Torben Sigsgaard

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

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

DOI

  • Anneli C S Bolund
  • Anna Starnawska
  • Martin R Miller, Institute of Occupational and Environmental Medicine, University of Birmingham, Birmingham, Storbritannien
  • Vivi Schlünssen
  • Vibeke Backer, Department of Respiratory Medicine, Bispebjerg University Hospital, Copenhagen, Denmark., Danmark
  • Anders D Børglum
  • Kaare Christensen, The Danish Twin Registry, Institute of Public Health, University of Southern Denmark, Odense, Denmark., The Danish Aging Research Center, Epidemiology, Biostatistics and Biodemography, Institute of Public Health, University of Southern Denmark, Odense, Denmark., Department of Clinical Genetics, Odense University Hospital, Odense, Denmark., 4 Department of Clinical Biochemistry and Pharmacology, Odense University Hospital , Odense C, Denmark ., Danmark
  • Qihua Tan, Department of Clinical Genetics, Odense University Hospital, Odense, Denmark., Danmark
  • Lene Christiansen, The Danish Twin Registry, Institute of Public Health, University of Southern Denmark, Odense, Denmark., The Danish Aging Research Center, Epidemiology, Biostatistics and Biodemography, Institute of Public Health, University of Southern Denmark, Odense, Denmark.
  • ,
  • Torben Sigsgaard

Background: Lung 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.

Results: We 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-Hochbergadjp value = 0.045), the receptor for TGFβ, a growth factor involved in normal lung tissue repair through pro-fibrotic effects.

Conclusions: Our 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.

OriginalsprogEngelsk
TidsskriftClinical Epigenetics (Print)
Vol/bind9
Sider (fra-til)132
Antal sider13
ISSN1868-7075
DOI
StatusUdgivet - 2017

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