Stefano Guerra1, Marilyn Halonen2, Monica M Vasquez3, Amber Spangenberg2, Debra A Stern2, Wayne J Morgan2, Anne L Wright2, Iris Lavi4, Lluïsa Tarès4, Anne-Elie Carsin5, Carlota Dobaño6, Esther Barreiro7, Jan-Paul Zock4, Jesús Martínez-Moratalla8, Isabel Urrutia9, Jordi Sunyer5, Dirk Keidel10, Medea Imboden10, Nicole Probst-Hensch10, Jenny Hallberg11, Erik Melén11, Magnus Wickman11, Jean Bousquet12, Danielle C M Belgrave13, Angela Simpson13, Adnan Custovic13, Josep M Antó5, Fernando D Martinez2. 1. Arizona Respiratory Center, University of Arizona, Tucson, AZ, USA; Centre for Research in Environmental Epidemiology (CREAL), Universitat Pompeu Fabra, and CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain. Electronic address: stefano@email.arizona.edu. 2. Arizona Respiratory Center, University of Arizona, Tucson, AZ, USA. 3. Arizona Respiratory Center, University of Arizona, Tucson, AZ, USA; Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA. 4. Centre for Research in Environmental Epidemiology (CREAL), Universitat Pompeu Fabra, and CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain. 5. Centre for Research in Environmental Epidemiology (CREAL), Universitat Pompeu Fabra, and CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain; IMIM Hospital del Mar Medical Research Institute, Barcelona, Spain. 6. ISGlobal, Barcelona Centre for International Health Research (CRESIB), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain. 7. Pulmonology Department-Muscle and Respiratory System Research Unit (URMAR), IMIM-Hospital del Mar and CIBER de Enfermedades Respiratorias (CIBERES), Universitat Pompeu Fabra, Barcelona, Spain. 8. Servicio de Neumología del Complejo Hospitalario Universitario de Albacete, and Servicio de Salud de Castilla-La Mancha, Albacete, Spain. 9. Pneumology Service, Galdakao-Usánsolo Hospital, Bizkaia, Spain. 10. Swiss Tropical and Public Health Institute, and University of Basel, Basel, Switzerland. 11. Institute of Environmental Medicine, Karolinska Institutet, and Sachs' Children and Youth Hospital, Stockholm, Sweden. 12. Department of Respiratory Diseases, University Hospital, Montpellier, France; Respiratory and Environmental Epidemiology Team, INSERM 1018, CESP Centre, Villejuif, France. 13. Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, University of Manchester and University Hospital of South Manchester, Manchester, UK.
Abstract
BACKGROUND: Low concentrations of the anti-inflammatory protein CC16 (approved symbol SCGB1A1) in serum have been associated with accelerated decline in forced expiratory volume in 1 s (FEV1) in patients with chronic obstructive pulmonary disease (COPD). We investigated whether low circulating CC16 concentrations precede lung function deficits and incidence of COPD in the general population. METHODS: We assessed longitudinal data on CC16 concentrations in serum and associations with decline in FEV1 and incidence of airflow limitation for adults who were free from COPD at baseline in the population-based Tucson Epidemiological Study of Airway Obstructive Disease ([TESAOD] n=960, mean follow-up 14 years), European Community Respiratory Health Survey ([ECRHS-Sp] n=514, 11 years), and Swiss Cohort Study on Air Pollution and Lung Diseases in Adults ([SAPALDIA] n=167, 8 years) studies. Additionally, we measured circulating CC16 concentrations in samples from children aged 4-6 years in the Tucson Children's Respiratory Study (n=427), UK Manchester Asthma and Allergy Study (n=481), and the Swedish Barn/children, Allergy, Milieu, Stockholm, Epidemiological survey (n=231) birth cohorts to assess whether low CC16 concentrations in childhood were predictive for subsequent lung function. FINDINGS: After adjustment for sex, age, height, smoking status and intensity, pack-years, asthma, and FEV1 at baseline, we found an inverse association between CC16 concentration and decline in FEV1 in adults in TESAOD (4·4 mL/year additional FEV1 decline for each SD decrease in baseline CC16 concentration, p=0·0014) and ECRHS-Sp (2·4 mL/year, p=0·023); the effect in SAPALDIA was marginal (4·5 mL/year, p=0·052). Low CC16 concentration at baseline was also associated with increased risk of incident stage 2 airflow limitation (ratio of FEV1 to forced expiratory volume [FEV1/FVC] less than 70% plus FEV1 % predicted less than 80%) in TESAOD and ECRHS-Sp. In children, the lowest tertile of CC16 concentrations was associated with a subsequent FEV1 deficit of 68 mL up to age 16 years (p=0·0001), which was confirmed in children who had never smoked by age 16 years (-71 mL, p<0·0001). INTERPRETATION: Low concentrations of CC16 in serum are associated with reduced lung function in childhood, accelerated lung function decline in adulthood, and development of moderate airflow limitation in the general adult population. FUNDING: National Heart, Lung, and Blood Institute and European Union Seventh Framework Programme.
BACKGROUND: Low concentrations of the anti-inflammatory protein CC16 (approved symbol SCGB1A1) in serum have been associated with accelerated decline in forced expiratory volume in 1 s (FEV1) in patients with chronic obstructive pulmonary disease (COPD). We investigated whether low circulating CC16 concentrations precede lung function deficits and incidence of COPD in the general population. METHODS: We assessed longitudinal data on CC16 concentrations in serum and associations with decline in FEV1 and incidence of airflow limitation for adults who were free from COPD at baseline in the population-based Tucson Epidemiological Study of Airway Obstructive Disease ([TESAOD] n=960, mean follow-up 14 years), European Community Respiratory Health Survey ([ECRHS-Sp] n=514, 11 years), and Swiss Cohort Study on Air Pollution and Lung Diseases in Adults ([SAPALDIA] n=167, 8 years) studies. Additionally, we measured circulating CC16 concentrations in samples from children aged 4-6 years in the Tucson Children's Respiratory Study (n=427), UK Manchester Asthma and Allergy Study (n=481), and the Swedish Barn/children, Allergy, Milieu, Stockholm, Epidemiological survey (n=231) birth cohorts to assess whether low CC16 concentrations in childhood were predictive for subsequent lung function. FINDINGS: After adjustment for sex, age, height, smoking status and intensity, pack-years, asthma, and FEV1 at baseline, we found an inverse association between CC16 concentration and decline in FEV1 in adults in TESAOD (4·4 mL/year additional FEV1 decline for each SD decrease in baseline CC16 concentration, p=0·0014) and ECRHS-Sp (2·4 mL/year, p=0·023); the effect in SAPALDIA was marginal (4·5 mL/year, p=0·052). Low CC16 concentration at baseline was also associated with increased risk of incident stage 2 airflow limitation (ratio of FEV1 to forced expiratory volume [FEV1/FVC] less than 70% plus FEV1 % predicted less than 80%) in TESAOD and ECRHS-Sp. In children, the lowest tertile of CC16 concentrations was associated with a subsequent FEV1 deficit of 68 mL up to age 16 years (p=0·0001), which was confirmed in children who had never smoked by age 16 years (-71 mL, p<0·0001). INTERPRETATION: Low concentrations of CC16 in serum are associated with reduced lung function in childhood, accelerated lung function decline in adulthood, and development of moderate airflow limitation in the general adult population. FUNDING: National Heart, Lung, and Blood Institute and European Union Seventh Framework Programme.
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