J Asthma 2021 Mar 10:1-20. Epub 2021 Mar 10.

Krefting Research Center, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.

Objective: Education in itself and as a proxy for socioeconomic status, may influence asthma control, but remains poorly studied in adult-onset asthma. Our aim was to study the association between the level of education and asthma control in adult-onset asthma.

Methods: Subjects with current asthma with onset >15 years were examined within the Obstructive Lung Disease in Northern Sweden study (OLIN,  = 593), Seinäjoki Adult Asthma Study (SAAS,  = 200), and West Sweden Asthma Study (WSAS,  = 301) in 2009-2014 in a cross-sectional setting. Educational level was classified as primary, secondary and tertiary. Uncontrolled asthma was defined as Asthma Control Test (ACT) score ≤19. Altogether, 896 subjects with complete data on ACT and education were included (OLIN  = 511, SAAS  = 200 and WSAS  = 185).

Results: In each cohort and in pooled data of all cohorts, median ACT score was lower among those with primary education than in those with secondary and tertiary education. Uncontrolled asthma was most common among those with primary education, especially among daily ICS users (42.6% primary, 28.6% secondary and 24.2% tertiary;  = 0.001). In adjusted analysis, primary education was associated with uncontrolled asthma in daily ICS users (OR 1.92, 95% CI 1.15-3.20). When stratified by atopy, the association between primary education and uncontrolled asthma was seen in non-atopic (OR 3.42, 95% CI 1.30-8.96) but not in atopic subjects.

Conclusions: In high-income Nordic countries, lower educational level was a risk factor for uncontrolled asthma in subjects with adult-onset asthma. Educational level should be considered in the management of adult-onset asthma.
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http://dx.doi.org/10.1080/02770903.2021.1871742DOI Listing
March 2021

Mortality prediction in chronic obstructive pulmonary disease comparing the GOLD 2015 and GOLD 2019 staging: a pooled analysis of individual patient data.

ERJ Open Res 2020 Oct 2;6(4). Epub 2020 Nov 2.

Centre for Clinical Documentation and Evaluation, Northern Norway Regional Health Authority, Tromso, Norway.

In 2019, The Global Initiative for Chronic Obstructive Lung Disease (GOLD) modified the grading system for patients with COPD, creating 16 subgroups (1A-4D). As part of the COPD Cohorts Collaborative International Assessment (3CIA) initiative, we aim to compare the mortality prediction of the 2015 and 2019 COPD GOLD staging systems. We studied 17 139 COPD patients from the 3CIA study, selecting those with complete data. Patients were classified by the 2015 and 2019 GOLD ABCD systems, and we compared the predictive ability for 5-year mortality of both classifications. In total, 17 139 patients with COPD were enrolled in 22 cohorts from 11 countries between 2003 and 2017; 8823 of them had complete data and were analysed. Mean±sd age was 63.9±9.8 years and 62.9% were male. GOLD 2019 classified the patients in milder degrees of COPD. For both classifications, group D had higher mortality. 5-year mortality did not differ between groups B and C in GOLD 2015; in GOLD 2019, mortality was greater for group B than C. Patients classified as group A and B had better sensitivity and positive predictive value with the GOLD 2019 classification than GOLD 2015. GOLD 2015 had better sensitivity for group C and D than GOLD 2019. The area under the curve values for 5-year mortality were only 0.67 (95% CI 0.66-0.68) for GOLD 2015 and 0.65 (95% CI 0.63-0.66) for GOLD 2019. The new GOLD 2019 classification does not predict mortality better than the previous GOLD 2015 system.
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http://dx.doi.org/10.1183/23120541.00253-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682666PMC
October 2020

MEPE loss-of-function variant associates with decreased bone mineral density and increased fracture risk.

Nat Commun 2020 10 23;11(1):4093. Epub 2020 Oct 23.

Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, 1500 E. Medical Center Dr., Ann Arbor, MI, 48109, USA.

