We examined associations between methylation levels of the repetitive elements Alu and LINE-1 in a cohort of older men in relation to lung function and COPD status. In cross-sectional analyses, we found that Alu hypomethylation was associated with lower FEV1 with a trend towards association with lower FVC and FEV1/FVC. LINE-1 hypomethylation was associated with more rapid lung function decline (FEV1 and FVC).
Prior studies have found associations between methylation of repetitive transposable elements such as Alu
and LINE-1 and several diseases including multiple cancers,7
and neurological disease,18
as well as with markers of inflammation.19
To our knowledge this is the first study to examine associations between methylation of Alu
and LINE-1 transposable elements and measures of lung function.
Previous work has shown that in normal subjects, Alu
hypomethylation is associated with increased age,8
greater alcohol use and gender (lower in males).34
In this same cohort (Normative Aging Study), hypomethylation has been associated with higher incidence of cancer in general and lung cancer specifically (LINE-1 methylation), as well as higher mortality from cancer (Alu
and LINE-1 methylation).38
A variety of environmental exposures such as lead,39
metals, air pollutants and endocrine disrupting agents,41
may all affect global methylation levels, specifically some that may relate to lung function such as various air pollutants.
Hypomethylation of transposable elements may or may not be causally linked to lower lung function and faster rates of lung function decline. Lower methylation of Alu
and LINE-1 may increase their activity as retrotransposable sequences, leading to greater genomic instability and more mutations.13
Furthermore, oxidative damage caused by environmental exposures may cause hypomethylation.42
This may lead to alteration of gene expression through a variety of mechanisms including disrupting transcription factor binding sites or reading frames, altering regulatory sequences, altering methylation patterns of gene promoters or introducing new transcription factor-binding sites.43–45
elements specifically are preferentially found in gene-rich regions.46
Black carbon and increased PM2.5
as well as PM10
have been found to be inversely associated with LINE-1 methylation and both Alu
and LINE-1 methylation, respectively, which may impact on lung function or lung function decline.47
LINE-1 hypomethylation may also increase transcription of genes that have LINE-1 in regulatory regions. It is possible that other specific environmental or dietary exposures previously not known to be associated with lung function may be mediated through epigenetic changes such as Alu
or LINE-1 hypomethylation. Alternatively, this may be a marker of a specific exposure but not causally linked to lower lung function. Lastly, because Alu
methylation decreases with increasing age, as does lung function, our findings may represent some other measure of ‘aging’ or exposures resulting in similar processes beyond just chronological age.8
We repeated all of our analyses using age2
, as an additional covariate to saturate for an age effect and found no differences in our results. As our understanding of epigenetic processes and the exposures that affect these processes increases, the implications of our findings will become clearer.
These data must be interpreted in the context of the study design. Our study was limited to older men the majority of whom were white, and our findings may or may not be generalisable to other populations. It is difficult to know how to interpret methylation of retrotransposons, as opposed to gene-specific methylation, in relation to specific outcomes such as lung function and lung function decline. Future studies in this and other cohorts should include gene-specific methylation analyses similar to Qiu et al
to elucidate mechanisms by which methylation changes may relate to these outcomes. We did not control for a variety of environmental exposures that may be associated with both lung function and methylation. However, alteration in methylation patterns may be the pathway through which these changes are mediated and thus including these exposures in multivariate models would be overadjusting. Methylation levels vary in different tissue types and it is possible that assessments of methylation in white blood cells may not reflect alterations seen in lung tissue. However, systemic processes involving white blood cells, such as inflammation, may play a role in the pathophysiology of lung function decline,48
and may nonetheless be markers of specific exposures (such as cigarette smoking) that exert a systemic effect.
In summary, we found that relative hypomethylation of Alu was associated with lower lung function measures, and that LINE-1 hypomethylation was associated with more rapid lung function decline. Future studies on both gene-specific methylation as well as exposures related to methylation of retrotransposons will improve our understanding of the relationship between epigenetic changes and lung function, potentially informing new diagnostic and therapeutic approaches to lung function decline and diseases such as COPD.