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1. DNA methylation signature of chronic low-grade inflammation and its role in cardio-respiratory diseases

Author

Wielscher, M. (Matthias), Mandaviya, P. R. (Pooja R.), Kuehnel, B. (Brigitte), Joehanes, R. (Roby), Mustafa, R. (Rima), Robinson, O. (Oliver), Zhang, Y. (Yan), Bodinier, B. (Barbara), Walton, E. (Esther), Mishra, P. P. (Pashupati P.), Schlosser, P. (Pascal), Wilson, R. (Rory), Tsai, P.-C. (Pei-Chien), Palaniswamy, S. (Saranya), Marioni, R. E. (Riccardo E.), Fiorito, G. (Giovanni), Cugliari, G. (Giovanni), Karhunen, V. (Ville), Ghanbari, M. (Mohsen), Psaty, B. M. (Bruce M.), Loh, M. (Marie), Bis, J. C. (Joshua C.), Lehne, B. (Benjamin), Sotoodehnia, N. (Nona), Deary, I. J. (Ian J.), Chadeau-Hyam, M. (Marc), Brody, J. A. (Jennifer A.), Cardona, A. (Alexia), Selvin, E. (Elizabeth), Smith, A. K. (Alicia K.), Miller, A. H. (Andrew H.), Torres, M. A. (Mylin A.), Marouli, E. (Eirini), Gao, X. (Xin), van Meurs, J. B. (Joyce B. J.), Graf-Schindler, J. (Johanna), Rathmann, W. (Wolfgang), Koenig, W. (Wolfgang), Peters, A. (Annette), Weninger, W. (Wolfgang), Farlik, M. (Matthias), Zhang, T. (Tao), Chen, W. (Wei), Xia, Y. (Yujing), Teumer, A. (Alexander), Nauck, M. (Matthias), Grabe, H. J. (Hans J.), Doerr, M. (Macus), Lehtimaki, T. (Terho), Guan, W. (Weihua), Milani, L. (Lili), Tanaka, T. (Toshiko), Fisher, K. (Krista), Waite, L. L. (Lindsay L.), Kasela, S. (Silva), Vineis, P. (Paolo), Verweij, N. (Niek), van der Harst, P. (Pim), Iacoviello, L. (Licia), Sacerdote, C. (Carlotta), Panico, S. (Salvatore), Krogh, V. (Vittorio), Tumino, R. (Rosario), Tzala, E. (Evangelia), Matullo, G. (Giuseppe), Hurme, M. A. (Mikko A.), Raitakari, O. T. (Olli T.), Colicino, E. (Elena), Baccarelli, A. A. (Andrea A.), Kahonen, M. (Mika), Herzig, K.-H. (Karl-Heinz), Li, S. (Shengxu), BIOS consortium, Conneely, K. N. (Karen N.), Kooner, J. S. (Jaspal S.), Kottgen, A. (Anna), Heijmans, B. T. (Bastiaan T.), Deloukas, P. (Panos), Relton, C. (Caroline), Ong, K. K. (Ken K.), Bell, J. T. (Jordana T.), Boerwinkle, E. (Eric), Elliott, P. (Paul), Brenner, H. (Hermann), Beekman, M. (Marian), Levy, D. (Daniel), Waldenberger, M. (Melanie), Chambers, J. C. (John C.), Dehghan, A. (Abbas), Järvelin, M.