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Meta-Analysis of Maternal Prenatal Smoking GFI1-Locus and Cardio-Metabolic Phenotypes in Adults

69 Pages Posted: 5 Oct 2018

See all articles by Priyanka Parmar

Priyanka Parmar

University of Oulu

Estelle Lowry

University of Oulu

Giovanni Cugliari

University of Turin - Department of Medical Sciences

Matthew Suderman

University of Bristol - Bristol Medical School

Rory P. Wilson

Swansea University - Swansea Lab for Animal Movement

Ville Karhunen

Imperial College London

Toby Andrew

Imperial College London

Petri Wiklund

University of Oulu

Matthias Wielscher

Imperial College London

Simonetta Guarrera

University of Turin - Department of Medical Sciences

Alexander Teumer

University of Greifswald - University Medicine Greifswald

Benjamin Lehne

Imperial College London

Lili Milani

University of Tartu

Niek de Klein

University of Groningen

Pashupati Mishra

Tampere University - Finnish Cardiovascular Research Centre - Tampere

Phillip Melton

Curtin University

Pooja R. Mandaviya

Erasmus University Rotterdam (EUR) - Erasmus Medical Center (MC)

Silva Kasela

University of Tartu

Jana Nano

Helmholtz Association of German Research Centres - German Research Centre for Environmental Health

Weihua Zhang

Imperial College London

Yan Zhang

Helmholtz Association of German Research Centres - German Research Centre for Environmental Health

Andre G. Uitterlinden

Erasmus University Rotterdam (EUR), Medical Center, Department of Internal Medicine ; Erasmus University Rotterdam (EUR), Medical Center, Department of Epidemiology

Annette Peters

Helmholtz Association of German Research Centres - German Research Centre for Environmental Health

Ben Schöttker

Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM GmbH) - German Cancer Research Center (DKFZ)

Christian Gieger

Helmholtz Association of German Research Centres - German Research Centre for Environmental Health

Denise Anderson

The University of Western Australia

Dorret I. Boomsma

VU University Amsterdam

Hans J. Grabe

University of Greifswald - University Medicine Greifswald

Jan H. Veldink

Utrecht University - Department of Neurology

Joyce B.J. van Meurs

Erasmus University Rotterdam (EUR) - Erasmus Medical Center (MC)

Leonard H. van den Berg

Utrecht University - Department of Neurology

Lawrence J. Beilin

The University of Western Australia

Lude Franke

University of Groningen - Groningen University Hospital

Marie Loh

Imperial College London

Marleen M.J. van Greevenbroek

University Hospital Maastricht

Matthias Nauck

University of Greifswald - University Medicine Greifswald

Mika Kähönen

Tampere University - Tampere University Hospital

Mikko A. Hurme

Tampere University

Olli Raitakari

University of Turku

Oscar H. Franco

Erasmus University Rotterdam (EUR) - Department of Epidemiology

Eline Slagboom

Leiden University - Medical Center (LUMC)

Pim van der Harst

University of Groningen - Department of Cardiology

Sonja Kunze

Helmholtz Association of German Research Centres - German Research Centre for Environmental Health

Stephan B. Felix

University of Greifswald - University Medicine Greifswald

Tao Zhang

Tulane University

Wei Chen

Tulane University

Trevor A. Mori

The University of Western Australia

Amelie Bonnefond

Imperial College London

B.T. Heijmans

University Medical Center

Taulant Muka

Erasmus University Rotterdam (EUR) - Erasmus Medical Center (MC)

Jaspal S. Kooner

Imperial College London

Krista Fischer

University of Tartu

Melanie Waldenberger

Helmholtz Association of German Research Centres - German Research Centre for Environmental Health

Philippe Froguel

Imperial College London

Rae-Chi Huang

The University of Western Australia

Terho Lehtimäki

University of Turku

Wolfgang Rathmann

Heinrich Heine University Dusseldorf

Caroline L. Relton

University of Bristol - Bristol Medical School

Giuseppe Matullo

University of Turin

Hermann Brenner

University of Kaiserslautern - German Research Center for Articial Intelligence (DFKI)

Niek Verweij

University of Groningen - Groningen University Hospital

Shengxu Li

Tulane University

John C. Chambers

Imperial College London

Marjo-Riitta Järvelin

University of Oulu

Sylvain P. Sébert

University of Oulu - Centre for Life Course Health Research

More...

