University of Oulu

Parmar, P., Lowry, E., Cugliari, G., Suderman, M., Wilson, R., Karhunen, V., Andrew, T., Wiklund, P., Wielscher, M., Guarrera, S., Teumer, A., Lehne, B., Milani, L., de Klein, N., Mishra, P., Melton, P., Mandaviya, P., Kasela, S., Nano, J., Zhang, W., Zhang, Y., Uitterlinden, A., Peters, A., Schöttker, B., Gieger, C., Anderson, D., Boomsma, D., Grabe, H., Panico, S., Veldink, J., van Meurs, J., van den Berg, L., Beilin, L., Franke, L., Loh, M., van Greevenbroek, M., Nauck, M., Kähönen, M., Hurme, M., Raitakari, O., Franco, O., Slagboom, P., van der Harst, P., Kunze, S., Felix, S., Zhang, T., Chen, W., Mori, T., Bonnefond, A., Heijmans, B., Muka, T., Kooner, J., Fischer, K., Waldenberger, M., Froguel, P., Huang, R., Lehtimäki, T., Rathmann, W., Relton, C., Matullo, G., Brenner, H., Verweij, N., Li, S., Chambers, J., Järvelin, M., Sebert, S. (2018) Association of maternal prenatal smoking GFI1-locus and cardio-metabolic phenotypes in 18,212 adults. EBioMedicine, 38 (), 206-216. doi:10.1016/j.ebiom.2018.10.066

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

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Author: Parmar, Priyanka1,2; Lowry, Estelle1,2; Cugliari, Giovanni3,4;
Organizations: 1Univ Oulu, Ctr Life Course Hlth Res, Oulu, Finland.
2Univ Oulu, Bioctr Oulu, Oulu, Finland.
3Univ Turin, Dept Med Sci, Turin, Italy.
4IIGM, Turin, Italy.
5Univ Bristol, Bristol Med Sch, MRC Integrat Epidemiol Unit, Populat Hlth Sci, Bristol, Avon, England.
6Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Bavaria, Germany.
7Helmholtz Zentrum Munchen, Inst Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Bavaria, Germany.
8Imperial Coll London, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.
9Imperial Coll London, Dept Med, Genom Common Dis, London, England.
10Univ Jyvaskyla, Dept Hlth Sci, Jyvaskyla, Finland.
11Univ Med Greifswald, Dept Internal Med B, Greifswald, Germany.
12Univ Tartu, Estonian Genome Ctr, Inst Genom, Tartu, Estonia.
13Uppsala Univ, Dept Med Sci, Sci Life Lab, Uppsala, Sweden.
14Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands.
15Fimlab Labs, Dept Clin Chem, Tampere, Finland.
16Univ Tampere, Fac Med & Life Sci, Dept Clin Chem, Finnish Cardiovasc Res Ctr Tampere, Tampere, Finland.
17Curtin Univ, Sch Pharm & Biomed Sci, Bentley, WA, Australia.
18Univ Western Australia, Curtin UWA Ctr Genet Origins Hlth & Dis, Sch Biomed Sci, Crawley, Australia.
19Erasmus Univ, Dept Internal Med, Med Ctr, Rotterdam, Netherlands.
20Erasmus Univ, Dept Epidemiol, Med Ctr, Rotterdam, Netherlands.
21North West Healthcare NHS Trust, Dept Cardiol, Ealing Hosp, London, England.
22German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany.
23German Ctr Cardiovasc Res DZHK, Partner Site Munich Heart Alliance, Munich, Germany.
24Heidelberg Univ, Network Aging Res, Bergheimer Str, Heidelberg, Germany.
25Univ Western Australia, Telethon Kids Inst, Perth, WA, Australia.
26Vrije Univ Amsterdam, Sch Publ Hlth, Dept Biol Psychol, Amsterdam, Netherlands.
27Univ Med Greifswald, Dept Psychiat & Psychotherapy, Greifswald, Germany.
28German Ctr Neurodegenerat Dis DZNF, Site Rostock Greifswald, Greifswald, Germany.
29Univ Naples Federico II, Dept Clin Med & Surg, Naples, Italy.
30Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Neurol, Utrecht, Netherlands.
31Univ Western Australia, Med Sch, Perth, WA, Australia.
32ASTAR, TLGM, 8A Biomed Grove,Level 5, Singapore, Singapore.
33Univ Oulu, Inst Hlth Sci, Oulu, Finland.
34Maastricht Univ, Dept Internal Med, Med Ctr, Maastricht, Netherlands.
35Maastricht Univ, Sch Cardiovasc Dis CARIM, Med Ctr, Maastricht, Netherlands.
36DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany.
37Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany.
38Tampere Univ Hosp, Dept Clin Physiol, Tampere, Finland.
39Univ Tampere, Fac Med & Life Sci, Finnish Cardiovasc Res Ctr Tampere, Dept Clin Physiol, Tampere, Finland.
40Fac Med & Life Sci Univ Tampere, Dept Microbiol & Immunol, Tampere, Finland.
41Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku, Finland.
42Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland.
43Leiden Univ, Dept Biomed Data Sci, Mol Epidemiol, Med Ctr, Leiden, Netherlands.
44Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands.
45ICIN Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, Utrecht, Netherlands.
46Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA USA.
47Shandong Univ, Sch Publ Hlth, Dept Biostat, Jinan, Shandong, Peoples R China.
48Univ Lille, EGID, Inst Pasteur Lille, CMS UMR 8199, Lille, France.
49Imperial Coll London, Natl Heart & Lung Inst, London, England.
50Childrens Minnesota Res Inst, Childrens Hosp & Clin, Minneapolis, MN 55404 USA.
51Heine Univ, Inst Biometr & Epidemiol, Leibniz Ctr Diabet Res Heinrich, German Diabet Ctr, Dusseldorf, Germany.
52Imperial Coll Healthcare NHS Trust, London, England.
53Nanyang Technol Univ Singapore, Lee Kong Chian Sch Med, Singapore, Singapore.
54Brunel Univ London, Dept Life Sci, Coll Hlth & Life Sci, Uxbridge, Middx, England.
55Univ Oulu, Med Res Ctr MRC Oulu, Oulu Univ Hosp, Oulu, Finland.
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1 MB)
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Language: English
Published: Elsevier, 2018
Publish Date: 2019-05-06


