HDHL: A precision nutri-epigenetic approach to tackle the mother-to-child transmission of impaired glucose metabolism

长期以来，人们一直在追踪血糖健康受损的风险从一代传给另一代的情况，这被认为是通过表观遗传机制将孕期暴露于不利的血糖健康与后代血糖健康之间存在因果联系。潜在的生物学和营养途径对于了解、预防或逆转妊娠期糖尿病对终生肥胖、血糖逆境和2型糖尿病的后果至关重要，这是这里的关键结果。Precision项目加入了一个具有互补专业知识和数据领域的联盟，以发现对怀孕期间母亲血糖健康变化敏感的DNA甲基化标记，认为产前和出生后饮食暴露是可能的调节因素，并确定它们在解释血糖健康受损的母子传播方面的重要性。我们通过重复测量，将从受孕前到50岁的人类数据与母亲、新生儿和成人的密集DNA甲基化数据整合在一起，以挑战可复制性、特异性和持久性的问题。准确地说，PRECISE联盟将把它的工作计划组织成三个工作包，以i)对子宫内葡萄糖水平暴露进行表观基因组广泛关联研究，然后在肝脏、骨骼肌和脂肪组织的生物库中进行下游分析，ii)推断出生前和出生后饮食暴露在调节甲基化与肥胖和血糖健康结果之间的主要作用，以及iii)将其结果进一步整合到肥胖和血糖健康结果的生命过程模型中，并在大量出生队列数据中进行训练。Precision将致力于回答电话会议的预期影响，重点是因果关系、营养和组织特异性。因果关系将通过三个互补性设计进行检验：随机对照试验、孟德尔随机化和因果模型，包括三角测量以验证结果。组织特有的分子通路将通过一种独特的转录切割DNA甲基化方法来解决。Precision项目将致力于为三个关键的可利用结果带来足够的证据：用于精确表观遗传学的母体葡萄糖反应基因座的DNA甲基化风险分数，帮助优化这些基因座DNA甲基化的饮食建议，以及为促进终身血糖健康的长期影响和机会向政策提供信息的生命过程模型。

There is a long-standing tracking of the risk of impaired glycaemic health being transmitted from one generation to another that is hypothesised to causally link exposure to adverse glycaemic health in pregnancy and the offspring glycaemic health via epigenetic mechanisms. The potential biological and nutritional pathways underlying the paradigm can be of paramount importance to understand, prevent or reverse the consequences of gestational diabetes for life-long obesity, glycaemic adversity and type 2 diabetes; the key outcomes here. PREcisE project joins a consortium with complementary domains of expertise and data to uncover DNA methylation markers sensitive to variation by maternal glycaemic health in pregnancy, considering pre- and postnatal dietary exposures as possible modulators, and characterise their importance in explaining the mother-to -offspring transmission of impaired glycaemic health. We integrate human data spanning from pre-conception to age 50 years with dense DNA methylation data in the mother, the newborn and the adult with repeated measure tochallenge the question of replicability, specificity and persistency. Precisely, PREcisE consortium will organise its working plan into three workpackages to i) perform epigenome wide association study on glucose level exposure in utero followed by downstream analysis in a biobank of liver, skeletal muscles and adipose tissues, ii) infer the primary role of pre- and postnatal dietary exposures in modulating the association of methylation with adiposity and glycaemic health outcomes and iii) integrate its findings further into a life-course model for adiposity and glycaemic health outcomes trained in large birth cohort data. PREcisE will aim to answer the expected impact of the call focusing on causality, nutrition and tissue specificity. Causality will be tested by three complementary design: randomised control trial, mendelian randomisation and causal modelling including triangulation to validate results. Tissue-specific molecular pathways will be addressed by a unique transcriptomic DNAmethylation approach. PREcisE project will aim to bring sufficient evidence to three key exploitable results: DNA methylation risk scores at maternal glucose response loci for precision epigenetics, dietary recommendations to help optimising the DNA methylation at these loci and a life-course model to inform policy on the long-lasting effects and opportunity to promote life-long glycaemic health.