Abstract

Background: DNA methylation at GFI1-locus has been repeatedly associated with exposure to smoking from foetal period onwards. We explored whether DNA methylation maybe a mechanism that links exposure to maternal prenatal smoking with offspring's adult cardio-metabolic health.

Methods: We meta-analysed the association between 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=18212). DNA methylation at GFI1-locus was measured in whole-blood. Multivariable regression analyses 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: Hypomethylation at four out of eight GFI1-CpGs was associated with exposure to maternal prenatal smoking, whereas, all eight CpGs were associated with adult own smoking. Cg14179389 hypomethylation, 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, hypomethylation 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, hypo-methylation at cg12876356, cg18316974, cg09662411, and cg18146737 was associated with decreased BMI and WC (5 x 10 - 8 < P < 0·001). Hypomethylation at all the CpGs was consistently associated with higher TG levels.

Interpretation: Epigenetic changes at GFI1 were linked to smoking exposure in-utero/in-adulthood and robustly associated with cardio-metabolic risk factors. This introduces a molecular mechanism and biomarker of smoking exposure.

Funding: Not applicable

Declaration of interests: The authors declare no competing interests.

Ethical Approval Statement: Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees.

Keywords: DNA Methylation, Maternal smoking, Adult Cardio-metabolic Health, Population Epigenetics

Suggested Citation

Parmar, Priyanka and Lowry, Estelle and Cugliari, Giovanni and Suderman, Matthew and Wilson, Rory P. and Karhunen, Ville and Andrew, Toby and Wiklund, Petri and Wielscher, Matthias and Guarrera, Simonetta and Teumer, Alexander and Lehne, Benjamin and Milani, Lili and de Klein, Niek and Mishra, Pashupati and Melton, Phillip and Mandaviya, Pooja R. and Kasela, Silva and Nano, Jana and Zhang, Weihua and Zhang, Yan and Uitterlinden, Andre G. and Peters, Annette and Schöttker, Ben and Gieger, Christian and Anderson, Denise and Boomsma, Dorret I. and Grabe, Hans J. and Veldink, Jan H. and van Meurs, Joyce B.J. and van den Berg, Leonard H. and Beilin, Lawrence J. and Franke, Lude and Loh, Marie and van Greevenbroek, Marleen M.J. and Nauck, Matthias and Kähönen, Mika and Hurme, Mikko A. and Raitakari, Olli and Franco, Oscar H. and Slagboom, Eline and van der Harst, Pim and Kunze, Sonja and Felix, Stephan B. and Zhang, Tao and Chen, Wei and Mori, Trevor A. and Bonnefond, Amelie and Heijmans, B.T. and Muka, Taulant and Kooner, Jaspal S. and Fischer, Krista and Waldenberger, Melanie and Froguel, Philippe and Huang, Rae-Chi and Lehtimäki, Terho and Rathmann, Wolfgang and Relton, Caroline L. and Matullo, Giuseppe and Brenner, Hermann and Verweij, Niek and Li, Shengxu and Chambers, John C. and Järvelin, Marjo-Riitta and Sébert, Sylvain P., Meta-Analysis of Maternal Prenatal Smoking GFI1-Locus and Cardio-Metabolic Phenotypes in Adults (August 22, 2018). Available at SSRN: https://ssrn.com/abstract=3237007

Priyanka Parmar

University of Oulu ( email )

P.O. Box 4600
Oulu FIN-90014
Finland

Estelle Lowry

University of Oulu

P.O. Box 4600
Oulu FIN-90014
Finland

Giovanni Cugliari

University of Turin - Department of Medical Sciences

Corso Dogliotti, 14
Torino, 10126
Italy

Matthew Suderman

University of Bristol - Bristol Medical School

Tyndall Avenue, Senate House
Bristol, BS8 1TH
United Kingdom

Rory P. Wilson

Swansea University - Swansea Lab for Animal Movement ( email )