A major challenge in genetic association studies is that most associated variants fall in the non-coding part of the human genome. We searched for variants associated with bone mineral density (BMD) after enriching the discovery cohort for loss-of-function (LoF) mutations by sequencing a subset of the Nord-Trøndelag Health Study, followed by imputation in the remaining sample (N = 19,705), and identified ten known BMD loci. However, one previously unreported variant, LoF mutation in MEPE, p.(Lys70IlefsTer26, minor allele frequency [MAF] = 0.8%), was associated with decreased ultradistal forearm BMD (P-value = 2.1 × 10), and increased osteoporosis (P-value = 4.2 × 10) and fracture risk (P-value = 1.6 × 10). The MEPE LoF association with BMD and fractures was further evaluated in 279,435 UK (MAF = 0.05%, heel bone estimated BMD P-value = 1.2 × 10, any fracture P-value = 0.05) and 375,984 Icelandic samples (MAF = 0.03%, arm BMD P-value = 0.12, forearm fracture P-value = 0.005). Screening for the MEPE LoF mutations before adulthood could potentially prevent osteoporosis and fractures due to the lifelong effect on BMD observed in the study. A key implication for precision medicine is that high-impact functional variants missing from the publicly available cosmopolitan panels could be clinically more relevant than polygenic risk scores.
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http://dx.doi.org/10.1038/s41467-020-17315-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585430PMC
October 2020

Parallel gradients in F and in the prevalences of asthma and atopy in adult general populations of Sweden, Finland and Estonia - A Nordic EpiLung study.

Respir Med 2020 11 17;173:106160. Epub 2020 Sep 17.

Unit of Clinical Physiology, Helsinki University Central Hospital and University of Helsinki, Finland.

The prevalence of asthma is higher in Sweden and Finland than in neighbouring eastern countries including Estonia. Corresponding difference in bronchial eosinophilic inflammation could be studied by F measurements. We aimed to compare F in adult general populations of Sweden, Finland, and Estonia, to test the plausibility of the west-east disparity hypothesis of allergic diseases. We conducted clinical interviews (N = 2658) with participants randomly selected from the general populations in Sweden (Stockholm and Örebro), Finland (Helsinki), and Estonia (Narva and Saaremaa), and performed F (n = 1498) and skin prick tests (SPT) in 1997-2003. The median (interquartile range) of F (ppb) was 15.5 (9.3) in Sweden, 15.4 (13.6) in Finland and 12.5 (9.6) in Estonia. We found the lowest median F values in the Estonian centres Saaremaa 13.1 (9.5) and Narva 11.8 (8.6). In the pooled population, asthma was associated with F ≥25 ppb, odds ratio (OR) 3.91 (95% confidence intervals: 2.29-6.32) after adjusting for SPT result, smoking, gender and study centre. A positive SPT test increased the likelihood of asthma OR 3.19 (2.02-5.11). Compared to Saaremaa, the likelihood of having asthma was higher in Helsinki OR 2.40 (1.04-6.02), Narva OR 2.45 (1.05-6.19), Örebro OR 3.38 (1.59-8.09), and Stockholm OR 5.54 (2.18-14.79). There was a higher prevalence of asthma and allergic airway inflammation in adult general populations of Sweden and Finland compared to those of Estonia. Atopy and elevated F level were independently associated with an increased risk of asthma. In conclusion, the findings support the earlier west-east disparity hypothesis of allergic diseases.
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http://dx.doi.org/10.1016/j.rmed.2020.106160DOI Listing
November 2020

Sex differences between women and men with COPD: A new analysis of the 3CIA study.

Respir Med 2020 09 13;171:106105. Epub 2020 Aug 13.

Centre for Clinical Documentation and Evaluation (SKDE), Troms, Norway.

Background: There is partial evidence that COPD is expressed differently in women than in men, namely on symptoms, pulmonary function, exacerbations, comorbidities or prognosis. There is a need to improve the characterization of COPD in females.

Methods: We obtained and pooled data of 17 139 patients from 22 COPD cohorts and analysed the clinical differences by sex, establishing the relationship between these characteristics in women and the prognosis and severity of the disease. Comparisons were established with standard statistics and survival analysis, including crude and multivariate Cox-regression analysis.

Results: Overall, 5355 (31.2%) women were compared with men with COPD. Women were younger, had lower pack-years, greater FEV%, lower BMI and a greater number of exacerbations (all p < 0.05). On symptoms, women reported more dyspnea, equal cough but less expectoration (p < 0.001). There were no differences in the BODE index score in women (2.4) versus men (2.4) (p = 0.5), but the distribution of all BODE components was highly variable by sex within different thresholds of BODE. On prognosis, 5-year survival was higher in COPD females (86.9%) than in males (76.3%), p < 0.001, in all patients and within each of the specific comorbidities that we assessed. The crude and adjusted RR and 95% C.I. for death in males was 1.82 (1.69-1.96) and 1.73 (1.50-2.00), respectively.

Conclusions: COPD in women has some characteristic traits expressed differently than compared to men, mainly with more dyspnea and COPD exacerbations and less phlegm, among others, although long-term survival appears better in female COPD patients.
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http://dx.doi.org/10.1016/j.rmed.2020.106105DOI Listing
September 2020

The association of anxiety and depression with mortality in a COPD cohort. The HUNT study, Norway.

