Association of maternal prenatal smoking GFI1-locus and cardio-metabolic phenotypes in 18,212 adults

Anno:

2018

Association of maternal prenatal smoking GFI1-locus and cardio-metabolic phenotypes in 18,212 adults

Parmar P1, Lowry E1, Cugliari G2, Suderman M3, Wilson R4, Karhunen V5, Andrew T6, Wiklund P7, Wielscher M5, Guarrera S2, Teumer A8, Lehne B5, Milani L9, de Klein N10, Mishra PP11, Melton PE12, Mandaviya PR13, Kasela S14, Nano J15, Zhang W16, Zhang Y17, Uitterlinden AG18, Peters A19, Schöttker B20, Gieger C19, Anderson D21, Boomsma DI22, Grabe HJ23, Panico S24, Veldink JH25, van Meurs JBJ13, van den Berg L25, Beilin LJ26, Franke L10, Loh M27, van Greevenbroek MMJ28, Nauck M29, Kähönen M30, Hurme MA31, Raitakari OT32, Franco OH33, Slagboom PE34, van der Harst P35, Kunze S4, Felix SB36, Zhang T37, Chen W38, Mori TA26, Bonnefond A39, Heijmans BT34; BIOS Consortium, Muka T33, Kooner JS40, Fischer K14, Waldenberger M19, Froguel P39, Huang RC21, Lehtimäki T11, Rathmann W41, Relton CL3, Matullo G2, Brenner H20, Verweij N42, Li S43, Chambers JC44, Järvelin MR45, Sebert S46; GLOBAL Meth QTL Consortium.

Medicine. 2018 Dec;38:206-216. doi: 10.1016/j.ebiom.2018.10.066. Epub 2018 Nov 13. PMID 30442561

Author information

1: Center for Life Course Health Research, University of Oulu, Oulu, Finland; Biocenter Oulu, University of Oulu, Oulu, Finland.
2: Department of Medical Sciences, University of Turin, Turin, Italy; Italian Institute for Genomic Medicine, IIGM, Turin, Italy.
3: MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, UK.
4: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Bavaria, Germany; Helmholtz Zentrum München, German Research Centre for Environmental Health, Institute of Epidemiology, Neuherberg, Bavaria, Germany.
5: Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London.
6: Genomics of Common Disease, Department of Medicine, Imperial College London, London, UK.
7: Center for Life Course Health Research, University of Oulu, Oulu, Finland; Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London; Department of Health Sciences, University of Jyväskylä, Jyväskylä, Finland.
8: Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany; Partner Site Greifswald, DZHK (German Centre for Cardiovascular Research), Greifswald, Germany.
9: Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia; Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Sweden.
10: Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
11: Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland; Department of Clinical Chemistry, Finnish Cardiovascular Research Centre - Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
12: School of Pharmacy and Biomedical Sciences, Curtin University, Bentley, Australia; Curtin UWA Centre for Genetic Origins of Health and Disease, School of Biomedical Sciences, The University of Western Australia, Crawley, Australia.
13: Department of Internal Medicine, Erasmus University Medical Centre, Rotterdam, The Netherlands.
14: Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
15: Helmholtz Zentrum München, German Research Centre for Environmental Health, Institute of Epidemiology, Neuherberg, Bavaria, Germany; Department of Epidemiology, Erasmus University Medical Centre, Rotterdam, The Netherlands.
16: Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London; Department of Cardiology, Ealing Hospital, North West Healthcare NHS Trust, London, UK.
17: Division of Clinical Epidemiology and Aging Research, German Cancer Research Centre (DKFZ), Im Neuenheimer Feld, Heidelberg, Germany.
18: Department of Internal Medicine, Erasmus University Medical Centre, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus University Medical Centre, Rotterdam, The Netherlands.
19: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Bavaria, Germany; Helmholtz Zentrum München, German Research Centre for Environmental Health, Institute of Epidemiology, Neuherberg, Bavaria, Germany; German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.
20: Division of Clinical Epidemiology and Aging Research, German Cancer Research Centre (DKFZ), Im Neuenheimer Feld, Heidelberg, Germany; Network Aging Research, University of Heidelberg, Bergheimer Straße, Heidelberg, Germany.
21: Telethon Kids Institute, University of Western Australia, Perth, Australia.
22: Department of Biological Psychology, School of Public Health, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
23: Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany; German Centre for Neurodegenerative Diseases DZNE, Site Rostock/Greifswald, Greifswald, Germany.
24: Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.
25: Department of Neurology, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht, The Netherlands.
26: Medical School, University of Western Australia, Perth, Australia.
27: Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London; Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos, Level 5, Singapore, Singapore; Institute of Health Sciences, University of Oulu, Finland.
28: Department of Internal Medicine and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Centre, Maastricht, The Netherlands.
29: Partner Site Greifswald, DZHK (German Centre for Cardiovascular Research), Greifswald, Germany; Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
30: Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland; Department of Clinical Physiology, Finnish Cardiovascular Research Centre - Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
31: Department of Microbiology and Immunology, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
32: Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland; Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
33: Department of Epidemiology, Erasmus University Medical Centre, Rotterdam, The Netherlands.
34: Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Centre, Leiden, The Netherlands.
35: Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands; Department of Cardiology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands; Durrer Centre for Cardiogenetic Research, ICIN - Netherlands Heart Institute, Utrecht, The Netherlands.
36: Partner Site Greifswald, DZHK (German Centre for Cardiovascular Research), Greifswald, Germany.
37: Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, USA; Department of Biostatistics, School of Public Health, Shandong University, Jinan, China.
38: Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, USA.
39: Genomics of Common Disease, Department of Medicine, Imperial College London, London, UK; European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, CNRS UMR 8199, Lille, France.
40: Department of Cardiology, Ealing Hospital, North West Healthcare NHS Trust, London, UK; Imperial College Healthcare NHS Trust, London, UK; Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London; Imperial College London, National Heart and Lung Institute, London, UK.
41: Institute for Biometrics and Epidemiology, German Diabetes Centre, Leibniz Centre for Diabetes Research at Heinrich, Heine University, Düsseldorf, Germany.
42: Department of Cardiology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
43: Children's Hospitals and Clinics of Minnesota, Children's Minnesota Research Institute, Minneapolis, MN 55404, USA.
44: Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London; Department of Cardiology, Ealing Hospital, North West Healthcare NHS Trust, London, UK; Imperial College Healthcare NHS Trust, London, UK; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
45: Center for Life Course Health Research, University of Oulu, Oulu, Finland; Biocenter Oulu, University of Oulu, Oulu, Finland; Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London; Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Uxbridge, UK. Electronic address: m.jarvelin@imperial.ac.uk.
46: Center for Life Course Health Research, University of Oulu, Oulu, Finland; Biocenter Oulu, University of Oulu, Oulu, Finland; Medical Research Centre (MRC) Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland. Electronic address: sylvain.sebert@oulu.fi.

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 × 10-7 < P < 0.01). Similarly, lower DNA methylation at cg12876356, cg18316974, cg09662411, and cg18146737 was associated with decreased BMI and WC (5 × 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.