Singleton Park
Swansea, Wales SA2 8PP
United Kingdom

Ville Karhunen

Imperial College London

South Kensington Campus
Exhibition Road
London, Greater London SW7 2AZ
United Kingdom

Toby Andrew

Imperial College London

South Kensington Campus
Exhibition Road
London, Greater London SW7 2AZ
United Kingdom

Petri Wiklund

University of Oulu

P.O. Box 4600
Oulu FIN-90014
Finland

Matthias Wielscher

Imperial College London

South Kensington Campus
Exhibition Road
London, Greater London SW7 2AZ
United Kingdom

Simonetta Guarrera

University of Turin - Department of Medical Sciences

Corso Dogliotti, 14
Torino, 10126
Italy

Alexander Teumer

University of Greifswald - University Medicine Greifswald

Fleischmannstraße 8
Greifswald, 17475
Germany

Benjamin Lehne

Imperial College London

South Kensington Campus
Exhibition Road
London, Greater London SW7 2AZ
United Kingdom

Lili Milani

University of Tartu

Ülikooli 18
Tartu 50090, 50090
Estonia

Niek De Klein

University of Groningen

P.O. Box 800
9700 AH Groningen, Groningen 9700 AV
Netherlands

Pashupati Mishra

Tampere University - Finnish Cardiovascular Research Centre - Tampere

Finland

Phillip Melton

Curtin University

Kent Street
Bentley
Perth, WA WA 6102
Australia

Pooja R. Mandaviya

Erasmus University Rotterdam (EUR) - Erasmus Medical Center (MC)

Doctor Molewaterplein 40
Rotterdam, South Holland 3015 GD
Netherlands

Silva Kasela

University of Tartu

Ülikooli 18
Tartu 50090, 50090
Estonia

Jana Nano

Helmholtz Association of German Research Centres - German Research Centre for Environmental Health

Ingolstädter Landstraße 1
Neuherberg, Bavaria D-85764
Germany

Weihua Zhang

Imperial College London

South Kensington Campus
Exhibition Road
London, Greater London SW7 2AZ
United Kingdom

Yan Zhang

Helmholtz Association of German Research Centres - German Research Centre for Environmental Health

Ingolstädter Landstraße 1
Neuherberg, Bavaria D-85764
Germany

Andre G. Uitterlinden

Erasmus University Rotterdam (EUR), Medical Center, Department of Internal Medicine

Doctor Molewaterplein 40
Rotterdam, South Holland 3015 GD
Netherlands

Erasmus University Rotterdam (EUR), Medical Center, Department of Epidemiology

Rotterdam
Netherlands

Annette Peters

Helmholtz Association of German Research Centres - German Research Centre for Environmental Health

Ingolstädter Landstraße 1
Neuherberg, Bavaria D-85764
Germany

Ben Schöttker

Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM GmbH) - German Cancer Research Center (DKFZ)

Im Neuenheimer Feld 280
Heidelberg, 69120
Germany

Christian Gieger

Helmholtz Association of German Research Centres - German Research Centre for Environmental Health

Ingolstädter Landstraße 1
Neuherberg, Bavaria D-85764
Germany

Denise Anderson

The University of Western Australia

35 Stirling Highway
Crawley, Western Australia 6009
Australia

Dorret I. Boomsma

VU University Amsterdam

De Boelelaan 1105
Amsterdam, ND North Holland 1081 HV
Netherlands

Hans J. Grabe

University of Greifswald - University Medicine Greifswald

Fleischmannstraße 8
Greifswald, 17475
Germany

Jan H. Veldink

Utrecht University - Department of Neurology

GA Utrecht
Netherlands

Joyce B.J. Van Meurs

Erasmus University Rotterdam (EUR) - Erasmus Medical Center (MC)

Doctor Molewaterplein 40
Rotterdam, South Holland 3015 GD
Netherlands

Leonard H. Van den Berg

Utrecht University - Department of Neurology

GA Utrecht
Netherlands

Lawrence J. Beilin

The University of Western Australia

35 Stirling Highway
Crawley, Western Australia 6009
Australia

Lude Franke

University of Groningen - Groningen University Hospital

P.O. Box 30.001
9700 AB Groningen
Netherlands

Marie Loh

Imperial College London

South Kensington Campus
Exhibition Road
London, Greater London SW7 2AZ
United Kingdom

