A precision nutri-epigenetic approach to tackle the mother-to-child transmission of impaired glucose metabolism
|Partner Organization||Partner Country|
|2.Forschergruppe Diabetes e.V. am Helmholtz Zentrum München||Germany|
|3.University of Granada||Spain|
|4.Universite de Lille||France|
|5.Erasmus Medical Center||The Netherlands|
|6.University of Melbourne||Australia|
1. Overall project description
PREcisE’s overarching goal is to use longitudinal data from the pre-conceptional period up until adulthood to explore the life-course and molecular pathways pertaining the mother to offspring transmissibility of impaired glycaemic health. The project harnesses very large data from cohorts/biobanks and studies from Spain, Germany, Finland, France and the Netherlands. It also joins hands with related projects (e.g. ALPHABET & NutriPROGRAM) and other consortia (e.g. PACE: Pregnancy And Childhood Epigenetics, EGG: Early Growth Genetics, MethQTL: Global Methylation Collaboration) to study and establish the mother-to-offspring transmission of glycaemic health through robust epigenetic factors. In particular, PREcisE’s main objectives are:
1. To identify robust epigenetic marks in the offspring demarking an exposure to adverse maternal glucose metabolism during pregnancy. Epigenome-wide association studies to identify Maternal Glucose Responsive (MGR) loci in the offspring will be performed.
2. To characterise the underpinning molecular pathways and the tissue specificity through gene expression analysis in human liver, skeletal muscles and adipose tissue.
3. To explore the role of pre- and postnatal nutrition in modifying impaired maternal glucose programming. Data on maternal and postnatal dietary behaviour across the different observational studies and RCTs in the Consortium will be harmonised to systematically analyse how dietary behaviour may be either causal or effect modifier of the programming induced by exposure to maternal glucose adversity.
4. To demonstrate the life-course pathways pertaining the mother-to-offspring transmission of impaired glycaemic health and identify the opportunity to impact. State of the art statistical methodology (Bayesian Structural Equation Models) will be employed to examine the interplays between maternal glucose, epigenetics and offspring impaired glycaemic health.
5. To exemplify the lasting impact of adopting healthy dietary behaviours from pregnancy onwards on lifelong health. The project’s main results will be exploited to support the development of
- DNA methylation MGR risk scores as nutri-epigenetic based diagnostic tools for preventive/intervention or treatment strategy,
- dietary recommendations for healthcare, nutritionists, policymakers,
- an EU-Nutri-Epigenetic-Data platform for researchers/academics, public health policy planners, and
- a life-course analysis framework for the mother to offspring transmissibility of impaired glycaemic health for scientists and public health specialists.
Evidence is emerging to support that a range of pre- and postnatal life-style exposures (e.g. gestational diabetes mellitus (GDM) of the mother, maternal smoking, nutrition) may have impact on the epigenome and can induce epigenetic marks (DNA methylation marks) that predict risk of metabolic disease later in life.
Here we will summarise also core from previous year and then update by reporting year’s progress. During the first year of the project we completed a work on prenatal smoke exposure within PREcisE (Wiklund et al, 2019) showing the dose-response relationship between maternal smoking and blood DNA methylation in the offspring, permanency of several of these methylation markers and associations with some causal evidence with adult disorders. These observations have clear public health importance. Public policy actions and guidelines may be improved to better guide strategies for prevention.
Within WP1 we have undertaken and completed multiple EWAs meta-analyses to investigate the associations of maternal glycemic health metabolism during pregnancy with offspring DNA methylation (DNAm), discovering one of the best studied epigenetic marks to date. In particular, we have investigated DNAm profiles in new-born blood and blood collected in later childhood in relation to maternal fasting glucose levels (plasma or whole blood values), maternal glucose response to oral glucose tolerance test (OGTT) and maternal fasted serum insulin levels during pregnancy. The projects are co-led by PREcisE researchers and our collaborators in the PACE consortium.