-R. (Marjo-Riitta), Wielscher, M. (Matthias), Mandaviya, P. R. (Pooja R.), Kuehnel, B. (Brigitte), Joehanes, R. (Roby), Mustafa, R. (Rima), Robinson, O. (Oliver), Zhang, Y. (Yan), Bodinier, B. (Barbara), Walton, E. (Esther), Mishra, P. P. (Pashupati P.), Schlosser, P. (Pascal), Wilson, R. (Rory), Tsai, P.-C. (Pei-Chien), Palaniswamy, S. (Saranya), Marioni, R. E. (Riccardo E.), Fiorito, G. (Giovanni), Cugliari, G. (Giovanni), Karhunen, V. (Ville), Ghanbari, M. (Mohsen), Psaty, B. M. (Bruce M.), Loh, M. (Marie), Bis, J. C. (Joshua C.), Lehne, B. (Benjamin), Sotoodehnia, N. (Nona), Deary, I. J. (Ian J.), Chadeau-Hyam, M. (Marc), Brody, J. A. (Jennifer A.), Cardona, A. (Alexia), Selvin, E. (Elizabeth), Smith, A. K. (Alicia K.), Miller, A. H. (Andrew H.), Torres, M. A. (Mylin A.), Marouli, E. (Eirini), Gao, X. (Xin), van Meurs, J. B. (Joyce B. J.), Graf-Schindler, J. (Johanna), Rathmann, W. (Wolfgang), Koenig, W. (Wolfgang), Peters, A. (Annette), Weninger, W. (Wolfgang), Farlik, M. (Matthias), Zhang, T. (Tao), Chen, W. (Wei), Xia, Y. (Yujing), Teumer, A. (Alexander), Nauck, M. (Matthias), Grabe, H. J. (Hans J.), Doerr, M. (Macus), Lehtimaki, T. (Terho), Guan, W. (Weihua), Milani, L. (Lili), Tanaka, T. (Toshiko), Fisher, K. (Krista), Waite, L. L. (Lindsay L.), Kasela, S. (Silva), Vineis, P. (Paolo), Verweij, N. (Niek), van der Harst, P. (Pim), Iacoviello, L. (Licia), Sacerdote, C. (Carlotta), Panico, S. (Salvatore), Krogh, V. (Vittorio), Tumino, R. (Rosario), Tzala, E. (Evangelia), Matullo, G. (Giuseppe), Hurme, M. A. (Mikko A.), Raitakari, O. T. (Olli T.), Colicino, E. (Elena), Baccarelli, A. A. (Andrea A.), Kahonen, M. (Mika), Herzig, K.-H. (Karl-Heinz), Li, S. (Shengxu), BIOS consortium, Conneely, K. N. (Karen N.), Kooner, J. S. (Jaspal S.), Kottgen, A. (Anna), Heijmans, B. T. (Bastiaan T.), Deloukas, P. (Panos), Relton, C. (Caroline), Ong, K. K. (Ken K.), Bell, J. T. (Jordana T.), Boerwinkle, E. (Eric), Elliott, P. (Paul), Brenner, H. (Hermann), Beekman, M. (Marian), Levy, D. (Daniel), Waldenberger, M. (Melanie), Chambers, J. C. (John C.), Dehghan, A. (Abbas), and Järvelin, M.-R. (Marjo-Riitta)

