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Background:
Genome-wide association studies have identified numerous genetic regions that influence cross-sectional lung function. Longitudinal decline in lung function also includes a heritable component but the genetic determinants have yet to be defined.
Objectives:
We aimed to determine whether regions associated with cross-sectional lung fu...
Context in source publication
Citations
... Previous epidemiological studies have indicated the associations of lead exposure with lung function impairment in both general population and occupational workers (Yang et al. 2019;Leem et al. 2015;Rokadia and Agarwal 2013;Gomes et al. 2018). Oxidative stress is a known mechanism underpinning lead (Matović et al. 2015), and numerous single nucleotide polymorphisms (SNPs) in genes associated to oxidative stress have been found to alter how air pollutants affect lung diseases (Castro-Giner et al. 2009;Thun et al. 2014;John et al. 2017;Kim et al. 2018). An occupational cohort study of 1243 workers in a coke-oven plant by Wei Wei et al. showed a considerable effect of lead exposure on the decline in FEV 1 , which was regulated by the NQO1 rs2917670 genotypes (Wei et al. 2020). ...
We examined 9556 individuals aged 18 to 79 years who had information on spirometry testing and heavy metals and used multivariable logistic or linear regression to evaluate associations between serum levels of cadmium, lead, and mercury and PRISm and lung function in U.S. adults, which were conducted first in all participants, and then separately in never/former smokers and current smokers. The overall prevalence of PRISm was 7.02%. High levels of serum cadmium were significantly associated with PRISm in all individuals, no matter in never/former smokers (quartile 4 vs 1, the OR = 2.517, 95% CI = 1.376–4.604, p-trend = 0.0077) and current smokers (quartile 4 vs 1, the OR = 2.201, 95% CI = 1.265–3.830, p-trend = 0.0020). Serum lead and mercury were not significantly correlated with PRISm, regardless of smoking status. Serum cadmium was strongly correlated with lower FEV1/FVC, regardless of smoking status. Besides, serum cadmium was also significantly related to lower FVC % predicted in never/former smokers and lower FEV1% predicted in current smokers. Serum lead was strongly correlated with lower FVC % predicted and FEV1/FVC in all individuals and never/former smokers. And serum mercury was significantly associated with decrements in FVC % predicted in all individuals and current smokers. These findings demonstrate that serum cadmium is associated with a higher risk of PRISm and lower lung function, with the most significant effect on FEV1/FVC in particular. Our results also indicate that exposure to lead and mercury negatively affects lung function in never/former smokers and current smokers, respectively.
Supplementary Information
The online version contains supplementary material available at 10.1007/s11356-023-29688-y.
... Epidemiologic and genetic investigations of pulmonary function require longitudinal observation of lung function trajectories. Although a few studies followed subjects for more than 10 years [17,18], to the best of our knowledge, none of these studies assessed heritability in unrelated subjects, or subjects with non-European ancestry. The advantage of using unrelated subjects to estimate heritability is that they do not suffer from confounding problems caused by epistatic interactions or shared environment, which are present in family and twin studies [19][20][21][22]. ...
Genetic influence on lung functions has been identified in previous studies; however, the relative longitudinal effects of genetic factors and their interactions with smoking on lung function remain unclear. Here, we identified the longitudinal effects of genetic variants on lung function by determining single nucleotide polymorphism (SNP) heritability and genetic correlations, and by analyzing interactions with smoking. Subject-specific means and annual change rates were calculated for eight spirometric measures obtained from 6622 Korean adults aged 40–69 years every two years for 14 years, and their heritabilities were estimated separately. Statistically significant (p < 0.05) heritability for the subject-specific means of all spirometric measures (8~32%) and change rates of forced expiratory volume in 1 s to forced vital capacity ratio (FEV1/FVC; 16%) and post-bronchodilator FEV1/FVC (17%) were detected. Significant genetic correlations of the change rate with the subject-specific mean were observed for FEV1/FVC (ρg = 0.64) and post-bronchodilator FEV1/FVC (ρg = 0.47). Furthermore, post-bronchodilator FEV1/FVC showed significant heritability of SNP-by-smoking interaction (hGXS2 = 0.4) for the annual change rate. The GWAS also detected genome-wide significant SNPs for FEV1 (rs4793538), FEV1/FVC (rs2704589, rs62201158, and rs9391733), and post-bronchodilator FEV1/FVC (rs2445936). We found statistically significant evidence of heritability role on the change in lung function, and this was shared with the effects on cross-sectional measurements. We also found some evidence of interaction with smoking for the change of lung function.
