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Rationale: Chronic obstructive pulmonary disease (COPD) is a complex disease characterized by airway obstruction and accelerated lung function decline. Our understanding of systemic protein biomarkers associated with COPD remains incomplete. Objectives: To determine what proteins and pathways are associated with impaired pulmonary function in a diverse population. Methods: We studied 6,722 participants across six cohort studies with both aptamer-based proteomic and spirometry data (4,566 predominantly White participants in a discovery analysis and 2,156 African American cohort participants in a validation). In linear regression models, we examined protein associations with baseline forced expiratory volume in 1 second (FEV 1 ) and FEV 1 /forced vital capacity (FVC). In linear mixed effects models, we investigated the associations of baseline protein levels with rate of FEV 1 decline (ml/yr) in 2,777 participants with up to 7 years of follow-up spirometry. Results: We identified 254 proteins associated with FEV 1 in our discovery analyses, with 80 proteins validated in the Jackson Heart Study. Novel validated protein associations include kallistatin serine protease inhibitor, growth differentiation factor 2, and tumor necrosis factor-like weak inducer of apoptosis (discovery β = 0.0561, Q  = 4.05 × 10 -10 ; β  = 0.0421, Q  = 1.12 × 10 -3 ; and β = 0.0358, Q  = 1.67 × 10 -3 , respectively). In longitudinal analyses within cohorts with follow-up spirometry, we identified 15 proteins associated with FEV 1 decline ( Q  < 0.05), including elafin leukocyte elastase inhibitor and mucin-associated TFF2 (trefoil factor 2; β = -4.3 ml/yr, Q  = 0.049; β = -6.1 ml/yr, Q  = 0.032, respectively). Pathways and processes highlighted by our study include aberrant extracellular matrix remodeling, enhanced innate immune response, dysregulation of angiogenesis, and coagulation. Conclusions: In this study, we identify and validate novel biomarkers and pathways associated with lung function traits in a racially diverse population. In addition, we identify novel protein markers associated with FEV 1 decline. Several protein findings are supported by previously reported genetic signals, highlighting the plausibility of certain biologic pathways. These novel proteins might represent markers for risk stratification, as well as novel molecular targets for treatment of COPD.

Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies., (© 2023. The Author(s).)

Chronic obstructive pulmonary disease (COPD) is a frequent diagnosis in older individuals and contributor to global morbidity and mortality. Given the link between lung disease and aging, we need to understand how molecular indicators of aging relate to lung function and disease. Using data from the population-based KORA (Cooperative Health Research in the Region of Augsburg) surveys, we associated baseline epigenetic (DNA methylation) age acceleration with incident COPD and lung function. Models were adjusted for age, sex, smoking, height, weight, and baseline lung disease as appropriate. Associations were replicated in the Normative Aging Study. Of 770 KORA participants, 131 developed incident COPD over 7 years. Baseline accelerated epigenetic aging was significantly associated with incident COPD. The change in age acceleration (follow-up - baseline) was more strongly associated with COPD than baseline aging alone. The association between the change in age acceleration between baseline and follow-up and incident COPD replicated in the Normative Aging Study. Associations with spirometric lung function parameters were weaker than those with COPD, but a meta-analysis of both cohorts provide suggestive evidence of associations. Accelerated epigenetic aging, both baseline measures and changes over time, may be a risk factor for COPD and reduced lung function.

Background: Various factors may affect lung function at different stages in life. Since investigations that simultaneously consider several factors are rare, we examined the relative importance of early life, current environmental/lifestyle factors and allergic diseases on lung function in 15-year-olds., Methods: Best subset selection was performed for linear regression models to investigate associations between 21 diverse early life events and current factors with spirometric parameters (forced vital capacity, forced expiratory volume in 1 s and maximal mid-expiratory flow (FEF 25-75 )) in 1326 participants of the German GINIplus and LISAplus birth cohorts. To reduce model complexity, one model for each spirometric parameter was replicated 1000 times in random subpopulations (N = 884). Only those factors that were included in >70% of the replication models were retained in the final analysis., Results: A higher peak weight velocity and early lung infections were the early life events prevalently associated with airflow limitation and FEF 25-75 . Current environmental/lifestyle factors at age 15 years and allergic diseases that were associated with lung function were: indoor second-hand smoke exposure, vitamin D concentration, body mass index (BMI) and asthma status. Sex and height captured the majority of the explained variance (>75%), followed by BMI (≤23.7%). The variance explained by early life events was comparatively low (median: 4.8%; range: 0.2-22.4%), but these events were consistently negatively associated with airway function., Conclusions: Although the explained variance was mainly captured by well-known factors included in lung function prediction equations, our findings indicate early life and current factors that should be considered in studies on lung health among adolescents.