The analyses show the association of maternal glucose OGTT (area under the curve) with child DNAm and identify two adjacent CpGs in the well-known TXNIP gene. TXNIP methylation has been previously found to be associated with metabolic phenotypes and future T2D risk. Both CpGs in TXNIP in our analyses have not yet been described in literature and follow-up in PREcisE partner cohorts show that DNAm at these CpGs is also associated with maternal T1D exposure in children and multiple glycaemic and anthropometric traits in adults.
These two probes will be further tested in WP3 within also a life-course context for associations with adult metabolic phenotypes taking into consideration potentially modifiable co-variates (e.g. genetic, behavioural and life-style factors of the mother and the offspring. These results will help to understand ways of avoiding related diseases which, from a public health perspective, may be used to improve guidelines and strategies for prevention.
Within WP2 we have completed the harmonisation of dietary indices between cohorts, to be included as pre- and postnatal exposure variables in ongoing meta-analysis on DNA methylation during childhood and adolescence. The harmonised dietary indices include the glycemic index and glycemic load as well as the dietary inflammatory index which has been revised to improve its application in multi-cohort collaborations. A manuscript on the revised calculation of the dietary inflammatory index is currently under preparation.
4.1 List of publications
|Authors||Title||Year, Issue, PP||Partners Number||Doi|
|Heil SG, Herzog EM, Griffioen PH, van Zelst B, Willemsen SP, de Rijke YB, Steegers-Theunissen* RPM, Steegers EAP. [ERASMUS]||Lower S-adenosylmethionine levels and DNA hypomethylation of placental growth factor (PlGF) in placental tissue of early-onset preeclampsia-complicated pregnancies.||2019||5||10.1371/journal.pone.0226969|
|Ott R*, Pawlow X*, Weiß A*, Hofelich A, Herbst M, Hummel N, Prehn C, Adamski J, Römisch-Margl W, Kastenmüller G, Ziegler AG, Hummel S*. [FDeV]||Intergenerational Metabolomic Analysis of Mothers with a History of Gestational Diabetes Mellitus and Their Offspring||2020,21(24),9647||2||10.3390/ijms21249647|
|Geurtsen ML, Jaddoe VWV, Gaillard R, Felix JF* [ERASMUS]||Associations of maternal early-pregnancy blood glucose and insulin concentrations with DNA methylation in newborns.||2020,12(1),134.||5||10.1186/s13148-020-00924-3.|
|Yeung EH, Guan W, Zeng X, Salas LA, Mumford SL, de Prado Bert P, van Meel ER, Malmberg A, Sunyer J, Duijts L, Felix JF*, Czamara D, Hämäläinen E, Binder EB, Räikkönen K, Lahti J, London SJ, Silver RM, Schisterman EF [ERASMUS]||Cord blood DNA methylation reflects cord blood C-reactive protein levels but not maternal levels: a longitudinal study and meta-analysis.||2020,12(1),60||5||10.1186/s13148-020-00852-2|
|Monasso GS, Jaddoe VWV, de Jongste JC, Duijts L, Felix JF* [ERASMUS]||Timing- and Dose-Specific Associations of Prenatal Smoke Exposure With Newborn DNA Methylation.||2020,22(10),1917.||5||10.1093/ntr/ntaa069.|
|Sharp GC, Alfano R, Ghantous A, Urquiza J, Rifas-Shiman SL, Page CM, Jin J, Fernández-Barrés S, Santorelli G, Tindula G; 36 other members of the Pregnancy and Childhood Epigenetics (PACE) consortium||Paternal body mass index and offspring DNA methylation: findings from the PACE consortium||2021,dyaa,267||5||10.1093/ije/dyaa267|