... The FEV 1 , FVC and PEF values of our cyclists are rather explained by a high level of endurance practice. A genetic component can also be discussed because high-level cycling practice requires individual selection of athletes who possess outsized spirometry abilities in relation to their anthropometric parameters [26]. A difference in trunk length relative to standing height associated with fat-free mass, chest dimensions and strength of respiratory muscles may be genetically explained [5]. ...
Several studies have demonstrated that spirometric theoretical values may not be applicable to the high-level sports population. No reference values exist for high-level professional cyclists. We aimed to establish predictive spirometric values by reference equations. One hundred and forty-five French Caucasian high-level professional cyclists, aged 18–38, performed basic anthropometric assessment and spirometry during the medical evaluation at the beginning of the sport season. Measured values were compared with theoretical values. Predictive equations were established from anthropometric parameters to explain variations of spirometric parameters. High-level cyclists had significantly higher spirometric values than the theoretical values established from a general population, except for forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and forced expiratory flow (FEF) at 25% of FVC. Only FVC and FEV1 were well predicted from body height. The FVC variation of 43.5% is explained by body height and weight. The FEV1 variation of 25.8% is explained only by body height. High-level cycling is associated with important respiratory adaptations depending on the body height and the sport specificity: intensive and prolonged endurance training. These findings are interesting for clinical individual application to diagnose obstructive disease and test reversibility with bronchodilator drugs.
... There are many genetic variants associated with lung function and COPD affection status, including the AGER locus which was among the first identified in large general population GWAS [36][37][38][39], and rs2070600 was recently included in a 279-SNP genetic risk score (GRS) for COPD based on a UK BioBank GWAS [36]. Since most large GWAS have only evaluated cross-sectional lung function phenotypes, there have been limited discoveries of genetic variation associated with progression of disease [40]. Furthermore, large studies of other longitudinal COPD outcomes such as exacerbations have suffered from inability to replicate significant findings across different populations [41]. ...
Abstract Background Soluble receptor for advanced glycation end products (sRAGE) is a proposed emphysema and airflow obstruction biomarker; however, previous publications have shown inconsistent associations and only one study has investigate the association between sRAGE and emphysema. No cohorts have examined the association between sRAGE and progressive decline of lung function. There have also been no evaluation of assay compatibility, receiver operating characteristics, and little examination of the effect of genetic variability in non-white population. This manuscript addresses these deficiencies and introduces novel data from Pittsburgh COPD SCCOR and as well as novel work on airflow obstruction. A meta-analysis is used to quantify sRAGE associations with clinical phenotypes. Methods sRAGE was measured in four independent longitudinal cohorts on different analytic assays: COPDGene (n = 1443); SPIROMICS (n = 1623); ECLIPSE (n = 2349); Pittsburgh COPD SCCOR (n = 399). We constructed adjusted linear mixed models to determine associations of sRAGE with baseline and follow up forced expiratory volume at one second (FEV1) and emphysema by quantitative high-resolution CT lung density at the 15th percentile (adjusted for total lung capacity). Results Lower plasma or serum sRAGE values were associated with a COPD diagnosis (P
... One study showed weak evidence that persistently low FEV 1 trajectory is associated with genetic factors in addition to multiple childhood exposures [10]. A recent study based on repeated measurement of lung function in adults reported that genetic variants associated with cross-sectional lung function measurements were not associated with a longitudinal decline of lung function [13]. These inconsistent findings in genetic studies and the clear impact of environmental factors on lung function motivated the investigation of the role of epigenetic factors such as DNA methylation (DNA-M) in determining variation in lung function between people and over time. ...
Background
The pattern of lung function development from pre-adolescence to adulthood plays a significant role in the pathogenesis of respiratory diseases. Inconsistent findings in genetic studies on lung function trajectories, the importance of DNA methylation (DNA-M), and the critical role of adolescence in lung function development motivated the present study of pre-adolescent DNA-M with lung function trajectories. This study investigated epigenome-wide associations of DNA-M at cytosine-phosphate-guanine dinucleotide sites (CpGs) at childhood with lung function trajectories from childhood to young adulthood.
Methods
DNA-M was measured in peripheral blood at age 10 years in the Isle of Wight (IOW) birth cohort. Spirometry was conducted at ages 10, 18, and 26 years. A training/testing-based method was used to screen CpGs. Multivariable logistic regressions were applied to assess the association of DNA-M with lung function trajectories from pre-adolescence to adulthood. To detect differentially methylated regions (DMRs) among CpGs, DMR enrichment analysis was conducted. Findings were further tested in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Pathway analyses were performed on the mapped genes of the identified CpGs and DMRs. Biological relevance of the identified CpGs was assessed with gene expression. All analyses were stratified by sex.
