Level of Education Modifies Asthma Mortality in Norway and Sweden. The Nordic EpiLung Study.

Background and Aim: The relationship between socioeconomic status (SES), asthma and mortality is complex and multifaceted, and it is not established if educational level modifies the association between asthma and mortality. The aim was to study the association between asthma and mortality in Sweden and Norway and to what extent educational level modifies this association. Participants and Methods: Within the Nordic EpiLung Study, >56,000 individuals aged 30-69 years participated in population-based surveys on asthma and associated risk factors in Sweden and Norway during 2005-2007. Data on educational level and 10-year all-cause mortality were linked by national authorities. The fraction of mortality risk attributable to asthma was calculated, and Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for mortality related to asthma, stratified by educational level. Results: In total, 5.5% of all deaths was attributed to asthma. When adjusted for potential confounders, the HR for mortality related to asthma was 1.71 (95% CI 1.52-1.93). Those with primary level of education had higher hazard of all-cause death related to asthma than those with tertiary level (HR 1.80, 95% CI 1.48-2.18, vs HR 1.39, 95% CI 0.99-1.95). Conclusion: Asthma was associated with an overall 71% increased all-cause mortality and 5.5% of deaths can be attributed to asthma. Educational levels modified the risk of mortality associated with asthma, with the highest risk among those with primary education.

Agreement between self-reported and registered age at asthma diagnosis in Finland.

INTRODUCTION: In epidemiological studies, the age at asthma onset is often defined by patients' self-reported age at diagnosis. The reliability of this report might be questioned. Our objective was to evaluate the agreement between self-reported and registered age at asthma diagnosis and assess features contributing to the agreement. METHODS: As part of the FinEsS respiratory survey in 2016, randomly selected population samples of 13,435 from Helsinki and 8000 from Western Finland were studied. Self-reported age at asthma diagnosis was compared to age at asthma diagnosis registered in the Finnish register on special reimbursement for asthma medication. The reimbursement right is based on lung function criteria according to GINA and Finnish guidelines. If the difference was less than 5 years, self-reported diagnosis was considered reliable. Features associated with the difference between self-reported and registered age at asthma diagnosis were evaluated. RESULTS: Altogether 197 subjects from Helsinki and 144 from Western Finland were included. Of these, 61.9% and 77.8%, respectively, reported age at diagnosis reliably. Median difference between self-reported and registered age at diagnoses was - 2.0 years (IQR - 9.0 to 0) in Helsinki and - 1.0 (IQR - 4.3 to 0) in Western Finland indicating earlier self-reported age at diagnosis. More reliable self-report was associated with non-allergic subjects and subjects who reported having asthma diagnosis more recently. CONCLUSIONS: Agreement between self-reported and registered age at asthma diagnosis was good especially with adult-onset asthma patients. Poor agreement in early-onset asthma could be related to delay in registration due to reimbursement criteria.

Large-scale circulating proteome association study (CPAS) meta-analysis identifies circulating proteins and pathways predicting incident hip fractures.

Hip fractures are associated with significant disability, high cost, and mortality. However, the exact biological mechanisms underlying susceptibility to hip fractures remain incompletely understood. In an exploratory search of the underlying biology as reflected through the circulating proteome, we performed a comprehensive Circulating Proteome Association Study (CPAS) meta-analysis for incident hip fractures. Analyses included 6430 subjects from two prospective cohort studies (Cardiovascular Health Study and Trøndelag Health Study) with circulating proteomics data (aptamer-based 5 K SomaScan version 4.0 assay; 4979 aptamers). Associations between circulating protein levels and incident hip fractures were estimated for each cohort using age and sex-adjusted Cox regression models. Participants experienced 643 incident hip fractures. Compared with the individual studies, inverse-variance weighted meta-analyses yielded more statistically significant associations, identifying 23 aptamers associated with incident hip fractures (conservative Bonferroni correction 0.05/4979, P < 1.0 × 10-5). The aptamers most strongly associated with hip fracture risk corresponded to two proteins of the growth hormone/insulin growth factor system (GHR and IGFBP2), as well as GDF15 and EGFR. High levels of several inflammation-related proteins (CD14, CXCL12, MMP12, ITIH3) were also associated with increased hip fracture risk. Ingenuity pathway analysis identified reduced LXR/RXR activation and increased acute phase response signaling to be overrepresented among those proteins associated with increased hip fracture risk. These analyses identified several circulating proteins and pathways consistently associated with incident hip fractures. These findings underscore the usefulness of the meta-analytic approach for comprehensive CPAS in a similar manner as has previously been observed for large-scale human genetic studies. Future studies should investigate the underlying biology of these potential novel drug targets.

