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 x 10(-7) < P < 0.01). Similarly, lower DNA methylation at cg12876356, cg18316974, cg09662411, and cg18146737 was associated with decreased BMI and WC (5 x 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. (c) 2018 The Authors. Published by Elsevier B.V.
In: 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 , Schottker , 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 , Kahonen , 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 , Lehtimaki , T , Rathman , W , Relton , C , Matullo , G , Brenner , H , Verweij , N , Li , S , Chambers , J , Jarvelin , M-R & Sebert , S 2018 , ' Association of maternal prenatal smoking GFI1-locus and cardio-metabolic phenotypes in 18,212 adults ' , EBioMedicine , vol. 38 , pp. 206-216 . https://doi.org/10.1016/j.ebiom.2018.10.066
Background:DNA methylation at theGFI1-locus has been repeatedly associated with exposure to smoking fromthe foetal period onwards. We explored whether DNA methylation may be a mechanism that links exposure tomaternal prenatal smoking with offspring's adult cardio-metabolic health.Methods:We meta-analysed the association between DNA methylation atGFI1-locus with maternal prenatalsmoking, adult own smoking, and cardio-metabolic phenotypes in 22 population-based studies from Europe,Australia, and USA (n= 18,212). DNA methylation at theGFI1-locus was measured in whole-blood. Multivari-able regression models werefitted 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), fastingglucose (FG), high-density lipoprotein cholesterol (HDL—C), triglycerides (TG), diastolic, and systolic blood pres-sure (BP).Findings:Lower DNA methylation at three out of eightGFI1-CpGs was associated with exposure to maternal pre-natal smoking, whereas, all eight CpGs were associated with adult own smoking. Lower DNA methylation atcg14179389, the strongest maternal prenatal smoking locus, was associated with increased WC and BP when ad-justed for sex, age, and adult smoking with Bonferroni-correctedPb0·012. In contrast, lower DNA methylationatcg09935388,thestrongest adultownsmokinglocus, wasassociated with decreasedBMI, WC,and BP (adjusted1×10−7bPb0.01). Similarly, lower DNA methylation at cg12876356, cg18316974, cg09662411, andcg18146737 was associated with decreased BMI and WC (5 × 10−8bPb0.001). Lower DNA methylation at allthe CpGs was consistently associated with higher TG levels.Interpretation:Epigenetic changes at theGFI1were linked to smoking exposurein-utero/in-adulthood and ro-bustly associated with cardio-metabolic risk factors.Fund:European Union's Horizon 2020 research and innovation programme under grant agreement no. 633595DynaHEALTH.
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.
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 under grant agreement no. 633595 DynaHEALTH.
In: Horwich , A , Babjuk , M , Bellmunt , J , Bruins , H M , de Reijke , T M , de Santis , M , Gillessen , S , James , N , Maclennan , S , Palou , J , Powles , T , Ribal , M J , Shariat , S F , van der Kwast , T , Xylinas , E , Agarwal , N , Arends , T , Bamias , A , Birtle , A , Black , P C , Bochner , B H , Bolla , M , Boormans , J L , Bossi , A , Briganti , A , Brummelhuis , I , Burger , M , Castellano , D , Cathomas , R , Chiti , A , Choudhury , A , Compérat , E , Crabb , S , Culine , S , de Bari , B , DeBlok , W , de Visschere , P J L , Decaestecker , K , Dimitropoulos , K , Dominguez-Escrig , J L , Fanti , S , Fonteyne , V , Frydenberg , M , Futterer , J J , Gakis , G , Geavlete , B , Gontero , P , Grubmüller , B , Hafeez , S , Hansel , D E , Hartmann , A , Hayne , D , Henry , A M , Hernandez , V , Herr , H , Herrmann , K , Hoskin , P , Huguet , J , Jereczek-Fossa , B A , Jones , R , Kamat , A M , Khoo , V , Kiltie , A E , Krege , S , Ladoire , S , Lara , P C , Leliveld , A , Linares-Espinós , E , Løgager , V , Lorch , A , Loriot , Y , Meijer , R , Carmen Mir , M , Moschini , M , Mostafid , H , Müller , A C , Müller , C R , N'Dow , J , Necchi , A , Neuzillet , Y , Oddens , J R , Oldenburg , J , Osanto , S , Oyen , W J G , Pacheco-Figueiredo , L , Pappot , H , Patel , M I , Pieters , B R , Plass , K , Remzi , M , Retz , M , Richenberg , J , Rink , M , Roghmann , F , Rosenberg , J E , Rouprêt , M , Rouvière , O , Salembier , C , Salminen , A , Sargos , P , Sengupta , S , Sherif , A , Smeenk , R J , Smits , A , Stenzl , A , Thalmann , G N , Tombal , B , Turkbey , B , Vahr Lauridsen , S , Valdagni , R , van der Heijden , A G , van Poppel , H , Vartolomei , M D , Veskimäe , E , Vilaseca , A , Vives Rivera , F A , Wiegel , T , Wiklund , P , Williams , A , Zigeuner , R & Witjes , J A 2019 , ' EAU–ESMO consensus statements on the management of advanced and variant bladder cancer—an international collaborative multi-stakeholder effort: under the auspices of the EAU and ESMO Guidelines Committees ' , Annals of Oncology , vol. 30 , no. 11 , pp. 1697-1727 . https://doi.org/10.1093/annonc/mdz296
Background: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial. Objective: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management. Design: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts before voting during a consensus conference. Setting: Online Delphi survey and consensus conference. Participants: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management. Outcome measurements and statistical analysis: Statements were ranked by experts according to their level of agreement: 1–3 (disagree), 4–6 (equivocal), 7–9 (agree). A priori (level 1) consensus was defined as ≥70% agreement and ≤15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus). Results and limitations: Overall, 116 statements were included in the Delphi survey. Of these, 33 (28%) statements achieved level 1 consensus and 49 (42%) statements achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease and the evolving role of checkpoint inhibitor therapy in metastatic disease. Conclusions: These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time where further evidence is available to guide our approach.
BACKGROUND: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial. OBJECTIVE: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management. DESIGN: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts before voting during a consensus conference. SETTING: Online Delphi survey and consensus conference. PARTICIPANTS: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Statements were ranked by experts according to their level of agreement: 1-3 (disagree), 4-6 (equivocal), 7-9 (agree). A priori (level 1) consensus was defined as ≥70% agreement and ≤15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus). RESULTS AND LIMITATIONS: Overall, 116 statements were included in the Delphi survey. Of these, 33 (28%) statements achieved level 1 consensus and 49 (42%) statements achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease and the evolving role of checkpoint inhibitor therapy in metastatic disease. CONCLUSIONS: These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time where further evidence is available to guide our approach.