Results
High and low trajectories of FVC, FEV 1 , and FEV 1 /FVC in each sex were identified. At P Bonferroni < 0.05, DNA-M at 96 distinct CpGs (41 in males) showed associations with FVC, FEV 1 , and FEV 1 /FVC trajectories in IOW cohort. These 95 CpGs (cg24000797 was disqualified) were further tested in ALSPAC; 44 CpGs (19 in males) of these 95 showed the same directions of association as in the IOW cohort; and three CpGs (two in males) were replicated. DNA-M at two and four CpGs showed significant associations with the corresponding gene expression in males and females, respectively. At P FDR < 0.05, 23 and 10 DMRs were identified in males and females, respectively. Pathways were identified; some of those were linked to lung function and chronic obstructive lung diseases.
Conclusion
The identified CpGs at pre-adolescence have the potential to serve as candidate markers for lung function trajectory prediction and chronic lung diseases.
... Since most large GWAS have only evaluated cross-sectional lung function phenotypes, there have been limited discoveries of genetic variation associated with progression of disease (40). Furthermore, large studies of other longitudinal COPD outcomes such as exacerbations have suffered from inability to replicate signi cant ndings across different populations (41). ...
Background:
Soluble receptor for advanced glycation end products (sRAGE) is a proposed emphysema and airflow obstruction biomarker; however, previous publication have shown inconsistent associations and only one study has investigate the association between sRAGE and emphysema. No cohorts have examined the association between sRAGE and progressive decline of lung function. There have also been no evaluation of assay compatibility, receiver operating characteristics, and little examination of the effect of genetic variability in non-white population. This manuscript addresses these deficiencies and introduces novel data from Pittsburgh COPD SCCOR and as well as novel work on airflow obstruction. A meta-analysis is used to quantify sRAGE associations with clinical phenotypes.
Methods: sRAGE was measured in four independent longitudinal cohorts on different analytic assays: COPDGene (n=1,443), SPIROMICS (n=1,623); ECLIPSE (n=2,349); Pittsburgh COPD SCCOR (n=399). We constructed adjusted linear mixed models to determine associations of sRAGE with baseline and follow up forced expiratory volume at one second (FEV1) and emphysema by quantitative high-resolution CT lung density at the 15th percentile (adjusted for total lung capacity).
Results: Lower plasma or serum sRAGE values were associated with a COPD diagnosis (P<0.001), reduced FEV1 (P < 0.001), and emphysema severity (P<0.001). In an inverse-variance weighted meta-analysis, one SD lower log10-transformed sRAGE was associated with 105 ± 22 mL lower FEV1 and 4.14 ± 0.55 g/L lower adjusted lung density. After adjusting for covariates, lower sRAGE at baseline was associated with greater FEV1 decline and emphysema progression only in the ECLIPSE cohort. Non-Hispanic white subjects carrying the rs2070600 minor allele (A) and non-Hispanic African Americans carrying the rs2071288 minor allele (A) had lower sRAGE measurements compare to those with the major allele, but their emphysema-sRAGE regression slopes were similar.
Conclusions: Lower blood sRAGE is associated with more severe airflow obstruction and emphysema, but associations with progression are inconsistent in the cohorts analyzed. In these cohorts, genotype influenced sRAGE measurements and strengthened variance modelling. Thus, genotype should be included in sRAGE evaluations.
... Genome-wide association studies (GWAS) and their relationship to lung function have been numerous in recent years [4][5][6][7] and are generally characterised by cross-sectional studies, although there are also longitudinal studies. However, the individual genetic determinants associated with lung function have not yet been fully identified, 8 although there is a lot of progress being made. The identification of the possible genes associated with lung function may provide a promising route for the treatment of diseases such as chronic obstructive pulmonary disease (COPD), usually diagnosed when lung function begins to decline. ...
Objectives
The aim of this work is to present a review on the impact of genetics and altitude on lung function from classic and recent studies.
Data source
A systematic search has been carried out in different databases of scientific studies, using keywords related to lung volumes, spirometry, altitude and genetics.
Results
The results of this work have been structured into three parts. First, the relationship between genes and lung function. Next, a review of the genetic predispositions related to respiratory adaptation of people who inhabit high‐altitude regions for millennia. Finally, temporary effects and long‐term acclimatisation on respiratory physiology at high altitude are presented.
Conclusions
The works focused on the influence of genetics and altitude on lung function are currently of interest in terms of studying the interactions between genetic, epigenetic and environmental factors in the configuration of the pathophysiological adaptation patterns.
... 67 Individual genetic variants associated with cross-sectional lung function measures have generally not been predictive of lung function decline. 68 Our risk score associates with reduced lung growth, and also with emphysema patterns characteristic of older smoking adults with severe COPD. Whether the latter includes structural abnormalities present in younger age, or is due to dysregulated pathways in adults, is still unclear. ...
Background
Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes.