|Mulder RH, Neumann A, Cecil CAM, Walton E, Houtepen LC, Simpkin AJ, Rijlaarsdam J, Heijmans BT, Gaunt TR, Felix JF*, Jaddoe VWV, Bakermans-Kranenburg MJ, Tiemeier H, Relton CL, van IJzendoorn MH, Suderman M||Epigenome-wide change and variation in DNA methylation in childhood: Trajectories from birth to late adolescence||2021,ddaa,280||5||10.1093/hmg/ddaa280|
|Vehmeijer FOL, Küpers LK, Sharp GC, Salas LA, Lent S, Jima DD, Tindula G, Reese S, Qi C, Gruzieva O, Page C, Rezwan FI, Melton PE, Nohr E, Escaramís G, Rzehak P, Heiskala A, Gong T, Tuominen ST, Gao L, Ross JP, Starling AP, Holloway JW, Yousefi P, Aasvang GM, Beilin LJ, Bergström A, Binder E, Chatzi L, Corpeleijn E, Czamara D, Eskenazi B, Ewart S, Ferre N, Grote V, Gruszfeld D, Håberg SE, Hoyo C, Huen K, Karlsson R, Kull I, Langhendries JP, Lepeule J, Magnus MC, Maguire RL, Molloy PL, Monnereau C, Mori TA, Oken E, Räikkönen K, Rifas-Shiman S, Ruiz-Arenas C, Sebert S*, Ullemar V, Verduci E, Vonk JM, Xu CJ, Yang IV, Zhang H, Zhang W, Karmaus W, Dabelea D, Muhlhausler BS, Breton CV, Lahti J, Almqvist C, Jarvelin MR*, Koletzko B, Vrijheid M, Sørensen TIA, Huang RC, Arshad SH, Nystad W, Melén E, Koppelman GH, London SJ, Holland N, Bustamante M, Murphy SK, Hivert MF, Baccarelli A, Relton CL, Snieder H, Jaddoe VWV, Felix JF*||DNA methylation and body mass index from birth to adolescence: meta-analyses of epigenome-wide association studies||2020,12(1),105||5||10.1186/s13073-020-00810-w|
|Van den Berg CB, Herzog EM, Duvekot JJ, Van der Spek PJ, Steegers EAP, Stoop MP, Willemsen SP, Steegers-Theunissen RPM*||Differences in DNA methylation of insulin-like growth factor 2 and cadherin 13 in patients with preeclampsia.||2020||5||https://doi.org/10.1016/j.preghy.2020.01.010|
|Elmar W. Tobi*, Catarina Almqvist, Anna Hedman, Ellika Andolf, Jan Holte, Jan I. Olofsson, Håkan Wramsby, Margaretha Wramsby, Göran Pershagen, Bastiaan T. Heijmans, Anastasia N. Iliadou||DNA methylation differences at birth after conception through ART.||2021,36,1||5||https://doi.org/10.1093/humrep/deaa253|
|Herzog EM, Eggink AJ, Willemsen SP, Slieker RC, Felix JF, Stubbs AP, Van der Spek PJ, Van Meurs JBJ, Heijmans BT, Steegers-Theunissen RPM*||The tissue-specific aspect of genome-wide DNA methylation in newborn and placental tissues: implications for epigenetic epidemiologic studies||2020||5||10.1017/S2040174420000136|
|Oliver Robinson, Alice R Carter, Mika Ala-Korpela, Juan P Casas, Nishi Chaturvedi, Jorgen Engmann, Laura D Howe, Alun D. Hughes , Marjo-Riitta Jarvelin*, Mika Ka¨ho¨ nen, Ville Karhunen*, Diana Kuh, Tina Shah, Yoav Ben-Shlomo, Reecha Sofat, Chung-Ho E Lau, Terho Lehtima¨ ki, Usha Menon, Olli Raitakari, Andy Ryan, Rui Providencia, Stephanie Smith, Julie Taylor, Therese Tillin, Jorma Viikari, Andrew Wong, Aroon D Hingorani, Mika Kivima¨ki and Paolo Vineis.||Metabolic profiles of socio-economic position: a multi-cohort analysis||2020||1||doi: 10.1093/ije/dyaa188|
|Palaniswamy S, Gill D, De Silva NM, Lowry E, Jokelainen J, Karhu T, Mutt SJ, Dehghan A, Sliz E, Chasman DI, Timonen M, Viinamäki H, Keinänen-Kiukaanniemi S, Hyppönen E, Herzig KH, Sebert S, Järvelin MR.*||Could vitamin D reduce obesity-associated inflammation? Observational and Mendelian randomization study.||2020,111(5),1036||1||10.1093/ajcn/nqaa056. (IF 6.568)|
