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


Parmar, P and Lowry, E and Cugliari, G and Suderman, M and Wilson, R and Karhunen, V and Andrew, T and Wiklund, P and Wielscher, M and Guarrera, S and Teumer, A and Lehne, B and Milani, L and de Klein, N and Mishra, PP and Melton, PE and Mandaviya, PR and Kasela, S and Nano, J and Zhang, W and Zhang, Y and Uitterlinden, AG and Peters, A and Schottker, B and Gieger, C and Anderson, D and Boomsma, DI and Grabe, HJ and Panico, S and Veldink, JH and van Meurs, JBJ and van den Berg, L and Beilin, LJ and Franke, L and Loh, M and van Greevenbroek, MMJ and Nauck, M and Kahonen, M and Hurme, MA and Raitakari, OT and Franco, OH and Slagboom, PE and van der Harst, P and Kunze, S and Felix, SB and Zhang, T and Chen, W and Mori, TA and Bonnefond, A and Heijmans, BT and Muka, T and Kooner, JS and Fischer, K and Waldenberger, M and Froguel, P and Huang, R-C and Lehtimaki, T and Rathmann, W and Relton, CL and Matullo, G and Brenner, H and Verweij, N and Li, S and Chambers, JC and Jarvelin, M-R and Sebert, S, Association of maternal prenatal smoking GFI1-locus and cardio-metabolic phenotypes in 18,212 adults, EBioMedicine, 38 pp. 206-216. ISSN 2352-3964 (2018) [Refereed Article]

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2018 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (

DOI: doi:10.1016/j.ebiom.2018.10.066


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 < 0012. 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.

Item Details

Item Type:Refereed Article
Keywords:DNA methylation, GFI1, smoking, heart disease, risk factors
Research Division:Biological Sciences
Research Group:Genetics
Research Field:Epigenetics (incl. genome methylation and epigenomics)
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Melton, PE (Dr Phillip Melton)
ID Code:144391
Year Published:2018
Web of Science® Times Cited:19
Deposited By:Menzies Institute for Medical Research
Deposited On:2021-05-20
Last Modified:2022-08-25
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