Respir Med 2020 09 5;171:106089. Epub 2020 Aug 5.

HUNT Research Centre, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Levanger, Norway.

Background: Anxiety and depression are prevalent among individuals with chronic obstructive pulmonary disease (COPD), but the impact of these comorbidities on long-term mortality is unknown.

Aims: This study aims to compare mortality in individuals with COPD who had or did not have symptoms of anxiety or depression as well as the impact of a change in these symptoms on mortality.

Methods: Individuals with COPD according to the Global Lung Initiative (GLI) LLN criteria (n = 2076) were recruited from the second (1995-97) and third (2006-08) surveys of the HUNT Study and followed until January 2019 for mortality. We assessed baseline status of anxiety or depression using the Hospital Anxiety and Depression Scale (HADS), and probable cases were defined by a score ≥8. We used Cox regression to calculate hazard ratios (HR) with 95% confidence intervals (CI). Change in HADS score over time was assessed using joint models.

Results: Among the individuals with COPD, 16.2% had symptoms of anxiety and 15.9% had symptoms of depression. Compared to those with HADS-A and -D score <8, symptoms of anxiety or depression increased mortality by 21% (95% CI 05-47%) and 21% (2-44%), respectively. Over the approximately 11-year period between surveys, change of HADS-A from ≥8 to <8 was associated with a decrease in mortality (HR 0.97 [95% CI 0.94-1.00]), but not in HADS-D (0.97 [95% CI 0.93-1.18]).

Conclusions: Individuals with COPD and symptoms of anxiety or depression have increased mortality, and improved HADS-A score with time is associated with lower mortality.
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http://dx.doi.org/10.1016/j.rmed.2020.106089DOI Listing
September 2020

Age-of-onset information helps identify 76 genetic variants associated with allergic disease.

PLoS Genet 2020 06 30;16(6):e1008725. Epub 2020 Jun 30.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Risk factors that contribute to inter-individual differences in the age-of-onset of allergic diseases are poorly understood. The aim of this study was to identify genetic risk variants associated with the age at which symptoms of allergic disease first develop, considering information from asthma, hay fever and eczema. Self-reported age-of-onset information was available for 117,130 genotyped individuals of European ancestry from the UK Biobank study. For each individual, we identified the earliest age at which asthma, hay fever and/or eczema was first diagnosed and performed a genome-wide association study (GWAS) of this combined age-of-onset phenotype. We identified 50 variants with a significant independent association (P<3x10-8) with age-of-onset. Forty-five variants had comparable effects on the onset of the three individual diseases and 38 were also associated with allergic disease case-control status in an independent study (n = 222,484). We observed a strong negative genetic correlation between age-of-onset and case-control status of allergic disease (rg = -0.63, P = 4.5x10-61), indicating that cases with early disease onset have a greater burden of allergy risk alleles than those with late disease onset. Subsequently, a multivariate GWAS of age-of-onset and case-control status identified a further 26 associations that were missed by the univariate analyses of age-of-onset or case-control status only. Collectively, of the 76 variants identified, 18 represent novel associations for allergic disease. We identified 81 likely target genes of the 76 associated variants based on information from expression quantitative trait loci (eQTL) and non-synonymous variants, of which we highlight ADAM15, FOSL2, TRIM8, BMPR2, CD200R1, PRKCQ, NOD2, SMAD4, ABCA7 and UBE2L3. Our results support the notion that early and late onset allergic disease have partly distinct genetic architectures, potentially explaining known differences in pathophysiology between individuals.
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http://dx.doi.org/10.1371/journal.pgen.1008725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367489PMC
June 2020

Differences in diagnostic patterns of obstructive airway disease between areas and sex in Sweden and Finland - the Nordic EpiLung study.

J Asthma 2021 09 13;58(9):1196-1207. Epub 2020 Jun 13.

Department of Public Health and Clinical Medicine, Section of Sustainable Health/the OLIN unit, Umeå University, Umeå, Sweden.

Objective: To investigate the current prevalence of physician-diagnosed obstructive airway diseases by respiratory symptoms and by sex in Sweden and Finland.

Method: In 2016, a postal questionnaire was answered by 34,072 randomly selected adults in four study areas: Västra Götaland and Norrbotten in Sweden, and Seinäjoki-Vaasa and Helsinki in Finland.