|Rauschert S, Melton PE, Heiskala A, Karhunen V, Burdge G, Craig JM, Godfrey KM, Lillycrop K, Mori TA, Beilin LJ, Oddy WH, Pennell C, Järvelin MR*, Sebert S*, Huang RC.||Machine Learning-Based DNA Methylation Score for Fetal Exposure to Maternal Smoking: Development and Validation in Samples Collected from Adolescents and Adults.||2020,128(9),97003||1||10.1289/EHP6076|
|Lowry E, Rautio N, Wasenius N, Bond TA, Lahti J, Tzoulaki I, Dehghan A, Heiskala A, Ala-Mursula L, Miettunen J, Eriksson J, Järvelin MR*, Sebert S*.||Early exposure to social disadvantages and later life body mass index beyond genetic predisposition in three generations of Finnish birth cohorts.||2020,20,708||1||10.1186/s12889-020-08763-w|
|Lowry E, Rautio N, Wasenius N, Bond TA, Lahti J, Tzoulaki I, Dehghan A, Heiskala A, Ala-Mursula L, Miettunen J, Eriksson J, Järvelin MR*, Sebert S*||Early exposure to social disadvantages and later life body mass index beyond genetic predisposition in three generations of Finnish birth cohorts.||2020; 20, 708||1||10.1186/s12889-020-08763-w|
|Parmar P, Lowry E, Vehmeijer F, El Marroun H, Lewin A, Tolvanen M, Tzala E*, Ala-Mursula L, Herzig KH, Miettunen J, Prokopenko I, Rautio N, Jaddoe VW, Järvelin MR*, Felix J*, Sebert S*.:||Understanding the Cumulative Risk of Maternal Prenatal Biopsychosocial Factors on Birth Weight: A DynaHEALTH Study on Two Birth Cohorts.||2020||1||10.1136/jech-2019-213154|
|Robinson O, Chadeau Hyam M, Karaman I, Climaco Pinto R, Ala-Korpela M, Handakas E, Fiorito G, Gao H, Heard A, Jarvelin MR*, Lewis M, Pazoki R, Polidoro S, Tzoulaki I, Wielscher M, Elliott P, Vineis P.||Determinants of Accelerated Metabolomic and Epigenetic Aging in a UK Cohort.||2020,19(6)||1||10.1111/acel.13149|
4.2 Presentation of the project
|Target group||Authors||Means of communication||Hyperlink|
|Master students and teachers||Marjo-Riitta Jarvelin (IC): Northern Finland Birth Cohort Studies – data and some results including early life epigenetics. MSc Health Data Analytics and Machine Learning, London, UK, Jan 2019.||Lecture|
|MSc students, clinicians, nutritionists||Marjo-Riitta Jarvelin (IC): Introduction – Genes and Environment short course, Understanding genetic influence on growth and development, London, UK, Feb 2019.||Lecture|
|Scientists||Janine Felix (ERASMUS); Early-life programming of life course health. Helmholtz Zentrum für Umweltforschung UFZ, Leipzig, Germany, Feb 2019.||Lecture|
|Scientists||Janine Felix (ERASMUS); Maternale Faktoren und (Epi-)genetik - 45 Jahrestagung der Gesellschaft für Neonatologie und Pädiatrische intensivmedizin, Leipzig, Germany, May 2019.||Lecture|
|Scientists||Evangelia Tzala (IC); Bayesian Life-Course Path Analysis Model: Application NFBC (national Finnish Birth Cohort) 1966. PREcisE kick-off meeting, Lille, France, Jun 2019.||Short talk|
|Scientists||Steegers-Theunissen RPM (ERASMUS). Periconception one carbon metabolism and embryonic and placental health, 12th International conference on One Carbon Metabolism, B Vitamins and Homocysteine, Reus, Jun 2019 (invited speaker).||Lecture|