Hip fractures are associated with significant disability, high cost, and mortality. However, the exact biological mechanisms underlying susceptibility to hip fractures remain incompletely understood. To increase the understanding of the underlying mechanisms, we performed a meta-analysis of the associations between 4860 circulating proteins and risk of fractures using two large cohorts, including 6430 participants with 643 incident hip fractures. We identified 23 proteins/aptamers associated with incident hip fractures. Two proteins of the growth hormone/insulin growth factor system (GHR and IGFBP2), as well as GDF15 and EGFR were most strongly associated with hip fracture risk. High levels of several inflammation-related proteins were also associated with increased hip fracture risk. Pathway analysis identified reduced LXR/RXR activation and increased acute phase response signaling to be overrepresented among those proteins associated with increased hip fracture risk. Future mechanistic studies should investigate the underlying biology of these novel protein biomarkers which may be potential drug targets.

Is there still a social gradient in respiratory symptoms? A population-based Nordic EpiLung-study.

BACKGROUND: Respiratory symptoms are a common public health issue that can partly be attributed to preventable risk factors, such as tobacco smoking and occupational exposure, which are more common in individuals with lower socioeconomic status. OBJECTIVE: Our aim was to evaluate the social gradient in respiratory symptoms in Nordic countries. METHODS: This study included participants aged 30-65 years from five cross-sectional population-based questionnaire surveys in 2016 in Finland and Sweden (N = 25,423) and in 2017-2019 in Norway (N = 27,107). Occupational skill levels 1 and 2 (occupations requiring compulsory education) were combined and compared to skill levels 3 and 4 (occupations requiring upper secondary and tertiary education). Meta-analysis was conducted to obtain pooled age- and sex adjusted odds ratios (aORs) of associations between occupational skill and the respiratory symptoms including recurrent wheeze, dyspnoea, and productive cough. RESULTS: In the meta-analysis, recurrent wheeze, dyspnoea, and productive cough showed a social gradient. The participants with occupational skill 1 and 2 had higher risk for recurrent wheeze (aOR 1.78, 95% CI 1.34-2.22) and dyspnoea (aOR 1.59, 95% CI 1.29-1.90) compared to occupational skill 3 and 4 in Sweden and Finland. Similarly increased risk was observed for combined assessment of dyspnoea and wheeze (aOR 1.05, 95% CI 1.03-1.07) in Norway. In a meta-analysis including all three countries, the aOR for productive cough was 1.31 95% CI 1.07-1.56. CONCLUSIONS: Occupations with lower, compared to higher, skill levels were associated with an increased risk of recurrent wheeze, dyspnoea, and productive cough.

Rheumatoid arthritis, disease-modifying antirheumatic drugs and risk of major osteoporotic fracture: prospective data from the HUNT Study, Norway.

