Association of maternal prenatal smoking GFI1-locus and cardiometabolic phenotypes in 18,212 adults
Abstract
Background: DNA methylation at the GFI1-locus has been repeatedly associated with exposure to smoking from the foetal period onwards. We explored whether DNA methylation may be a mechanism that links exposure to maternal prenatal smoking with offspring's adult cardio-metabolic health. Methods: We meta-analysed the association between DNA methylation at GFI1-locus with maternal prenatal smoking, adult own smoking, and cardio-metabolic phenotypes in 22 population-based studies from Europe, Australia, and USA (n= 18,212). DNA methylation at the GFI1-locus was measured in whole-blood. Multivariable regression models were fitted to examine its association with exposure to prenatal and own adult smoking. DNA methylation levels were analysed in relation to body mass index (BMI), waist circumference (WC), fasting glucose (FG), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), diastolic, and systolic blood pressure (BP). Findings: Lower DNA methylation at three out of eight GFI1-CpGs was associated with exposure to maternal prenatal smoking, whereas, all eight CpGs were associated with adult own smoking. Lower DNA methylation at cg14179389, the strongest maternal prenatal smoking locus, was associated with increased WC and BP when adjusted for sex, age, and adult smoking with Bonferroni-corrected P < 0.012. In contrast, lower DNA methylation at cg09935388, the strongest adult own smoking locus, was associated with decreased BMI, WC, and BP (adjusted 1 x 10(-7) < P < 0.01). Similarly, lower DNA methylation at cg12876356, cg18316974, cg09662411, and cg18146737 was associated with decreased BMI and WC (5 x 10(-8) < P < 0.001). Lower DNA methylation at all the CpGs was consistently associated with higher TG levels. Interpretation: Epigenetic changes at the GFI1 were linked to smoking exposure in-utero/in-adulthood and robustly associated with cardio-metabolic risk factors. Fund: European Union's Horizon 2020 research and innovation programme under grant agreement no. 633595 DynaHEALTH.
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Uppsala universitet, Molekylär medicin; Univ Oulu, Ctr Life Course Hlth Res, Oulu, Finland;Univ Oulu, Bioctr Oulu, Oulu, Finland; Univ Turin, Dept Med Sci, Turin, Italy;IIGM, Turin, Italy; Univ Bristol, Bristol Med Sch, MRC Integrat Epidemiol Unit, Populat Hlth Sci, Bristol, Avon, England; Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Bavaria, Germany;Helmholtz Zentrum Munchen, Inst Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Bavaria, Germany; Imperial Coll London, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England; Imperial Coll London, Dept Med, Genom Common Dis, London, England; Univ Oulu, Ctr Life Course Hlth Res, Oulu, Finland;Imperial Coll London, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England;Univ Jyvaskyla, Dept Hlth Sci, Jyvaskyla, Finland; Univ Med Greifswald, Dept Internal Med B, Greifswald, Germany; Univ Tartu, Estonian Genome Ctr, Inst Genom, Tartu, Estonia; Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands; Fimlab Labs, Dept Clin Chem, Tampere, Finland;Univ Tampere, Fac Med & Life Sci, Dept Clin Chem, Finnish Cardiovasc Res Ctr Tampere, Tampere, Finland; Curtin Univ, Sch Pharm & Biomed Sci, Bentley, WA, Australia;Univ Western Australia, Curtin UWA Ctr Genet Origins Hlth & Dis, Sch Biomed Sci, Crawley, Australia; Erasmus Univ, Dept Internal Med, Med Ctr, Rotterdam, Netherlands; Helmholtz Zentrum Munchen, Inst Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Bavaria, Germany;Erasmus Univ, Dept Epidemiol, Med Ctr, Rotterdam, Netherlands; Imperial Coll London, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England;North West Healthcare NHS Trust, Dept Cardiol, Ealing Hosp, London, England; German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany; Erasmus