Results: The prevalence of asthma symptoms was higher in Norrbotten (13.2%), Seinäjoki-Vaasa (14.8%) and Helsinki (14.4%) than in Västra Götaland (10.7%), and physician-diagnosed asthma was highest in Norrbotten (13.0%) and least in Västra Götaland (10.1%). Chronic productive cough was most common in the Finnish areas (7.7-8.2% versus 6.3-6.7%) while the prevalence of physician-diagnosed chronic bronchitis (CB) or chronic obstructive pulmonary disease (COPD) varied between 1.7 and 2.7% in the four areas. Among individuals with respiratory symptoms, the prevalence of asthma was most common in Norrbotten, while a diagnosis of COPD or CB was most common in Västra Götaland and Seinäjoki-Vaasa. More women than men with respiratory symptoms reported a diagnosis of asthma in Sweden and Seinäjoki-Vaasa but there were no sex differences in Helsinki. In Sweden, more women than men with symptoms of cough or phlegm reported a diagnosis of CB or COPD, while in Finland the opposite was found.

Conclusion: The prevalence of respiratory symptoms and corresponding diagnoses varied between and within the countries. The proportion reporting a diagnosis of obstructive airway disease among individuals with respiratory symptoms varied, indicating differences in diagnostic patterns both between areas and by sex.
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http://dx.doi.org/10.1080/02770903.2020.1776727DOI Listing
September 2021

The association between normal lung function and peak oxygen uptake in patients with exercise intolerance and coronary artery disease.

PLoS One 2020 4;15(5):e0232693. Epub 2020 May 4.

Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.

In coronary artery disease (CAD), exercise intolerance with reduced oxygen uptake at peak exercise (VO2peak) is assumed to primarily reflect cardiovascular limitation. However, oxygen transport and utilization depends on an integrated organ response, to which the normal pulmonary system may influence overall capacity. This study aimed to investigate the associations between normal values of lung function measures and VO2peak in patients with exercise intolerance and CAD. We hypothesized that forced expiratory lung volume in one second (FEV1), transfer factor of the lung for carbon monoxide (TLCO) and TLCO/alveolar volume (TLCO/VA) above lower limits of normal (LLN) are associated with VO2peak in these patients. We assessed patients with established CAD (n = 93; 21 women) referred for evaluation due to exercise intolerance from primary care to a private specialist clinic in Norway. Lung function tests and cardiopulmonary exercise testing (CPET) were performed. Z-scores of FEV1, FEV1/forced vital capacity (FVC), TLCO and TLCO/VA were calculated using the Global Lung Function Initiative (GLI) software and LLN was defined as the fifth percentile (z = -1.645). Non-obstructive patients, defined by both FEV1 and FEV1/FVC above LLN, were assessed. The associations of FEV1Z-score, TLCOZ-score and TLCO/VAZ-score above LLN with VO2peak were investigated using linear regression models. Mean VO2peak ± standard deviation (SD) was 23.8 ± 6.4 ml/kg/min in men and 19.7 ± 4.4 ml/kg/min in women. On average, one SD increase in FEV1, TLCO and TLCO/VA were associated with 1.4 (95% CI 0.2, 2.6), 2.6 (95% CI 1.2, 4.0) and 1.3 (95% CI 0.2, 2.5) ml/kg/min higher VO2peak, respectively. In non-obstructive patients with exercise intolerance and CAD, FEV1, TLCO and TLCO/VA above LLN are positively associated with VO2peak. This may imply a clinically significant influence of normal lung function on exercise capacity in these patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232693PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197783PMC
August 2020

Is the Disease Burden from COPD in Norway Falling off? A Study of Time Trends in Three Different Data Sources.

Int J Chron Obstruct Pulmon Dis 2020 12;15:323-334. Epub 2020 Feb 12.

Norwegian Institute of Public Health, Department of Non-Communicable Diseases, Oslo, Norway.

Background: Less smoking should lead to fewer COPD cases. We aimed at estimating time trends in the prevalence and burden of COPD in Norway from 2001 to 2017.

Methods: We used pre-bronchodilator spirometry and other health data from persons aged 40-84 years in three surveys of the Tromsø Study, 2001-2002, 2007-2008 and 2015-2016. We applied spirometry lower limits of normal (LLN) according to Global Lung Initiative 2012. Age-standardized prevalence was determined. We defined COPD as FEV/FVC
Results: In the Tromsø Study, the age-standardized prevalence of daily smoking dropped from 29.9% to 14.1% among women and from 31.4% to 12.8% among men (<0.0001). The age-standardized prevalence of COPD dropped from 7.6% to 5.6% among women (=0.2) and from 7.3% to 5.6% among men (=0.003) and of moderate to severe COPD from 5.2% to 2.7% among women (=0.0003) and from 4.6% to 3.2% among men (=0.0008). Among men, the yearly age-standardized prevalence of hospitalization due to COPD exacerbation decreased from 3.6 to 3.0 per 1000 inhabitants aged 40-84 years (<0.0001). Correspondingly, dispensing oral corticosteroids or/and antibiotics for COPD exacerbations dropped from 6.6 to 5.8 per 1000 (<0.0001), while dispensing maintenance treatment increased (<0.0001).