OBJECTIVES: Rheumatoid arthritis has been associated with increased fracture risk. New treatments have improved the course of the disease substantially, but it is not clear if this influences fracture risk. We examined if rheumatoid arthritis, overall and according to disease-modifying antirheumatic drugs (DMARDs), is associated with a risk of major osteoporotic fractures. METHODS: Overall, 92 285 participants in the population-based Nord-Trndelag Health Study (HUNT), Norway were included and linked with hospital records for a validated rheumatoid arthritis diagnosis (n=605), type of DMARD treatment and fracture diagnosis. Participants were followed up until the first major osteoporotic fracture, death, emigration or end of follow-up. Cox regression was used to estimate HRs for fractures among individuals with rheumatoid arthritis, overall and by DMARD treatment, compared with participants without rheumatoid arthritis. RESULTS: A total of 9670 fractures were observed during follow-up, of which 88 were among those with rheumatoid arthritis. Compared with the reference group of participants without rheumatoid arthritis, those with the disease had an HR of fracture of 1.41 (95% CI 1.13 to 1.74). The association was largely similar for users of csDMARDs (HR 1.44; 95% CI 1.15 to 1.81), whereas the association for bDMARD users was weaker and less precise (HR 1.19; 95% CI 0.64 to 2.21). CONCLUSION: Participants with rheumatoid arthritis had a 40% higher risk of fracture than participants without the disease. A similar fracture risk was observed for conventional synthetic DMARD use, whereas there was weak evidence that the use of biological DMARDs may be associated with a somewhat lower fracture risk.

Occupational exposure to vapors, gasses, dusts, and fumes in relation to causes of death during 24 years in Helsinki, Finland.

PURPOSE: Environmental particulate matter (PM) exposure has been shown to cause excess all-cause and disease-specific mortality. Our aim was to compare disease-specific mortality by estimated occupational exposure to vapors, gasses, dusts, and fumes (VGDF). METHODS: The data source is the Helsinki part of the population-based FinEsS study on chronic obstructive pulmonary diseases including information on age, education level, main occupation, sex, and tobacco smoking combined with death registry information. We compared estimated VGDF exposure to mortality using adjusted competing-risks regression for disease-specific survival analysis for a 24-year follow-up. RESULTS: Compared to the no-exposure group, the high occupational VGDF exposure group had sub-hazard ratios (sHR) of 1.7 (95% CI 1.3-2.2) for all cardiovascular-related and sHR 2.1 (1.5-3.9) for just coronary artery-related mortality. It also had sHR 1.7 (1.0-2.8) for Alzheimer's or vascular dementia-related mortality and sHR 1.7(1.2-2.4) for all respiratory disease-related mortality. CONCLUSION: Long-term occupational exposure to VGDF increased the hazard of mortality- to cardiovascular-, respiratory-, and dementia-related causes. This emphasizes the need for minimizing occupational long-term respiratory exposure to dust, gasses, and fumes.

National health registries - a 'goldmine' for studying non-communicable disease occurrence in Norway - the NCDNOR project.

To estimate occurrence of non-communicable diseases (NCDs) over the life-course in the Norwegian population, national health registries are a vital source of information since they fully represent the entire non-institutionalised population. However, as they are mainly established for administrative purposes, more knowledge about how NCDs are recorded in the registries is needed. To establish this, we begin by counting the number of individuals registered annually with one or more NCDs in any of the registries. The study population includes all inhabitants who lived in Norway from 2004 to 2020 (N~6.4m). The NCD outcomes are diabetes, cardiovascular diseases, chronic obstructive lung diseases, cancer and mental disorders/substance use disorders. Further, we included hip fractures in our NCD concept. The data sources used to identify individuals with NCDs, including detailed information on diagnoses in primary and secondary health care and dispensings of prescription drugs, are the Cancer Registry of Norway, The Norwegian Patient Registry, The Norwegian Control and Payment of Health Reimbursement database, and The Norwegian Prescription Database. The number of individuals registered annually with an NCD diagnosis and/or a dispensed NCD drug increased over the study period. Changes over time may reflect changes in disease incidence and prevalence, but also changes in disease-specific guidelines, reimbursement schemes and access to and use of health services. Data from more than one health registry to identify individuals with NCDs are needed since the registries reflect different levels of health care services and therefore may reflect disease severity.

