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Erasmus University Rotterdam (EUR), Medical Center, Department of Internal Medicine ; Erasmus University Rotterdam (EUR), Medical Center, Department of Epidemiology
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
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). , EBioMedicine, Volume 38, December 2018, Pages 206-216, https://doi.org/10.1016/j.ebiom.2018.10.066, Available at SSRN: https://ssrn.com/abstract=3237007 or http://dx.doi.org/10.2139/ssrn.3237007
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