Conclusion: COPD morbidity decreased between 2001 and 2017, which might partly be due to less smoking. The drop in smoking prevalence gives promise of a further substantial decrease in the coming decades.
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http://dx.doi.org/10.2147/COPD.S235106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024866PMC
February 2021

GOLD Classifications, COPD Hospitalization, and All-Cause Mortality in Chronic Obstructive Pulmonary Disease: The HUNT Study.

Int J Chron Obstruct Pulmon Dis 2020 31;15:225-233. Epub 2020 Jan 31.

Clinic of Thoracic and Occupational Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.

Purpose: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) has published three classifications of COPD from 2007 to 2017. No studies have investigated the ability of these classifications to predict COPD-related hospitalizations. We aimed to compare the discrimination ability of the GOLD 2007, 2011, and 2017 classifications to predict COPD hospitalization and all-cause mortality.

Patients And Methods: We followed 1300 participants with COPD aged ≥40 years who participated in the HUNT Study (1995-1997) through to December 31, 2015. Survival analysis and time-dependent area under receiver operating characteristics curves (AUC) were used to compare the discrimination abilities of the GOLD classifications.

Results: Of the 1300 participants, 522 were hospitalized due to COPD and 896 died over 20.4 years of follow-up. In adjusted models, worsening GOLD 2007, GOLD 2011, or GOLD 2017 categories were associated with higher hazards for COPD hospitalization and all-cause mortality, except for the GOLD 2017 classification and all-cause mortality (p=0.114). In crude models, the AUCs (95% CI) for the GOLD 2007, GOLD 2011, and GOLD 2017 for COPD hospitalization were 63.1 (58.7-66.9), 60.9 (56.1-64.4), and 56.1 (54.0-58.1), respectively, at 20-years' follow-up. Corresponding estimates for all-cause mortality were 57.0 (54.8-59.1), 54.1 (52.1-56.0), and 52.6 (51.0-54.3). The differences in AUCs between the GOLD classifications to predict COPD hospitalization and all-cause mortality were constant over the follow-up time.

Conclusion: The GOLD 2007 classification was better than the GOLD 2011 and 2017 classifications at predicting COPD hospitalization and all-cause mortality.
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http://dx.doi.org/10.2147/COPD.S228958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6999582PMC
February 2021

Smoking related lung cancer mortality by education and sex in Norway.

BMC Cancer 2019 Nov 21;19(1):1132. Epub 2019 Nov 21.

Department of Community Medicine, Faculty of Health Sciences, The UiT Arctic University of Norway, Tromsø, Norway.

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http://dx.doi.org/10.1186/s12885-019-6330-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873553PMC
November 2019

The Association of Bone Mineral Density with Mortality in a COPD Cohort. The HUNT Study, Norway.

COPD 2019 12 11;16(5-6):321-329. Epub 2019 Nov 11.

HUNT Research Centre, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Levanger, Norway.

In individuals with chronic obstructive pulmonary disease (COPD), the presence of comorbidities is associated with increased mortality risk. We wanted to study the association between bone mineral density (BMD) and mortality among individuals with COPD in a population-based cohort study. Participants were recruited from the second (1995-1997) and third (2006-2008) surveys of the HUNT Study and followed until February 2019. Hip and forearm BMD were included as continuous -scores or categorized according to WHO criteria (normal, osteopenia, and osteoporosis). Hazard ratios with 95% confidence intervals were estimated by multivariable Cox regression models. In total, 2076 and 3239 participants were identified as having COPD by FEV/FVC below lower limit of normal (LLN) or <0.70, respectively, according to Global Lung Initiative (GLI) and Global Initiative for Chronic Obstructive Lung Disease (GOLD). The prevalence of osteoporosis was 15.7% vs. 16.6% in the GLI-COPD vs. GOLD-COPD cohorts. Mean follow-up was 12.7 and 11.9 years. Lower -scores were associated with a 5% (95% confidence interval (CI) 1.01-1.09) increased mortality in the GLI-COPD and GOLD-COPD cohorts, respectively. However, the presence of osteoporosis ( < -2.5), compared to normal BMD, was not associated with mortality in neither GLI-COPD (HR 1.13, 95% CI 0.91-1.41) nor GOLD-COPD cohorts (HR 1.22, 95% CI 0.99-1.51). Thus, a small positive association was found between decreasing BMD -score and mortality in both GLI-COPD and GOLD-COPD. However, osteoporosis as defined by WHO was not associated with mortality, probably due to loss of power upon categorization.
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http://dx.doi.org/10.1080/15412555.2019.1685482DOI Listing
December 2019