An atlas of genetic determinants of forearm fracture.

Osteoporotic fracture is among the most common and costly of diseases. While reasonably heritable, its genetic determinants have remained elusive. Forearm fractures are the most common clinically recognized osteoporotic fractures with a relatively high heritability. To establish an atlas of the genetic determinants of forearm fractures, we performed genome-wide association analyses including 100,026 forearm fracture cases. We identified 43 loci, including 26 new fracture loci. Although most fracture loci associated with bone mineral density, we also identified loci that primarily regulate bone quality parameters. Functional studies of one such locus, at TAC4, revealed that Tac4-/- mice have reduced mechanical bone strength. The strongest forearm fracture signal, at WNT16, displayed remarkable bone-site-specificity with no association with hip fractures. Tall stature and low body mass index were identified as new causal risk factors for fractures. The insights from this atlas may improve fracture prediction and enable therapeutic development to prevent fractures.

Underdiagnosis and misclassification of COPD in Sweden - A Nordic Epilung study.

INTRODUCTION: The prevalence of COPD tends to level off in populations with decreasing prevalence of smoking but the extent of underdiagnosis in such populations needs further investigation. AIM: To investigate underdiagnosis and misclassification of COPD with a focus on socio-economy, lifestyle determinants and healthcare utilization. METHOD: The 1839 participants were selected from two ongoing large-scale epidemiological research programs: The Obstructive Lung Disease in Northern Sweden Studies and the West Sweden Asthma Study. COPDGOLD was defined according to the fixed post-bronchodilator spirometric criteria FEV1/FVC<0.70 in combination with respiratory symptoms. RESULTS: Among the 128 participants who fulfilled the criteria for COPDGOLD, the underdiagnosis was 83.6% (n = 107) of which 57.9% were men. The undiagnosed participants were younger, had higher FEV1% of predicted and less frequently a family history of bronchitis. One in four of the undiagnosed had utilized healthcare and had more frequently utilized healthcare due to a burden of respiratory symptoms than the general population without COPD. Underdiagnosis was not related to educational level. Misclassification of COPD was characterized by being a woman with low education, ever smoker, having respiratory symptoms and having a previous asthma diagnosis. CONCLUSION: In the high income country Sweden, the underdiagnosis of COPD was highly prevalent. Reduced underdiagnosis can contribute to risk factor modification, medical treatment and self-management strategies in early stages of the disease, which may prevent disease progression and improve the quality of life among those affected. Therefore, there is a need to increase the use of spirometry in primary care to improve the diagnostic accuracy.

Transplantation of gut microbiota from old mice into young healthy mice reduces lean mass but not bone mass.

Aging is associated with low bone and lean mass as well as alterations in the gut microbiota (GM). In this study, we determined whether the reduced bone mass and relative lean mass observed in old mice could be transferred to healthy young mice by GM transplantation (GMT). GM from old (21-month-old) and young adult (5-month-old) donors was used to colonize germ-free (GF) mice in three separate studies involving still growing 5- or 11-week-old recipients and 17-week-old recipients with minimal bone growth. The GM of the recipient mice was similar to that of the donors, demonstrating successful GMT. GM from old mice did not have statistically significant effects on bone mass or bone strength, but significantly reduced the lean mass percentage of still growing recipient mice when compared with recipients of GM from young adult mice. The levels of propionate in the cecum of mice receiving old donor GM were significantly lower than those in mice receiving young adult donor GM. Bacteroides ovatus was enriched in the microbiota of recipient mice harboring GM from young adult donors. The presence of B. ovatus was not only significantly associated with high lean mass percentage in mice, but also with lean mass adjusted for fat mass in the large human HUNT cohort. In conclusion, GM from old mice reduces lean mass percentage but not bone mass in young, healthy, still growing recipient mice. Future studies are warranted to determine whether GM from young mice improves the musculoskeletal phenotype of frail elderly recipient mice.