|Public Outreach||Janine Felix (ERASMUS); Biosamples panel session during the “Born in Bradford” Science Festival 2019, Bradford, UK, Oct 2019 (participated in the panel).||Panel session|
|PhD students||Marjo-Riitta Jarvelin (IC): Research Design for Social Sciences and Medicine. Three-hour interactive session including aspects of genetic/epigenetic studies. Imperial College Graduate School, London, UK, Feb 2019.||Lecture|
|Master students and teachers||Marjo-Riitta Jarvelin (IC): Lifecourse models – data – on metabolic traits addressing early life epigenetics. MSc Health Data Analytics and Machine Learning, London, UK, Nov 2019.||Lecture|
|Master students||Janine Felix (ERASMUS). DNA methylation. Course “SNPs and human diseases”, Erasmus MC, Rotterdam, the Netherlands, Nov 2019.||Lecture|
|Scientists||Sandra Hummel (FDeV); Intergenerational metabolomics in women with GDM and their offspring – DZD Workshop, Munich, Germany. Oct 2019.||Short talk|
|Clinicians, nurses, scientists||Sandra Hummel (FDeV); The role of dietary behaviour during pregnancy and lactation on health outcomes in women with GDM – with a special focus on the role of migration. Autumn meeting of the German Diabetes Association, Leipzig, Germany, Nov 2019||Lecture|
|Scientists and policy makers||Marjo-Riitta Jarvelin (IC); Data Sharing: More Incentives, Better Science - The euCanSHare Consortium virtual workshop, Sept 2020 .||Invited Facilitator and Discussant.|
|Scientists||Marjo-Riitta Jarvelin (IC); PREcisE - A precision nutri-epigenetic approach to tackle the mother-to-child transmission,- Virtual JPI workshop , Nov 2020||Presentation|
|Scientists and students.||Marjo-Riitta Jarvelin (IC); Early Growth Genetics (EGG) International Symposium organised by Imperial College London (MRJ), UK, Univesity of Exeter, UK, and University of Oulu, Finland – Jun 2020||Member of Organising Committee, introduction of key note, facilitator and chair of a session.|
|Scientists, reporters (public event)||Marjo-Riitta Jarvelin (IC); Early growth and adult metabolic disease risk – role of genetic factors- Science Day of the Kontinkangas Campus (University of Oulu), Feb 2020||Invited key note speaker|
|Students and teachers.||Marjo-Riitta Jarvelin (IC); Career Development two-day workshop for international PhD students (academia and industry), May 2020||Organiser, developer, chair and facilitator including extensive review and marking of course works|
|Students and pathway leaders||Marjo-Riitta Jarvelin (IC); Interactive introductory session (1.5 hours) for new PhD students in the pathway of Life Course, Psychology and Health (n ~40 ) of the London Interdisciplinary Social Science Programme (LISS, between Imperial College Graduate School, King’s College London and Queen Mary University London) Oct 2020. The theme falls into the remits of Precise.||Lecture|
|Patients||Sandra Hummel (FDeV); World Diabetes Day – social media campaign: Answers to questions on the social media pages of the institute.||Answers to questions.|
|Clinicians, asthma-trainers, nurses||Sandra Hummel (FDeV); Annual Conference Asthma/Atopic eczema, Rosenheim, Germany: Diabetes prevention in the family, Feb 2020||Seminar|
|Teachers||Sandra Hummel (FDeV); Teachers training, Helmholtz Zentrum München, Diabetes-information portal; Munich, Germany: Prediction and Prevention of diabetes, Mar 2020||Seminar|