Adiposity and asthma in adults: a bidirectional Mendelian randomisation analysis of The HUNT Study.

Thorax 2020 03 14;75(3):202-208. Epub 2019 Oct 14.

Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Norway

Background: We aimed to investigate the potential causal associations of adiposity with asthma overall, asthma by atopic status or by levels of symptom control in a large adult population and stratified by sex. We also investigated the potential for reverse causation between asthma and risk of adiposity.

Methods: We performed a bidirectional one-sample Mendelian randomisation (MR) study using the Norwegian Nord-Trøndelag Health Study population including 56 105 adults. 73 and 47 genetic variants were included as instrumental variables for body mass index (BMI) and waist-to-hip ratio (WHR), respectively. Asthma was defined as ever asthma, doctor-diagnosed asthma and doctor-diagnosed active asthma, and was further classified by atopic status or levels of symptom control. Causal OR was calculated with the Wald method.

Results: The ORs per 1 SD (4.1 kg/m) increase in genetically determined BMI were ranged from 1.36 to 1.49 for the three asthma definitions and similar for women and men. The corresponding ORs for non-atopic asthma (range 1.42-1.72) appeared stronger than those for the atopic asthma (range 1.18-1.26), but they were similar for controlled versus partly controlled doctor-diagnosed active asthma (1.43 vs 1.44). There was no clear association between genetically predicted WHR and asthma risk or between genetically predicted asthma and the adiposity markers.

Conclusions: Our MR study provided evidence of a causal association of BMI with asthma in adults, particularly with non-atopic asthma. There was no clear evidence of a causal link between WHR and asthma or of reverse causation.
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http://dx.doi.org/10.1136/thoraxjnl-2019-213678DOI Listing
March 2020

Asthma, asthma control and risk of acute myocardial infarction: HUNT study.

Eur J Epidemiol 2019 Oct 11;34(10):967-977. Epub 2019 Sep 11.

Department of Public Health and Nursing, Faculty of Medicine and Health Science, NTNU, Norwegian University of Science and Technology, Postbox 8905, 7491, Trondheim, Norway.

Asthma, a chronic inflammatory airway disease, shares several common pathophysiological mechanisms with acute myocardial infarction (AMI). Our aim was to assess the prospective associations between asthma, levels of asthma control and risk of AMI. We followed 57,104 adults without previous history of AMI at baseline from Nord-Trøndelag health study (HUNT) in Norway. Self-reported asthma was categorised as active asthma (i.e., using asthma medication) and non-active asthma (i.e., not using asthma medication). Levels of asthma control were defined as controlled, partly controlled, and uncontrolled based on the Global Initiative for Asthma guidelines. AMI was ascertained by linking HUNT data with hospital records. A total of 2868 AMI events (5.0%) occurred during a mean (SD) follow-up of 17.2 (5.4) years. Adults with active asthma had an estimated 29% higher risk of developing AMI [adjusted hazard ratio (HR) 1.29, 95% CI 1.08-1.54] compared with adults without asthma. There was a significant dose-response association between asthma control and AMI risk, with highest risk in adults with uncontrolled asthma (adjusted HR 1.73, 95% CI 1.13-2.66) compared to adults with controlled asthma (p for trend < 0.05). The associations were not explained by smoking status, physical activity and C-reactive protein levels. Our study suggests that active asthma and poor asthma control are associated with moderately increased risk of AMI. Further studies are needed to evaluate causal relationship and the underlying mechanisms and to clarify the role of asthma medications in the risk of AMI.
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http://dx.doi.org/10.1007/s10654-019-00562-xDOI Listing
October 2019

Comparison of pre- and post-bronchodilator lung function as predictors of mortality: The HUNT Study.

Respirology 2020 04 24;25(4):401-409. Epub 2019 Jul 24.

MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.

Background And Objective: Post-bronchodilator (BD) lung function is recommended for the diagnosis of chronic obstructive pulmonary disease (COPD). However, often only pre-BD lung function is used in clinical practice or epidemiological studies. We aimed to compare the discrimination ability of pre-BD and post-BD lung function to predict all-cause mortality.