Lung cancer risk discrimination of prediagnostic proteomics measurements compared with existing prediction tools.

BACKGROUND: We sought to develop a proteomics-based risk model for lung cancer and evaluate its risk-discriminatory performance in comparison with a smoking-based risk model (PLCOm2012) and a commercially available autoantibody biomarker test. METHODS: We designed a case-control study nested in 6 prospective cohorts, including 624 lung cancer participants who donated blood samples at most 3 years prior to lung cancer diagnosis and 624 smoking-matched cancer free participants who were assayed for 302 proteins. We used 470 case-control pairs from 4 cohorts to select proteins and train a protein-based risk model. We subsequently used 154 case-control pairs from 2 cohorts to compare the risk-discriminatory performance of the protein-based model with that of the Early Cancer Detection Test (EarlyCDT)-Lung and the PLCOm2012 model using receiver operating characteristics analysis and by estimating models' sensitivity. All tests were 2-sided. RESULTS: The area under the curve for the protein-based risk model in the validation sample was 0.75 (95% confidence interval [CI] = 0.70 to 0.81) compared with 0.64 (95% CI = 0.57 to 0.70) for the PLCOm2012 model (Pdifference = .001). The EarlyCDT-Lung had a sensitivity of 14% (95% CI = 8.2% to 19%) and a specificity of 86% (95% CI = 81% to 92%) for incident lung cancer. At the same specificity of 86%, the sensitivity for the protein-based risk model was estimated at 49% (95% CI = 41% to 57%) and 30% (95% CI = 23% to 37%) for the PLCOm2012 model. CONCLUSION: Circulating proteins showed promise in predicting incident lung cancer and outperformed a standard risk prediction model and the commercialized EarlyCDT-Lung.

Evaluation of pre-diagnostic blood protein measurements for predicting survival after lung cancer diagnosis.

BACKGROUND: To evaluate whether circulating proteins are associated with survival after lung cancer diagnosis, and whether they can improve prediction of prognosis. METHODS: We measured up to 1159 proteins in blood samples from 708 participants in 6 cohorts. Samples were collected within 3 years prior to lung cancer diagnosis. We used Cox proportional hazards models to identify proteins associated with overall mortality after lung cancer diagnosis. To evaluate model performance, we used a round-robin approach in which models were fit in 5 cohorts and evaluated in the 6th cohort. Specifically, we fit a model including 5 proteins and clinical parameters and compared its performance with clinical parameters only. FINDINGS: There were 86 proteins nominally associated with mortality (p < 0.05), but only CDCP1 remained statistically significant after accounting for multiple testing (hazard ratio per standard deviation: 1.19, 95% CI: 1.10-1.30, unadjusted p = 0.00004). The external C-index for the protein-based model was 0.63 (95% CI: 0.61-0.66), compared with 0.62 (95% CI: 0.59-0.64) for the model with clinical parameters only. Inclusion of proteins did not provide a statistically significant improvement in discrimination (C-index difference: 0.015, 95% CI: -0.003 to 0.035). INTERPRETATION: Blood proteins measured within 3 years prior to lung cancer diagnosis were not strongly associated with lung cancer survival, nor did they importantly improve prediction of prognosis beyond clinical information. FUNDING: No explicit funding for this study. Authors and data collection supported by the US National Cancer Institute (U19CA203654), INCA (France, 2019-1-TABAC-01), Cancer Research Foundation of Northern Sweden (AMP19-962), and Swedish Department of Health Ministry.

Identification of three bacterial species associated with increased appendicular lean mass: the HUNT study.