Vitamin D plays a role in the development of the immune system and the lung, as well as in airway remodelling. Therefore, this study investigated the association between serum 25-hydroxyvitamin D (25(OH)D) concentrations and spirometric lung function parameters at age 15 years.In the German birth cohorts GINIplus and LISAplus, lung function testing by spirometry and 25(OH)D measurements were performed during the 15-year follow-up examinations. Valid lung function measurements pre- and/or post-bronchodilation and serum 25(OH)D concentrations, which were adjusted for the date of blood sampling to account for seasonal variability, were available for 2607 adolescents. Associations between 25(OH)D concentrations and spirometric parameters were analysed using generalised additive models adjusted for confounding factors.Serum 25(OH)D concentrations were significantly associated with forced vital capacity (FVC), forced expiratory volume in 1 s (FEV 1 ) and FEV 1 /FVC measured before bronchodilation after adjustment for potential confounders: FEV 1 increased by 10 mL (95% CI 2-17), FVC by 20 mL (95% CI 12-28) and FEV 1 /FVC decreased by 0.177% (95% CI -0.286 to -0.067) per 10 nmol·L -1 increase in 25(OH)D concentrations. Flow rates (forced expiratory flow rates at 25, 50 and 75% of exhaled FVC (FEF 25 , FEF 50 , FEF 75 ) and mean flow rate between 25 and 75% of FVC (FEF 25-75 )) were not associated with vitamin D. Similar associations were observed for lung function parameters measured after bronchodilation.Vitamin D concentrations are positively associated with volume-related lung function parameters pre- and post-bronchodilation, suggesting structural changes in peripheral airways., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.)

A hallmark of the newly published GLI (Global Lungs Initiative) spirometric reference values is their "all-age" (3-95yr) predictive power, accomplished by incorporating non-linear age dependencies into modelling parameters. This modelling strategy is especially promising for the age range of puberty; however, the performance of GLI-values for adolescents is currently unknown. We calculated GLI-based z-scores for children/adolescents without apparent respiratory diseases from two different German studies, LUNOKID (N = 1943, 4-19 years) and GINIplus (N = 1042, 15 years) and determined the goodness of fit for specific age groups. We defined fit sufficient if the absolute mean of z-scores was <0.5. For children (<10yr) the mean GLI-based z-scores for FEV1 and FVC reached a good fit with mean z-scores for FEV1 between -0.11 and 0.01 and mean z-scores for FVC between 0.01 and 0.16, but larger deviations were observed in adolescents, especially boys (mean z-score -0.58 for FEV1 and -0.57 for FVC in GINIplus). The fit for FEV1/FVC was sufficient. GLI reference values provided reasonable estimates for the individuals enrolled in our studies, which span the age range of lung growth and development. However, we found that GLI-predictions overestimated lung volumes, especially those for German adolescent boys, which may, left unrecognised, lead to erroneous diagnosis of lung disease. Caution should be taken when applying these reference values to epidemiologic studies.

Background: Children born preterm or with a small size for gestational age are at increased risk for childhood asthma., Objective: We sought to assess the hypothesis that these associations are explained by reduced airway patency., Methods: We used individual participant data of 24,938 children from 24 birth cohorts to examine and meta-analyze the associations of gestational age, size for gestational age, and infant weight gain with childhood lung function and asthma (age range, 3.9-19.1 years). Second, we explored whether these lung function outcomes mediated the associations of early growth characteristics with childhood asthma., Results: Children born with a younger gestational age had a lower FEV1, FEV1/forced vital capacity (FVC) ratio, and forced expiratory volume after exhaling 75% of vital capacity (FEF75), whereas those born with a smaller size for gestational age at birth had a lower FEV1 but higher FEV1/FVC ratio (P < .05). Greater infant weight gain was associated with higher FEV1 but lower FEV1/FVC ratio and FEF75 in childhood (P < .05). All associations were present across the full range and independent of other early-life growth characteristics. Preterm birth, low birth weight, and greater infant weight gain were associated with an increased risk of childhood asthma (pooled odds ratio, 1.34 [95% CI, 1.15-1.57], 1.32 [95% CI, 1.07-1.62], and 1.27 [95% CI, 1.21-1.34], respectively). Mediation analyses suggested that FEV1, FEV1/FVC ratio, and FEF75 might explain 7% (95% CI, 2% to 10%) to 45% (95% CI, 15% to 81%) of the associations between early growth characteristics and asthma., Conclusions: Younger gestational age, smaller size for gestational age, and greater infant weight gain were across the full ranges associated with childhood lung function. These associations explain the risk of childhood asthma to a substantial extent., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Lung function measures are used in the diagnosis of chronic obstructive pulmonary disease. In 38,199 European ancestry individuals, we studied genome-wide association of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC with 1000 Genomes Project (phase 1)-imputed genotypes and followed up top associations in 54,550 Europeans. We identify 14 novel loci (P<5 × 10(-8)) in or near ENSA, RNU5F-1, KCNS3, AK097794, ASTN2, LHX3, CCDC91, TBX3, TRIP11, RIN3, TEKT5, LTBP4, MN1 and AP1S2, and two novel signals at known loci NPNT and GPR126, providing a basis for new understanding of the genetic determinants of these traits and pulmonary diseases in which they are altered.