Methods: Participants aged ≥40 years with airflow limitation (n = 2538) and COPD (n = 1262) in the second survey of the Nord-Trøndelag Health Study (HUNT2, 1995-1997) were followed up until 31 December 2015. Survival analysis and time-dependent area under the receiver operating characteristic curves (AUC) were used to compare the discrimination ability of pre-BD and post-BD lung function (percent-predicted forced expiratory volume in the first second (FEV ) (ppFEV ), FEV z-score, FEV quotient (FEV Q), modified Global Initiative for Chronic Obstructive Lung Disease (GOLD) categories or GOLD grades).

Results: Among 2538 participants, 1387 died. The AUC for pre-BD and post-BD ppFEV to predict mortality were 60.8 and 61.8 (P = 0.005), respectively, at 20 years' follow-up. The corresponding AUC for FEV z-score were 58.5 and 60.4 (P < 0.001), for FEV Q were 68.7 and 70.1 (P = 0.002) and for modified GOLD categories were 62.3 and 64.5 (P < 0.001). Among participants with COPD, the AUC for pre-BD and post-BD ppFEV were 57.0 and 58.8 (P < 0.001), respectively. The corresponding AUC for FEV z-score were 53.1 and 55.8 (P < 0.001), for FEV Q were 63.6 and 65.1 (P = 0.037) and for GOLD grades were 56.0 and 57.0 (P = 0.268).

Conclusion: Mortality was better predicted by post-BD than by pre-BD lung function; however, they differed only by a small margin. The discrimination ability using GOLD grades among COPD participants was similar.
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http://dx.doi.org/10.1111/resp.13648DOI Listing
April 2020

Circulating markers of cellular immune activation in prediagnostic blood sample and lung cancer risk in the Lung Cancer Cohort Consortium (LC3).

Int J Cancer 2020 05 22;146(9):2394-2405. Epub 2019 Jul 22.

Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN.

Cell-mediated immune suppression may play an important role in lung carcinogenesis. We investigated the associations for circulating levels of tryptophan, kynurenine, kynurenine:tryptophan ratio (KTR), quinolinic acid (QA) and neopterin as markers of immune regulation and inflammation with lung cancer risk in 5,364 smoking-matched case-control pairs from 20 prospective cohorts included in the international Lung Cancer Cohort Consortium. All biomarkers were quantified by mass spectrometry-based methods in serum/plasma samples collected on average 6 years before lung cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer associated with individual biomarkers were calculated using conditional logistic regression with adjustment for circulating cotinine. Compared to the lowest quintile, the highest quintiles of kynurenine, KTR, QA and neopterin were associated with a 20-30% higher risk, and tryptophan with a 15% lower risk of lung cancer (all p < 0.05). The strongest associations were seen for current smokers, where the adjusted ORs (95% CIs) of lung cancer for the highest quintile of KTR, QA and neopterin were 1.42 (1.15-1.75), 1.42 (1.14-1.76) and 1.45 (1.13-1.86), respectively. A stronger association was also seen for KTR and QA with risk of lung squamous cell carcinoma followed by adenocarcinoma, and for lung cancer diagnosed within the first 2 years after blood draw. This study demonstrated that components of the tryptophan-kynurenine pathway with immunomodulatory effects are associated with risk of lung cancer overall, especially for current smokers. Further research is needed to evaluate the role of these biomarkers in lung carcinogenesis and progression.
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http://dx.doi.org/10.1002/ijc.32555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960354PMC
May 2020

in relation to asthma and allergy modified by abdominal obesity: The HUNT study in Norway.

World Allergy Organ J 2019 6;12(5):100035. Epub 2019 Jun 6.

Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California Irvine, USA.

Objective: It is unknown whether the decreasing prevalence of infections is associated with the increase in obesity and asthma and allergy. In this study, we assessed if obesity plays an intermediate role between . infections and allergy.

Design: A population-based, nested case-control study of 10,005 participants within the second Nord-Trøndelag Health Study (HUNT2), Norway, was performed in 1995-1997. The presence of was tested by an enzyme immunoassay Pyloriset EIA-IgG, and weight, height, and waist circumference were measured. Body mass index (BMI) and waist circumference were used as measures of general and abdominal obesity, respectively. Self-reported asthma and allergic diseases were collected through questionnaires. The odds ratios of relative to asthma and allergic diseases were estimated by logistic regression models stratified by waist circumference categories.