Appendicular lean mass (ALM) associates with mobility and bone mineral density (BMD). While associations between gut microbiota composition and ALM have been reported, previous studies rely on relatively small sample sizes. Here, we determine the associations between prevalent gut microbes and ALM in large discovery and replication cohorts with information on relevant confounders within the population-based Norwegian HUNT cohort (n = 5196, including women and men). We show that the presence of three bacterial species - Coprococcus comes, Dorea longicatena, and Eubacterium ventriosum - are reproducibly associated with higher ALM. When combined into an anabolic species count, participants with all three anabolic species have 0.80 kg higher ALM than those without any. In an exploratory analysis, the anabolic species count is positively associated with femoral neck and total hip BMD. We conclude that the anabolic species count may be used as a marker of ALM and BMD. The therapeutic potential of these anabolic species to prevent sarcopenia and osteoporosis needs to be determined.

A cross-sectional study of inflammatory markers as determinants of circulating kynurenines in the Lung Cancer Cohort Consortium.

Circulating concentrations of metabolites (collectively called kynurenines) in the kynurenine pathway of tryptophan metabolism increase during inflammation, particularly in response to interferon-gamma (IFN-γ). Neopterin and the kynurenine/tryptophan ratio (KTR) are IFN-γ induced inflammatory markers, and together with C-reactive protein (CRP) and kynurenines they are associated with various diseases, but comprehensive data on the strength of associations of inflammatory markers with circulating concentrations of kynurenines are lacking. We measured circulating concentrations of neopterin, CRP, tryptophan and seven kynurenines in 5314 controls from 20 cohorts in the Lung Cancer Cohort Consortium (LC3). The associations of neopterin, KTR and CRP with kynurenines were investigated using regression models. In mixed models, one standard deviation (SD) higher KTR was associated with a 0.46 SD higher quinolinic acid (QA), and 0.31 SD higher 3-hydroxykynurenine (HK). One SD higher neopterin was associated with 0.48, 0.44, 0.36 and 0.28 SD higher KTR, QA, kynurenine and HK, respectively. KTR and neopterin respectively explained 24.1% and 16.7% of the variation in QA, and 11.4% and 7.5% of HK. CRP was only weakly associated with kynurenines in regression models. In summary, QA was the metabolite that was most strongly associated with the inflammatory markers. In general, the inflammatory markers were most strongly related to metabolites located along the tryptophan-NAD axis, which may support suggestions of increased production of NAD from tryptophan during inflammation.

Design and methodological considerations for biomarker discovery and validation in the Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Program.

The Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) program is an NCI-funded initiative with an objective to develop tools to optimize low-dose CT (LDCT) lung cancer screening. Here, we describe the rationale and design for the Risk Biomarker and Nodule Malignancy projects within INTEGRAL. The overarching goal of these projects is to systematically investigate circulating protein markers to include on a panel for use (i) pre-LDCT, to identify people likely to benefit from screening, and (ii) post-LDCT, to differentiate benign versus malignant nodules. To identify informative proteins, the Risk Biomarker project measured 1161 proteins in a nested-case control study within 2 prospective cohorts (n = 252 lung cancer cases and 252 controls) and replicated associations for a subset of proteins in 4 cohorts (n = 479 cases and 479 controls). Eligible participants had a current or former history of smoking and cases were diagnosed up to 3 years following blood draw. The Nodule Malignancy project measured 1078 proteins among participants with a heavy smoking history within four LDCT screening studies (n = 425 cases diagnosed up to 5 years following blood draw, 430 benign-nodule controls, and 398 nodule-free controls). The INTEGRAL panel will enable absolute quantification of 21 proteins. We will evaluate its performance in the Risk Biomarker project using a case-cohort study including 14 cohorts (n = 1696 cases and 2926 subcohort representatives), and in the Nodule Malignancy project within five LDCT screening studies (n = 675 cases, 680 benign-nodule controls, and 648 nodule-free controls). Future progress to advance lung cancer early detection biomarkers will require carefully designed validation, translational, and comparative studies.

Airway Symptoms among Farmers in Central Norway. A Comparative Study of Risks. The HUNT Study.