Introduction: The impact of outdoor air pollution exposure on long-term lung development and potential periods of increased lung susceptibility remain unknown. This study assessed associations between early-life and current residential exposure to air pollution and lung function at 15-years of age in two German birth cohorts., Methods: Fifteen year-old participants living in an urban and rural area in Germany underwent spirometry before and after bronchodilation (N=2266). Annual average (long-term) exposure to nitrogen dioxide (NO(2)), particles with aerodynamic diameters less than 2.5 μg/m(3) (PM2.5) mass and less than 10 μg/m(3) (PM(10)) mass, PM(2.5) absorbance and ozone were estimated to each participant's birth-, 10- and 15-year home address using land-use regression and kriging (ozone only) modelling. Associations between lung function variables and long-term pollutant concentrations were assessed using linear regression models adjusted for host and environmental covariates and recent short-term air pollution exposures., Results: Long-term air pollution concentrations assessed to the birth-, 10- and 15-year home addresses were not associated with lung function variables, before and after bronchodilation, in the complete or study area specific populations. However, several lung function variables were negatively associated with long-term NO2 concentrations among asthmatics. For example, NO(2) estimated to the 15-year home address was associated with the ratio of forced expiratory volume in one second to forced vital capacity (FEV(1)/FVC) and the mean flow rate between 25% and 75% of FVC (-3.5%, 95% confidence interval [-6.0, -1.0] and -297.4 ml/s [-592.6, -2.1] per 5.9 μg/m(3) increase in NO(2), respectively). Nearly all effect estimates for the associations between the short-term PM(2.5) mass, PM(10) mass and ozone concentrations and the lung function variables were negative in the complete population., Conclusions: Early-life and current long-term air pollution exposures and lung function at the age of 15 years were not associated in the complete study population. Asthmatics may represent a vulnerable group., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

Background: The prevalence of allergen sensitization reaches up to 46.6% in 14- to 17-year-old German adolescents. Polysensitization is strongly associated with a higher risk of allergic rhinitis or asthma. Whether or how sensitization also is related to lung function remains uncertain., Objective: To assess whether sensitization to common inhalant allergens is associated with lung function in adolescents after stratification by allergic respiratory disease., Methods: In total, 1,719 15-year-old participants of the German Infant Study on the Influence of Nutrition Intervention plus Air Pollution and Genetics on Allergy Development (GINIplus) birth cohort provided valid spirometric indices, including forced expiratory volume in 1 second, forced vital capacity (FVC), forced expiratory flow rate at 25% to 75% of the FVC, and specific immunoglobulin E (IgE) screening test to 8 inhalant allergens (ImmunoCAP). Complete information on allergic rhinitis and asthma status was available for 1,128 subjects. Associations between lung function parameters and sensitization, classified into 4 groups (no sensitization to polysensitization) were analyzed using adjusted linear regression models., Results: Among participants, 21.1% (n = 347) had allergic rhinitis, 10.1% (n = 119) had asthma, and 46.4% (n = 798) had a positive screening test to inhalant allergens. Prevalences were consistently higher in boys. The percentage of subjects with rhinitis or asthma increased from 5.8% in non-sensitized subjects (n = 620) to 69.4% in polysensitized subjects (n = 144). Sensitization was not associated with any spirometric parameter considered in subjects with allergic rhinitis, asthma, or neither disease., Conclusion: Although allergen-specific IgE concentrations can contribute to the identification of subjects at higher risk for allergic rhinitis and asthma, sensitization to inhalant allergens is not related to impaired spirometric lung parameters within the different allergic respiratory disease subgroups., (Copyright © 2015 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)