Abstract

We performed a multi-ethnic Epigenome Wide Association study on 22,774 individuals to describe the DNA methylation signature of chronic low-grade inflammation as measured by C-Reactive protein (CRP). We find 1,511 independent differentially methylated loci associated with CRP. These CpG sites show correlation structures across chromosomes, and are primarily situated in euchromatin, depleted in CpG islands. These genomic loci are predominantly situated in transcription factor binding sites and genomic enhancer regions. Mendelian randomization analysis suggests altered CpG methylation is a consequence of increased blood CRP levels. Mediation analysis reveals obesity and smoking as important underlying driving factors for changed CpG methylation. Finally, we find that an activated CpG signature significantly increases the risk for cardiometabolic diseases and COPD.

Published
2022

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

Author

Parmar, P. (Priyanka), Lowry, E. (Estelle), Cugliari, G. (Giovanni), Suderman, M. (Matthew), Wilson, R. (Rory), Karhunen, V. (Ville), Andrew, T. (Toby), Wiklund, P. (Petri), Wielscher, M. (Matthias), Guarrera, S. (Simonetta), Teumer, A. (Alexander), Lehne, B. (Benjamin), Milani, L. (Lili), de Klein, N. (Niek), Mishra, P. P. (Pashupati P.), Melton, P. E. (Phillip E.), Mandaviya, P. R. (Pooja R.), Kasela, S. (Silva), Nano, J. (Jana), Zhang, W. (Weihua), Zhang, Y. (Yan), Uitterlinden, A. G. (Andre G.), Peters, A. (Annette), Schoettker, B. (Ben), Gieger, C. (Christian), Anderson, D. (Denise), Boomsma, D. I. (Dorret, I), Grabe, H. J. (Hans J.), Panico, S. (Salvatore), Veldink, J. H. (Jan H.), van Meurs, J. B. (Joyce B. J.), van den Berg, L. (Leonard), Beilin, L. J. (Lawrence J.), Franke, L. (Lude), Loh, M. (Marie), van Greevenbroek, M. M. (Marleen M. J.), Nauck, M. (Matthias), Kahonen, M. (Mika), Hurme, M. A. (Mikko A.), Raitakari, O. T. (Olli T.), Franco, O. H. (Oscar H.), Slagboom, P. E. (P. Eline), van der Harst, P. (Pim), Kunze, S. (Sonja), Felix, S. B. (Stephan B.), Zhang, T. (Tao), Chen, W. (Wei), Mori, T. A. (Trevor A.), Bonnefond, A. (Amelie), Heijmans, B. T. (Bastiaan T.), Muka, T. (Taulant), Kooner, J. S. (Jaspal S.), Fischer, K. (Krista), Waldenberger, M. (Melanie), Froguel, P. (Philippe), Huang, R.-C. (Rae-Chi), Lehtimaki, T. (Terho), Rathmann, W. (Wolfgang), Relton, C. L. (Caroline L.), Matullo, G. (Giuseppe), Brenner, H. (Hermann), Verweij, N. (Niek), Li, S. (Shengxu), Chambers, J. C. (John C.), Jarvelin, M.-R. (Marjo-Riitta), Sebert, S. (Sylvain), Parmar, P. (Priyanka), Lowry, E. (Estelle), Cugliari, G. (Giovanni), Suderman, M. (Matthew), Wilson, R. (Rory), Karhunen, V. (Ville), Andrew, T. (Toby), Wiklund, P. (Petri), Wielscher, M. (Matthias), Guarrera, S. (Simonetta), Teumer, A. (Alexander), Lehne, B. (Benjamin), Milani, L. (Lili), de Klein, N. (Niek), Mishra, P. P. (Pashupati P.), Melton, P. E. (Phillip E.), Mandaviya, P. R. (Pooja R.), Kasela, S. (Silva), Nano, J. (Jana), Zhang, W. (Weihua), Zhang, Y. (Yan), Uitterlinden, A. G. (Andre G.), Peters, A. (Annette), Schoettker, B. (Ben), Gieger, C. (Christian), Anderson, D. (Denise), Boomsma, D. I. (Dorret, I), Grabe, H. J. (Hans J.), Panico, S. (Salvatore), Veldink, J. H. (Jan H.), van Meurs, J. B. (Joyce B. J.), van den Berg, L. (Leonard), Beilin, L. J. (Lawrence J.), Franke, L. (Lude), Loh, M. (Marie), van Greevenbroek, M. M. (Marleen M. J.), Nauck, M. (Matthias), Kahonen, M. (Mika), Hurme, M. A. (Mikko A.), Raitakari, O. T. (Olli T.), Franco, O. H. (Oscar H.), Slagboom, P. E. (P. Eline), van der Harst, P. (Pim), Kunze, S. (Sonja), Felix, S. B. (Stephan B.), Zhang, T. (Tao), Chen, W. (Wei), Mori, T. A. (Trevor A.), Bonnefond, A. (Amelie), Heijmans, B. T. (Bastiaan T.), Muka, T. (Taulant), Kooner, J. S. (Jaspal S.), Fischer, K. (Krista), Waldenberger, M. (Melanie), Froguel, P. (Philippe), Huang, R.-C. (Rae-Chi), Lehtimaki, T. (Terho), Rathmann, W. (Wolfgang), Relton, C. L. (Caroline L.), Matullo, G. (Giuseppe), Brenner, H. (Hermann), Verweij, N. (Niek), Li, S. (Shengxu), Chambers, J. C. (John C.), Jarvelin, M.-R. (Marjo-Riitta), and Sebert, S. (Sylvain)

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

Published
2018

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