Lung function discordance in monozygotic twins and associated differences in blood DNA methylation

Abstract

BackgroundLung function is an important predictor of morbidity and mortality, with accelerated lung function decline reported to have immense consequences for the world’s healthcare systems. The lung function decline across individual’s lifetime is a consequence of age-related changes in lung anatomical structure and combination of various environmental factors; however, the exact molecular mechanisms contributing to this decline are not fully understood. DNA methylation is an epigenetic modification that changes across individual’s lifetime, as well as allows for interplay between environmental and genetic factors. DNA methylation plays a crucial role in regulation of gene expression, with increasing evidence linking aberrant DNA methylation levels with a number of common human diseases. In this study, we investigated possible associations between genome-wide DNA methylation levels and lung function in 169 pairs of middle-aged monozygotic twins (86 male pairs: mean age (min-max) = 66 years (57–79); 83 female pairs: mean age (min-max) = 66 years (56–78)). The twins were collected from the Danish Twin Registry and were examined at baseline (1998–1999) and follow-up (2008–2011) visits. Using the twin design, we correlated intra-pair differences in cross-sectional and longitudinal lung function with intra-pair blood DNA methylation differences at follow-up by linear regression analyses adjusted for sex, age, BMI, smoking, and blood cell composition measured for each individual with the use of flow cytometry.ResultsWe identified several differentially methylated CpG sites associated with forced expiratory volume the first second (FEV1) and forced vital capacity (FVC). Three probes identified for level of FVC were located in GLIPR1L2 gene (lowest p value = 7.14 × 10−8), involved in innate immunity and tumour-suppressor/pro-oncogenic mechanisms. Change in FEV1 during the 11-year follow-up period was associated with blood DNA methylation level in TRIM27 gene (p value = 1.55 × 10−6), a negative regulator of CD4 T cells, and also involved in cancer development. Several enriched pathways were identified, especially for FEV1, with one being “TGFBR” (Benjamini-Hochbergadj p value = 0.045), the receptor for TGFβ, a growth factor involved in normal lung tissue repair through pro-fibrotic effects.ConclusionsOur findings suggest that epigenetic regulation of immunological- and cancer-related genes, as well as TGF-β-receptor-related genes, may be involved in the cross-sectional level and longitudinal change in lung function in middle-aged monozygotic twins.Electronic supplementary materialThe online version of this article (10.1186/s13148-017-0427-2) contains supplementary material, which is available to authorized users.

SERPINA1 methylation and lung function in tobacco-smoke exposed European children and adults: a meta-analysis of ALEC population-based cohorts

“…Similarly no cross-sectional association with post-bronchodilation lung function was observed for SERPINA1 gene methylation measured in blood samples from a small rural Korean COPD case-control study [ 29 ]. Furthermore, in a study of middle-aged monozygotic twins, DNAm in SERPINA1 was not associated with intra-pair differences in lung function decline [ 30 ].…”

Quantification of the pace of biological aging in humans through a blood test: The DunedinPoAm DNA methylation algorithm

“…Step 3, which we report here, we distill the Pace of Aging into a measurement that can be obtained from a single blood sample. Here we focused on blood DNA methylation as an accessible molecular measurement that is sensitive to changes in physiology occurring in multiple organ systems (Birney et al, 2016;Bolund et al, 2017;Chambers et al, 2015;Chu et al, 2017;Hedman Åsa K. et al, 2017;Ma et al, 2019;Mill and Heijmans, 2013;Morris et al, 2017;Wahl et al, 2017). We used data about the Pace of Aging from age 26 to 38 years in the Dunedin Study along with whole-genome methylation data at age 38 years.…”

Polyamine Metabolism and Gene Methylation in Conjunction with One-Carbon Metabolism

“…These twins share the same genes and they developed in the same environment. However, a considerable difference in DNA methylation pattern is observed in aged twins in comparison with young twins [ 176 , 177 ]. Many environmental factors have been shown to affect DNA methylation status.…”