Methods
We constructed a polygenic risk score using a genome-wide association study of lung function (FEV1 and FEV1/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV1/FVC <0·7 and FEV1 <80% of predicted). Associations were tested using logistic regression models, adjusting for age, sex, height, smoking pack-years, and principal components of genetic ancestry. We assessed predictive performance of models by area under the curve. In a subset of studies, we also studied quantitative and qualitative CT imaging phenotypes that reflect parenchymal and airway pathology, and patterns of reduced lung growth.
Findings
The polygenic risk score was associated with COPD in European (odds ratio [OR] per SD 1·81 [95% CI 1·74–1·88] and non-European (1·42 [1·34–1·51]) populations. Compared with the first decile, the tenth decile of the polygenic risk score was associated with COPD, with an OR of 7·99 (6·56–9·72) in European ancestry and 4·83 (3·45–6·77) in non-European ancestry cohorts. The polygenic risk score was superior to previously described genetic risk scores and, when combined with clinical risk factors (ie, age, sex, and smoking pack-years), showed improved prediction for COPD compared with a model comprising clinical risk factors alone (AUC 0·80 [0·79–0·81] vs 0·76 [0·75–0·76]). The polygenic risk score was associated with CT imaging phenotypes, including wall area percent, quantitative and qualitative measures of emphysema, local histogram emphysema patterns, and destructive emphysema subtypes. The polygenic risk score was associated with a reduced lung growth pattern.
Interpretation
A risk score comprised of genetic variants can identify a small subset of individuals at markedly increased risk for moderate-to-severe COPD, emphysema subtypes associated with cigarette smoking, and patterns of reduced lung growth.
Funding
US National Institutes of Health, Wellcome Trust.
... Although the early environment has been implicated in the etiology of impaired lung function, there has been no systematic investigation of the role of genes known to play a vital role in lung development. Genetic variants affecting adult crosssectional lung function have shown little or no effect on longitudinal lung function decline (8), and some of these variants have been identified in children as well as adults. These observations suggest that lung function at a given point in adulthood may be more influenced by genetic factors that affect the developmental trajectory of lung function rather than the rate of subsequent decline. ...
Rationale:
Poor lung health in adult life may occur partly through suboptimal growth and development, as suggested by epidemiological evidence pointing to early life risk factors.
Objectives:
To systematically investigate the effects of lung development genes on adult lung function.
Methods:
Using UK Biobank data, we tested the association of 391 genes known to influence lung development with FVC and FEV1/FVC. We split the dataset into two random subsets of 207,616 and 138,411 individuals, using the larger to select the most promising signals and the smaller for replication.
Measurements and main results:
We identified 55 genes, of which 36 (16 for FVC; 19 for FEV1/FVC; 1 for both) had not been identified in the largest, most recent genome-wide study of lung function. Most of these 36 signals were intronic variants; expression data from blood and lung tissue showed that the majority affect the expression of the genes they lie within. Further testing of 34 of these 36 signals in the CHARGE and SpiroMeta consortia showed that 16 replicated after Bonferroni correction and another 12 at nominal significance level. 53 of the 55 genes fell into four biological categories whose function is to regulate organ size and cell integrity (growth factors; transcriptional regulators; cell-cell adhesion; extra-cellular matrix), suggesting that these specific processes are important for adult lung health.
Conclusions:
Our study demonstrates the importance of lung development genes in regulating adult lung function and influencing both restrictive and obstructive patterns. Further investigation of these developmental pathways could lead to druggable targets.
... Tang and colleagues (41) performed a GWAS meta-analysis of FEV1 change in 27,249 European ancestry subjects from 14 cohorts in the CHARGE and SpiroMeta consortia; no genome-wide significant associations were found. John et al. (42) performed GWAS of longitudinal change in FEV1 and FEV1/FVC in 4,167 subjects; they did not identify any genome-wide significant associations. Moreover, none of the 26 previously identified genetic determinants of lung function level was associated with lung function decline. ...
Although chronic obstructive pulmonary disease (COPD) risk is strongly influenced by cigarette smoking, genetic factors are also important determinants of COPD. In addition to Mendelian syndromes such as alpha-1 antitrypsin deficiency, many genomic regions that influence COPD susceptibility have been identified in genome-wide association studies. Similarly, multiple genomic regions associated with COPD-related phenotypes, such as quantitative emphysema measures, have been found. Identifying the functional variants and key genes within these association regions remains a major challenge. However, newly identified COPD susceptibility genes are already providing novel insights into COPD pathogenesis. Network-based approaches that leverage these genetic discoveries have the potential to assist in decoding the complex genetic architecture of COPD.
Expected final online publication date for the Annual Review of Physiology, Volume 82 is February 10, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