OBJECTIVES: The objective of this study was to compare the risk of developing respiratory symptoms in farmers and other occupational groups over a period of 11 to 23 years. METHODS: The study includes data from questionnaires and interviews in HUNT1-3 in The Trøndelag Health study (HUNT). In all three surveys, farmers can be identified. Two control groups are used. Control group 1 consists of all HUNT participants who are not farmers or fishermen. Control group 2 consists of occupational groups who presumably have low exposure to dust, chemicals or gases, but similar educational status as farmers. The data are analysed in SPSS 25 (IBM, Armonk NY), with use of frequency analyses and multiple binary logistic regressions. RESULTS: Our main finding is that healthy farmers have increased risk of developing respiratory symptoms as wheezing or breathlessness over a period of 11 and 23 years. This increased risk is statistically significant after 11 years of follow-up (HUNT1 to HUNT2), and also after 23 years (HUNT1 to HUNT3). Corresponding results regarding wheezing and breathlessness are found for healthy farmers in HUNT2 after 12 years of follow-up in HUNT3. In a subgroup analysis, we find a highly significant difference in both wheezing and shortness of breath when at work, in believing that the symptoms are caused by work, and in having to change jobs or quit because of breathing problems. CONCLUSION: Farmers have more respiratory symptoms than controls, and the main symptom is attacks of wheezing or breathlessness. Preventive measures such as ventilation and respiratory protection should be implemented on the farm.

Mortality Associated With Occupational Exposure in Helsinki, Finland-A 24-Year Follow-up.

OBJECTIVES: Our objective was to study mortality related to different obstructive lung diseases, occupational exposure, and their potential joint effect in a large, randomized population-based cohort. METHODS: We divided the participants based on the answers to asthma and chronic obstructive pulmonary disease (COPD) diagnoses and occupational exposure and used a combined effects model and compared the results to no asthma or COPD with no occupational exposure. RESULTS: High exposure had a hazards ratio (HR) of 1.34 (1.11-1.62) and asthma and COPD coexistence of 1.58 (1.10-2.27). The combined effects of intermediate exposure and coexistence had an HR of 2.20 (1.18-4.09), high exposure with coexistence of 1.94 (1.10-3.42) for overall mortality, and sub-HR for respiratory-related mortality of 3.21 (1.87-5.50). CONCLUSIONS: High occupational exposure increased overall but not respiratory-related mortality hazards, while coexisting asthma and COPD overall and respiratory-related hazards of mortality.

Reproductive Factors in Relation to Incidence of Lung and Colorectal Cancers in a Cohort of Norwegian Women: The HUNT Study.

Context: The roles of reproductive factors in the etiology of lung and colorectal cancers, among the most common cancers in women, are unclear. Objective: We aimed to explore whether female reproductive factors were associated with the incidence of lung and colorectal cancers. Methods: We followed up 33 314 cancer-free women who participated in the HUNT Study in Norway from 1995-1997 to 2018. A large panel of reproductive factors were self-reported at baseline. Incident lung and colorectal cancer cases were ascertained from the Cancer Registry of Norway. Cox regression models were used to estimate hazard ratios (HRs) with 95% CIs after adjustment for important confounders. Results: During a median follow-up interval of 22.2 years, 467 women developed lung cancer (including 169 lung adenocarcinoma), 660 developed colon cancer, and 211 had rectal cancer. Early menarche (≤12 years) was associated with an increased incidence of lung adenocarcinoma (HR 1.43; 95% CI, 1.02-2.03). Women with one or no child had an increased colon cancer incidence (HR 1.26; 95% CI, 1.03-1.54). Hormone therapy appeared to be associated with a decreased incidence of rectal cancer (HR 0.68; 95% CI, 0.44-1.04). Results in the subgroup of postmenopausal women were similar or strengthened. Other reproductive factors were not related to the risk of lung, colon, and rectal cancers. Conclusion: Certain reproductive factors might play a role in the etiology of lung and colorectal cancers. Further investigations are warranted to study if they are causal associations.