Results: infection was present in 31%, ever asthma was reported in 10.4% and allergic rhinitis in 16.2%. The mean BMI was 26.4 ​kg/m and the mean waist circumference was 86.6 ​cm. infection was neither associated with asthma nor allergic diseases. However, when stratified by waist circumference, infection was associated with 30-40% reduced odds of asthma and 25% reduced odds of allergic diseases in individuals with abdominal obesity (waist circumference ≥86 ​cm in women and ≥96 ​cm in men).

Conclusion: infection is associated with reduced risk of asthma and allergy in individuals with abdominal obesity, suggesting a possible causal pathway from reduced infections through obesity to increased risk of asthma and allergy.
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http://dx.doi.org/10.1016/j.waojou.2019.100035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555905PMC
June 2019

External Validation and Recalculation of the CODEX Index in COPD Patients. A 3CIAplus Cohort Study.

COPD 2019 02 14;16(1):8-17. Epub 2019 Mar 14.

ae Servicio de Neumología , Hospital Universitario de la Princesa (IISP), Universidad Autónoma de Madrid, Cátedra UAM-Linde , Madrid , Spain.

The CODEX index was developed and validated in patients hospitalized for COPD exacerbation to predict the risk of death and readmission within one year after discharge. Our study aimed to validate the CODEX index in a large external population of COPD patients with variable durations of follow-up. Additionally, we aimed to recalculate the thresholds of the CODEX index using the cutoffs of variables previously suggested in the 3CIA study (mCODEX). Individual data on 2,755 patients included in the COPD Cohorts Collaborative International Assessment Plus (3CIA+) were explored. A further two cohorts (ESMI AND EGARPOC-2) were added. To validate the CODEX index, the relationship between mortality and the CODEX index was assessed using cumulative/dynamic ROC curves at different follow-up periods, ranging from 3 months up to 10 years. Calibration was performed using univariate and multivariate Cox proportional hazard models and Hosmer-Lemeshow test. A total of 3,321 (87.8% males) patients were included with a mean ± SD age of 66.9 ± 10.5 years, and a median follow-up of 1,064 days (IQR 25-75% 426-1643), totaling 11,190 person-years. The CODEX index was statistically associated with mortality in the short- (≤3 months), medium- (≤1 year) and long-term (10 years), with an area under the curve of 0.72, 0.70 and 0.76, respectively. The mCODEX index performed better in the medium-term (<1 year) than the original CODEX, and similarly in the long-term. In conclusion, CODEX and mCODEX index are good predictors of mortality in patients with COPD, regardless of disease severity or duration of follow-up.
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http://dx.doi.org/10.1080/15412555.2018.1484440DOI Listing
February 2019

Prolonged Sitting, Its Combination With Physical Inactivity and Incidence of Lung Cancer: Prospective Data From the HUNT Study.

Front Oncol 2019 25;9:101. Epub 2019 Feb 25.

Department of Public Health and Nursing, Faculty of Medicine and Health Science, Norwegian University of Science and Technology, Trondheim, Norway.

Prolonged sitting as a major sedentary behavior potentially contributes to illness, but its relation with lung cancer risk is unclear. Prolonged sitting can be presented in physically active or inactive individuals. Those who are extendedly seated and also physically inactive may represent the most sedentary people. We therefore aimed to prospectively examine if total sitting time daily itself or in combination with physical activity is associated with lung cancer incidence overall and histologic types. We included 45,810 cancer-free adults who participated in the second survey of HUNT Study in Norway (1995-97), with a median follow-up of 18.3 years. Total sitting time daily and physical activity were self-reported at baseline. Lung cancer cases were ascertained from the Cancer Registry of Norway. Cox regression was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). In total, 549 participants developed lung cancer during the follow-up. Total sitting time daily was not associated with the incidence of lung cancer overall and histologic subtypes. Compared with participants sitting < 8 h daily and being physically active, those sitting ≥8 h daily (prolonged sitting) and being physically inactive had an increased incidence of lung cancer (overall: adjusted HR = 1.44, 95% CI: 1.07-1.94; small cell lung cancer: adjusted HR = 2.58, 95% CI: 1.23-5.41). Prolonged sitting only or physical inactivity only was not associated with the incidence of lung cancer. Our study suggested that prolonged sitting was not independently associated with lung cancer incidence. The combination of prolonged sitting and physical inactivity might increase the risk of lung cancer. However, residual confounding by smoking cannot be excluded completely even though smoking was adjusted for with detailed information.
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http://dx.doi.org/10.3389/fonc.2019.00101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397867PMC
February 2019
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