|MSc (Epidemiology) students||Sandra Hummel (FDeV); Lecture MSc Epidemiology, Ludwig-Maximilians University, Munich, Germany: Prediction and Prevention of Diabetes – Intergenerational transmission of obesity and diabetes, Apr 2020||Lecture|
|Scientists||Evangelia Tzala (IC); Bayesian Life-course Path Analysis Model for body mass development in Northern Finland Cohort Study 1996 – NFBC1966 – until 46 years of age. EGG virtual symposium, Jun 2020||Presentation|
|Scientists||Steegers-Theunissan (ErasmusMC): Periconception nutrition, one carbon metabolism and fetal programming. Symposium Fetal Programming: Molecular and Clinical aspects – University of Groningen, Feb 2020||Lecture|
|Clinicians, scientists||Elmar Tobi (Erasmus): A precise meta-analysis on maternal glycemic traits and cord blood DNA methylation. - Erasmus MC department talk Nov 2020||Lecture|
|Public (for the lower income parts of Rotterdam)||Steegers-Theunissen RPM [ERASMUS}. Een gezonde baby: wat kun je zelf doen? For You Magazine editie Rotterdam 2019, 2: 30. Title in English: A healthy baby; what can you do?||Magazine interview|
|Scientists. policy makers, general public||Marjo-Riitta Jarvelin (IC); Protective and preventive healthcare. Highlights of the importance of lifestyle factors and early years intervention (www.healtheuropa.eu) 2020||Interview paper (profile):|
4.3 List of submitted patents and other outputs
|Patent licence||Partners involved||Year||International eu or national patent||Comment|
|Book chapter||Hoek J, Steegers-Theunissen RPM* [ERASMUS], Sinclair K., Schoenmakers S. The science of preconception. In: Shawe J, Steegers EAP, Verbiest S (eds) Preconception health and care: A life course approach. (2020) ISBN 978-3-030-31752-2. https://doi.org/10.1007/978-3-030-31753-9_3||2020|
|Textbook chapter||Akhter Z, Van der Windt M, Van der Kleij R, Heslehurst N, Steegers-Theunissen RPM* [ERASMUS]. (2019) Preconception health and care: a life-course approach. Textbook, chapter 5.||2019|
|Handbook||Van der Kleij R, Van der Windt M, Steegers-Theunissen RPM*[ERASMUS]. Handboek Leeftstijlgeneeskunde – De eerste 1000 dagen en de 100 ervoor | rond de zwangerschap. (2019) ISBN 9789036823234||2019||Aimed at Dutch general practitioners and mid-wifes.|
|Textbook chapter||Ganzevoort W, Painter RC, Van Wassemaer-Leemhuis AG, De Bakker BS, Steegers-Theunissen RPM*, Faas MM [ERASMUS]. Textbook of obstetrics and gynaecology. A life course approach. Part II Conception and foetal health. Embryonic, placental and foetal growth and development. 121-138. (2019) ISBN 978 90 368 2130 8||2019||For a textbook used for Medical training (used at the Erasmus Medical Centre among others)|
|Textbook chapter||Schoenmakers S, Koster MPH, Steegers-Theunissen RPM* [ERASMUS]. Textbook of obstetrics and gynaecology. A life course approach. Part II Conception and foetal health. Preconception health and care. 107-120. (2019) ISBN 978 90 368 2130 8||2019||For a textbook used for Medical training (used at the Erasmus Medical Centre among others)|
|PhD thesis||Ville Karhunen [IC]; Statistical modelling strategies in molecular epidemiology, with an application to attention-deficit hyperactivity disorder,||2020 (year completed)||Supervisor: Marjo-Riitta Jarvelin [IC]|