Marleen M.J. Van Greevenbroek

University Hospital Maastricht

PO Box 5800
Maastricht, Limburg 6202 AZ
Netherlands

Matthias Nauck

University of Greifswald - University Medicine Greifswald

Fleischmannstraße 8
Greifswald, 17475
Germany

Mika Kähönen

Tampere University - Tampere University Hospital

Tampere
Finland

Mikko A. Hurme

Tampere University

Tampere, FIN-33101
Finland

Olli Raitakari

University of Turku

Turku, 20014
Finland

Oscar H. Franco

Erasmus University Rotterdam (EUR) - Department of Epidemiology

Rotterdam
Netherlands

Eline Slagboom

Leiden University - Medical Center (LUMC)

Albinusdreef 2
Leiden, 2333 ZA
Netherlands

Pim Van der Harst

University of Groningen - Department of Cardiology ( email )

Groningen
Netherlands

Sonja Kunze

Helmholtz Association of German Research Centres - German Research Centre for Environmental Health

Ingolstädter Landstraße 1
Neuherberg, Bavaria D-85764
Germany

Stephan B. Felix

University of Greifswald - University Medicine Greifswald

Fleischmannstraße 8
Greifswald, 17475
Germany

Tao Zhang

Tulane University

6823 St Charles Ave
New Orleans, LA 70118
United States

Wei Chen

Tulane University

6823 St Charles Ave
New Orleans, LA 70118
United States

Trevor A. Mori

The University of Western Australia

35 Stirling Highway
Crawley, Western Australia 6009
Australia

Amelie Bonnefond

Imperial College London

South Kensington Campus
Exhibition Road
London, Greater London SW7 2AZ
United Kingdom

B.T. Heijmans

University Medical Center

2300 RC
Leiden
Netherlands

Taulant Muka

Erasmus University Rotterdam (EUR) - Erasmus Medical Center (MC)

Doctor Molewaterplein 40
Rotterdam, South Holland 3015 GD
Netherlands

Jaspal S. Kooner

Imperial College London

South Kensington Campus
Exhibition Road
London, Greater London SW7 2AZ
United Kingdom

Krista Fischer

University of Tartu

Ülikooli 18
Tartu 50090, 50090
Estonia

Melanie Waldenberger

Helmholtz Association of German Research Centres - German Research Centre for Environmental Health

Ingolstädter Landstraße 1
Neuherberg, Bavaria D-85764
Germany

Philippe Froguel

Imperial College London

South Kensington Campus
Exhibition Road
London, Greater London SW7 2AZ
United Kingdom

Rae-Chi Huang

The University of Western Australia ( email )

35 Stirling Highway
Crawley, Western Australia 6009
Australia

Terho Lehtimäki

University of Turku

Turku, 20014
Finland

Wolfgang Rathmann

Heinrich Heine University Dusseldorf

Universitätsstrasse 1
Duesseldorf, DE NRW 40225
Germany

Caroline L. Relton

University of Bristol - Bristol Medical School

Tyndall Avenue, Senate House
Bristol, BS8 1TH
United Kingdom

Giuseppe Matullo

University of Turin

Via Po 53
Torino, Turin - Piedmont 10100
Italy

Hermann Brenner

University of Kaiserslautern - German Research Center for Articial Intelligence (DFKI)

Paul-Ehrlich-Straße 14
Campus D3_2
Kaiserslautern, D-66123
Germany

Niek Verweij

University of Groningen - Groningen University Hospital

P.O. Box 30.001
9700 AB Groningen
Netherlands

Shengxu Li

Tulane University

6823 St Charles Ave
New Orleans, LA 70118
United States

John C. Chambers

Imperial College London

South Kensington Campus
Exhibition Road
London, Greater London SW7 2AZ
United Kingdom

Marjo-Riitta Järvelin

University of Oulu

P.O. Box 4600
Oulu FIN-90014
Finland

Sylvain P. Sébert (Contact Author)

University of Oulu - Centre for Life Course Health Research ( email )

Finland
+358 503440842 (Phone)

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