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.

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Series: EBioMedicine
ISSN: 2352-3964
ISSN-E: 2352-3964
ISSN-L: 2352-3964
Volume: 38
Pages: 206 - 216
DOI: 10.1016/j.ebiom.2018.10.066
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Funding: The UK Medical Research Council and Wellcome (grant number 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and Matthew Suderman will serve as guarantor for the ALSPAC-related contents of this paper. Analysis of the ALSPAC data was funded by UK Economic & Social Research Council grant (grant number ES/N000498/1). ARIES was funded by the BBSRC (BBI025751/1 and BB/I025263/ 1). Supplementary funding to generate DNA methylation data which are (or will be) included in ARIES has been obtained from the MRC, ESRC, NIH and other sources. ARIES is maintained under the auspices of the MRC Integrative Epidemiology Unit at the University of Bristol (grant numbers MC_UU_12013/2, MC_UU_12013/8 and MC_UU_12013/9). Matthew Suderman was supported by the BBSRC and ESRC (grant number ES/N000498/1). BHS The study is supported by grant 2R01AG016592 from the National Institute on Aging. Shengxu Li was partly supportly by grant 13SDG14650068 from the American Heart Association. NTR, LLS, CODAM and PAN were supported from the Netherlands Cardiovascular Research Initiative (the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences) for the GENIUS project “Generating the best evidence-based pharmaceutical targets for atherosclerosis” (CVON2011–19). This work was performed within the framework of the Biobank-Based Integrative Omics Studies (BIOS) Consortium funded by BBMRI-NL, a research infrastructure financed by the Dutch government (NWO 184.021.007). EGCUT was supported by the Estonian Research Council Grants PRG184, PUT1665, IUT20-60, EU H2020 grant ePerMed (Grant No. 692145), and European Union through the European Regional Development Fund (Project No. 2014–2020.4.01.15–0012). Lili Milani was supported by Uppsala University Strategic Research Grant as part of the Science for Life Laboratory fellowship program. EPICOR was supported by the Compagnia di San Paolo for the EPIC-Italy and EPICOR projects, the Italian Institute for Genomic Medicine (IIGM, formerly Human Genetics Foundation-Torino, HuGeF, Turin, Italy) and the MIUR ex60% grant. EPIC-Italy is further supported by a grant from the “Associazione Italiana per la Ricerca sul Cancro” (AIRC, Milan). The EPICOR study was also supported by a MIUR grant to the Department of Medical Sciences, project “Dipartimenti di Eccellenza 2018 – 2022”. The ESTHER study was supported by the Baden-Württemberg State Ministry of Science, Research and Arts (Stuttgart, Germany), the Federal Ministry of Education and Research (Berlin, Germany), and the Federal Ministry of Family Affairs, Senior Citizens, Women and Youth (Berlin, Germany). The KORA study was initiated and financed by the Helmholtz Zentrum München – German Research Centre for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research has been supported within the Munich Centre of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. The research leading to these results has received funding from the European Union Seventh Framework Program under grant agreement [n°602736] (Multi-dimensional omics approach to stratification of patients with low back pain - PAIN-OMICS; and under grant agreement [n°603288] (Systems Biology to Identify Molecular Targets for Vascular Disease Treatment – SysVasc; This work was further supported by a grant (WA 4081/1–1) from the German Research Foundation. N. Verweij was supported by NWO VENI (016.186.125). L. Franke is supported by ZonMW-VIDI 917.14.374 and ERC Starting Grant, grant agreement 637640 (ImmRisk). The LOLIPOP study is supported by the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust, the British Heart Foundation (SP/04/002), the Medical Research Council (G0601966, G0700931), the Wellcome Trust (084723/Z/08/Z, 090532 & 098381) the NIHR (RP-PG-0407-10371), the NIHR