Abstract
Previous reports link differential DNA methylation (DNAme) to environmental exposures that are associated with lung function. Direct evidence on lung function DNAme is, however, limited. We undertook an agnostic epigenome-wide association study (EWAS) on pre-bronchodilation lung function and its change in adults.In a discovery–replication EWAS design, DNAme in blood and spirometry were measured twice, 6–15 years apart, in the same participants of three adult population-based discovery cohorts (n=2043). Associated DNAme markers (p<5×10−7) were tested in seven replication cohorts (adult: n=3327; childhood: n=420). Technical bias-adjusted residuals of a regression of the normalised absolute β-values on control probe-derived principle components were regressed on level and change of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and their ratio (FEV1/FVC) in the covariate-adjusted discovery EWAS. Inverse-variance-weighted meta-analyses were performed on results from discovery and replication samples in all participants and never-smokers.EWAS signals were enriched for smoking-related DNAme. We replicated 57 lung function DNAme markers in adult, but not childhood samples, all previously associated with smoking. Markers not previously associated with smoking failed replication. cg05575921 (AHRR (aryl hydrocarbon receptor repressor)) showed the statistically most significant association with cross-sectional lung function (FEV1/FVC: pdiscovery=3.96×10−21 and pcombined=7.22×10−50). A score combining 10 DNAme markers previously reported to mediate the effect of smoking on lung function was associated with lung function (FEV1/FVC: p=2.65×10−20).Our results reveal that lung function-associated methylation signals in adults are predominantly smoking related, and possibly of clinical utility in identifying poor lung function and accelerated decline. Larger studies with more repeat time-points are needed to identify lung function DNAme in never-smokers and in children.
Highlights
Lung function has an estimated heritability of between 30% and 70% [1]
Across all discovery epigenome-wide association study (EWAS) meta-analyses, we identified 111 CpG markers for replication ( p
Successful replication was observed for cg05575921 (AHRR), showing the strongest signal for FEV1 and FEV1/FVC (FEV1/FVC: p-value combining discovery and replication cohorts=7.22×10−50) among all identified lung function DNA methylation (DNAme) markers
Summary
Lung function has an estimated heritability of between 30% and 70% [1]. The variance in phenotype remains incompletely explained by genetic variation, but the impact of environmental exposure on respiratory health and lung function over the life course is well recognised. Pro-inflammatory and oxidative inhalants such as cigarette and environmental tobacco smoke, air pollution, and occupational exposures are important contributors to the increased risk of respiratory symptoms, accelerated lung function decline in adults and poor lung growth in children. A large body of evidence including results from epigenome-wide association studies (EWASs) shows differentially methylated CpG (5′-cytosine-phosphate-guanine-3′ dinucleotide) sites throughout the genome in response to environmental exposures, in particular cigarette smoking [2,3,4]. Reports of DNAme associated with respiratory diseases and lung function show inconsistent findings [5, 6]. Independent reports pointed to the consistent association of DNAme in the AHRR gene, cg05575921, with lung function in adults [4, 6, 7]
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