Univ, Dept Internal Med, Med Ctr, Rotterdam, Netherlands;Erasmus Univ, Dept Epidemiol, Med Ctr, Rotterdam, Netherlands; Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Bavaria, Germany;Helmholtz Zentrum Munchen, Inst Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Bavaria, Germany;German Ctr Cardiovasc Res DZHK, Partner Site Munich Heart Alliance, Munich, Germany; German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany;Heidelberg Univ, Network Aging Res, Bergheimer Str, Heidelberg, Germany; Univ Western Australia, Telethon Kids Inst, Perth, WA, Australia; Vrije Univ Amsterdam, Sch Publ Hlth, Dept Biol Psychol, Amsterdam, Netherlands; Univ Med Greifswald, Dept Psychiat & Psychotherapy, Greifswald, Germany;German Ctr Neurodegenerat Dis DZNF, Site Rostock Greifswald, Greifswald, Germany; Univ Naples Federico II, Dept Clin Med & Surg, Naples, Italy; Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Neurol, Utrecht, Netherlands; Univ Western Australia, Med Sch, Perth, WA, Australia; Imperial Coll London, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England;ASTAR, TLGM, 8A Biomed Grove,Level 5, Singapore, Singapore;Univ Oulu, Inst Hlth Sci, Oulu, Finland; Maastricht Univ, Dept Internal Med, Med Ctr, Maastricht, Netherlands;Maastricht Univ, Sch Cardiovasc Dis CARIM, Med Ctr, Maastricht, Netherlands; DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany;Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany; Tampere Univ Hosp, Dept Clin Physiol, Tampere, Finland;Univ Tampere, Fac Med & Life Sci, Finnish Cardiovasc Res Ctr Tampere, Dept Clin Physiol, Tampere, Finland; Fac Med & Life Sci Univ Tampere, Dept Microbiol & Immunol, Tampere, Finland; Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku, Finland;Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland; Erasmus Univ, Dept Epidemiol, Med Ctr, Rotterdam, Netherlands; Leiden Univ, Dept Biomed Data Sci, Mol Epidemiol, Med Ctr, Leiden, Netherlands; Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands;Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands;ICIN Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, Utrecht, Netherlands; DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany; Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA USA;Shandong Univ, Sch Publ Hlth, Dept Biostat, Jinan, Shandong, Peoples R China; Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA USA; Imperial Coll London, Dept Med, Genom Common Dis, London, England;Univ Lille, EGID, Inst Pasteur Lille, CMS UMR 8199, Lille, France; Imperial Coll London, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England;North West Healthcare NHS Trust, Dept Cardiol, Ealing Hosp, London, England;Imperial Coll London, Natl Heart & Lung Inst, London, England;Childrens Minnesota Res Inst, Childrens Hosp & Clin, Minneapolis, MN 55404 USA; Heine Univ, Inst Biometr & Epidemiol, Leibniz Ctr Diabet Res Heinrich, German Diabet Ctr, Dusseldorf, Germany; Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands; Childrens Minnesota Res Inst, Childrens Hosp & Clin, Minneapolis, MN 55404 USA; Imperial Coll London, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England;North West Healthcare NHS Trust, Dept Cardiol, Ealing Hosp, London, England;Imperial Coll Healthcare NHS Trust, London, England;Nanyang Technol Univ Singapore, Lee Kong Chian Sch Med, Singapore, Singapore; Univ Oulu, Ctr Life Course Hlth Res, Oulu, Finland;Univ Oulu, Bioctr Oulu, Oulu, Finland;Imperial Coll London, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England;Brunel Univ London, Dept Life Sci, Coll Hlth & Life Sci, Uxbridge, Middx, England; Univ Oulu, Ctr Life Course Hlth Res, Oulu, Finland;Univ Oulu, Bioctr Oulu, Oulu, Finland;Univ Oulu, Med Res Ctr MRC Oulu, Oulu Univ Hosp, Oulu, Finland
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