Official Development Assistance (ODA, award 16/136/68), the European Union FP7 (EpiMigrant, 279143) and H2020 programs (iHealth-T2D, 643774). John Chambers is supported by Singapore Ministry of Health's National Medical Research Council under its Singapore Translational Research Investigator (STaR) Award (NMRC/STaR/0028/2017). NFBC1966 received financial support from University of Oulu Grant no. 65354, Oulu University Hospital Grant no. 2/97, 8/97, Ministry of Health and Social Affairs Grant no. 23/251/97, 160/97, 190/97, National Institute for Health and Welfare, Helsinki Grant no. 54121, Regional Institute of Occupational Health, Oulu, Finland Grant no. 50621, 54231. NFBC1986 received financial support from EU QLG1-CT-2000-01643 (EUROBLCS) Grant no. E51560, NorFA Grant no. 731, 20056, 30167, USA / NIHH 2000 G DF682 Grant no. 50945. MRC no: MR/M013138/1, ERDF European Regional Development Fund Grant no. 539/2010 A31592. Matthias Wielscher was supported by the European Union's Horizon 2020 research and innovation program under grant agreement No 633212. Priyanka Parmar, Sylvain Sebert and Marjo-Riitta Jarvelin received support by H2020–633595 DynaHEALTH, H2020 733206 LifeCycle, the academy of Finland EGEA-project (285547) and the Biocenter Oulu. The authors acknowledge the contributions to core funding of the Raine Study by the University of Western Australia, the Telethon Kids Institute, the Raine Medical Research Foundation, the Faculty of Medicine, Dentistry and Health Science (UWA), the Women and Infants Research Foundation, Curtin University, and Edith Cowan University. The authors also acknowledge the long-term support of the National Health and Medical Research Council of Australia (NHMRC). The epigenetic data collection is supported by NHMRC grant #1059711. Rae-Chi Huang and Trevor A Mori are supported by NHMRC Research Fellowships #1053384 and #1042255, respectively. The Rotterdam Study is funded by Erasmus Medical Centre and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The EWAS data was funded by the Genetic Laboratory of the Department of Internal Medicine, Erasmus Medical Centre, and by the Netherlands Organization for Scientific Research (NWO; project no. 184021007) and made available as a Rainbow Project (RP3; BIOS) of the Bio banking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL). SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network ‘Greifswald Approach to Individualized Medicine (GANI_MED)’ funded by the Federal Ministry of Education and Research (grant 03IS2061A). DNA methylation data have been supported by the DZHK (grant 81 × 34000104). The University of Greifswald is a member of the Caché Campus program of the InterSystems GmbH. The YFS has been financially supported by the Academy of Finland: grants 286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi); the Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals (grant X51001); Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research; Finnish Cultural Foundation; The Sigrid Juselius Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Yrjö Jahnsson Foundation; Signe and Ane Gyllenberg Foundation; Diabetes Research Foundation of Finnish Diabetes Association; and EU Horizon 2020 (grant 755320 for TAXINOMISIS); and European Research Council (grant 742927 for MULTIEPIGEN project); Tampere University Hospital Supporting Foundation.
EU Grant Number: (279143) EPI-MIGRANT - Identification of epigenetic markers underlying increased risk of T2D in South Asians
(643774) iHealth-T2D - Family-based intervention to improve healthy lifestyle and prevent Type 2 Diabetes amongst South Asians with central obesity and prediabetes
(633595) DYNAHEALTH - Understanding the dynamic determinants of glucose homeostasis and social capability to promote Healthy and active aging
(733206) LIFECYCLE - Early-life stressors and LifeCycle health
Academy of Finland Grant Number: 285547
Detailed Information: 285547 (Academy of Finland Funding decision)
Copyright information: © 2018 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (