title: Hormone Replacement Therapy Associated White Blood Cell DNA Methylation and Gene Expression are Associated With Within-Pair Differences of Body Adiposity and Bone Mass.
abstract: The loss of estrogen during menopause causes changes in the female body, with wide-ranging effects on health. Estrogen-containing hormone replacement therapy (HRT) leads to a relief of typical menopausal symptoms, benefits bone and muscle health, and is associated with tissue-specific gene expression profiles. As gene expression is controlled by epigenetic factors (including DNA methylation), many of which are environmentally sensitive, it is plausible that at least part of the HRT-associated gene expression is due to changes in DNA methylation profile. We investigated genome-wide DNA methylation and gene expression patterns of white blood cells (WBCs) and their associations with body composition, including muscle and bone measures of monozygotic (MZ) female twin pairs discordant for HRT. We identified 7,855 nominally significant differentially methylated regions (DMRs) associated with 4,044 genes. Of the genes with DMRs, five (ACBA1, CCL5, FASLG, PPP2R2B, and UHRF1) were also differentially expressed. All have been previously associated with HRT or estrogenic regulation, but not with HRT-associated DNA methylation. All five genes were associated with bone mineral content (BMC), and ABCA1, FASLG, and UHRF1 were also associated with body adiposity. Our study is the first to show that HRT associates with genome-wide DNA methylation alterations in WBCs. Moreover, we show that five differentially expressed genes with DMRs associate with clinical measures, including body fat percentage, lean body mass, bone mass, and blood lipids. Our results indicate that at least part of the known beneficial HRT effects on body composition and bone mass may be regulated by DNA methylation associated alterations in gene expression in circulating WBCs.
authors.affiliation: Department of Public Health,University of Helsinki,Helsinki,Finland.
authors.forename: Aileen
authors.initials: A
authors.lastname: Bahl
authors.affiliation: Gerontology Research Center,Department of Health Sciences,University of Jyväskylä,Jyväskylä,Finland.
authors.forename: Eija
authors.initials: E
authors.lastname: Pöllänen
authors.affiliation: Department of Public Health,University of Helsinki,Helsinki,Finland.
authors.forename: Khadeeja
authors.initials: K
authors.lastname: Ismail
authors.affiliation: Gerontology Research Center,Department of Health Sciences,University of Jyväskylä,Jyväskylä,Finland.
authors.forename: Sarianna
authors.initials: S
authors.lastname: Sipilä
authors.affiliation: Gerontology Research Center,Department of Health Sciences,University of Jyväskylä,Jyväskylä,Finland.
authors.forename: Tuija M
authors.initials: TM
authors.lastname: Mikkola
authors.affiliation: Department of Medical Sciences,Molecular Medicine and Science for Life Laboratory,Uppsala University,Uppsala,Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Berglund
authors.affiliation: Department of Medical Sciences,Molecular Medicine and Science for Life Laboratory,Uppsala University,Uppsala,Sweden.
authors.forename: Carl Mårten
authors.initials: CM
authors.lastname: Lindqvist
authors.affiliation: Department of Medical Sciences,Molecular Medicine and Science for Life Laboratory,Uppsala University,Uppsala,Sweden.
authors.forename: Ann-Christine
authors.initials: AC
authors.lastname: Syvänen
authors.affiliation: Gerontology Research Center,Department of Health Sciences,University of Jyväskylä,Jyväskylä,Finland.
authors.forename: Taina
authors.initials: T
authors.lastname: Rantanen
authors.affiliation: Department of Public Health,University of Helsinki,Helsinki,Finland.
authors.forename: Jaakko
authors.initials: J
authors.lastname: Kaprio
authors.affiliation: Gerontology Research Center,Department of Health Sciences,University of Jyväskylä,Jyväskylä,Finland.
authors.forename: Vuokko
authors.initials: V
authors.lastname: Kovanen
authors.affiliation: Department of Public Health,University of Helsinki,Helsinki,Finland.
authors.forename: Miina
authors.initials: M
authors.lastname: Ollikainen
mesh_terms: D050154:Adiposity / Q000235:genetics*; D015992:Body Mass Index; D015519:Bone Density; D019175:DNA Methylation; D005260:Female; D015870:Gene Expression; D055106:Genome-Wide Association Study; D020249:Hormone Replacement Therapy; D006801:Humans; D007962:Leukocytes; D017698:Postmenopause / Q000235:genetics*
keywords: DNA methylation; HRT; body composition; bone mineral content; discordant monozygotic twin pair design; epigenetic regulation; gene expression; hormone replacement therapy; menopause; skeletal muscle composition