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Context Antenatal hyperglycemia is associated with increased risk of future adverse health outcomes in both mother and child. Variations in offspring’s epigenome can reflect the impact and response to in utero glycemic exposure, and may have different consequences for the child. Objective We examined possible differences in associations of basal glucose status and glucose handling during pregnancy with both clinical covariates and offspring cord tissue DNA methylation. Research Design and Methods This study included 830 mother-offspring dyads from the Growing Up in Singapore Towards Healthy Outcomes cohort. The fetal epigenome of umbilical cord tissue was profiled using Illumina HumanMethylation450 arrays. Associations of maternal mid-pregnancy fasting (fasting plasma glucose [FPG]) and 2-hour plasma glucose (2hPG) after a 75-g oral glucose challenge with both maternal clinical phenotypes and offspring epigenome at delivery were investigated separately. Results Maternal age, prepregnancy body mass index, and blood pressure measures were associated with both FPG and 2hPG, whereas Chinese ethnicity (P = 1.9 × 10-4), maternal height (P = 1.1 × 10-4), pregnancy weight gain (P = 2.2 × 10-3), prepregnancy alcohol consumption (P = 4.6 × 10-4), and tobacco exposure (P = 1.9 × 10-3) showed significantly opposite associations between the 2 glucose measures. Most importantly, we observed a dichotomy in the effects of these glycemic indices on the offspring epigenome. Offspring born to mothers with elevated 2hPG showed global hypomethylation. CpGs most associated with the 2 measures also reflected differences in gene ontologies and had different associations with offspring birthweight. Conclusions Our findings suggest that 2 traditionally used glycemic indices for diagnosing gestational diabetes may reflect distinctive pathophysiologies in pregnancy, and have differential impacts on the offspring’s DNA methylome.

Asians are underrepresented across many omics databases, thereby limiting the potential of precision medicine in nearly 60% of the global population. As such, there is a pressing need for multi-omics derived quantitative trait loci (QTLs) to fill the knowledge gap of complex traits in populations of Asian ancestry. Here, we provide the first blood-based multi-omics analysis of Asian pregnant women, constituting high-resolution genotyping (N = 1079), DNA methylation (N = 915) and transcriptome profiling (N = 238). Integrative omics analysis identified 219 154 CpGs associated with cis-DNA methylation QTLs (meQTLs) and 3703 RNAs associated with cis-RNA expression QTLs (eQTLs). Ethnicity was the largest contributor of inter-individual variation across all omics datasets, with 2561 genes identified as hotspots of this variation; 395 of these hotspot genes also contained both ethnicity-specific eQTLs and meQTLs. Gene set enrichment analysis of these ethnicity QTL hotspots showed pathways involved in lipid metabolism, adaptive immune system and carbohydrate metabolism. Pathway validation by profiling the lipidome (~480 lipids) of antenatal plasma (N = 752) and placenta (N = 1042) in the same cohort showed significant lipid differences among Chinese, Malay and Indian women, validating ethnicity-QTL gene effects across different tissue types. To develop deeper insights into the complex traits and benefit future precision medicine research in Asian pregnant women, we developed iMOMdb, an open-access database.

Summary Background & aims For patients in the intensive care unit (ICU), nutritional risk assessment is often difficult. Traditional scoring systems cannot be used for patients who are sedated or unconscious since they are unable to provide information on their history of food intake and weight loss. We aim to validate the NUTRIC (NUTrition RIsk in Critically ill) score, an ICU-specific nutrition risk assessment tool in Asian patients. Methods This was an observational study in the medical ICU of a university-affiliated tertiary hospital. We included all adult patients (≥18years) admitted between October 2013 and September 2014 who stayed for more than 24 hours in the ICU. Components of the modified NUTRIC (mNUTRIC) score, demographic details, body mass index (BMI), use of mechanical ventilation (MV), vasopressor drugs, and renal replacement therapy (RRT) were obtained from the ICU database. For patients on MV (maximum 12 days), we calculated the energy intake and nutritional adequacy (energy received ÷ energy recommended) from enteral or parenteral feeding data. Multivariable logistic regression analysis was used with 28-day mortality as the outcome of interest. Results 401 patients (62% male, mean age 60.0 ± 16.3 years, mean BMI 23.9 ± 6.2 kg/m 2 ) were included. In the univariate analysis, BMI, mNUTRIC score, MV, vasopressor drug, and RRT were associated with 28-day mortality. In the multivariable logistic regression analysis, mNUTRIC score (Odds ratio, OR 1.48, Confidence Interval, CI 1.25–1.74, p Nutritional adequacy was assessed in a subgroup of 273 (68%) patients who received MV for at least 48 hours. Median (IQR) nutritional adequacy was 0.44 (0.15–0.70). In patients with high mNUTRIC score (5–9), higher nutritional adequacy was associated with a lower predicted 28-day mortality; this was not observed in patients with low mNUTRIC (0–4) score (effect modification, p interaction Conclusion In a mixed Asian ICU population, mNUTRIC score is independently associated with 28-day mortality. Increased nutritional adequacy may reduce the 28-day mortality in patients with a high mNUTRIC score.

The short-term effect of soya protein, polydextrose and their combination on energy intake (EI) was investigated in Chinese. In total, twenty-seven healthy, normotensive and lean Chinese men aged 21–40 years were given four different soyabean curd preloads with or without polydextrose. The study was a repeated-measure, randomised, cross-over design. The consumption of high-protein soyabean curd alone or in addition with polydextrose as a preload led to greater reduction in EI at a subsequent meal. A similar observation was also found after intake of low-protein soyabean curd with polydextrose. The gut hormone responses mirrored the reduction in food intake. It appears that incorporation of polydextrose either with low- or high-protein soyabean curd could be a potential strategy to reduce EI and assist with weight management. The popular consumption of soyabean curd in Chinese makes it an ideal vehicle for incorporation of polydextrose. This evidence-based dietary approach can serve as a guideline for developing functional foods for weight reduction and weight maintenance.

Background: Escherichia coli(E. coli) resides inside the human body and during the course of infection is exposed to reactive nitrogen species (RNS) such as nitric oxide (NO) and S-nitrosoglutathione (GSNO). NO plays an important role in the mammalian immune system and regulation of blood flow. GSNO sometimes serves as a donor of NO, but its thiol chemistry also has effects distinct from NO. This work applies the recently developed Principal Component Analysis (PCA) technique of Rollins et al. (in review) in determining NO and GSNO response genes in an E. coli network. PCA is a powerful data mining method that is able to analyze and extract critical information from large microarray data sets even though the number of genes is much greater than the number of experimental runs. Result: The application of Rollins et al. technique identified a signature of NO-specific and GSNOspecific genes, containing those that were previously identified by Hyduke et. al. (2007) and Jarboe et. al. (2008) as well as new genes which may affect NO and GSNO activity. Three genes not previously identified as affecting NO and GSNO response were selected for experimental analysis to evaluate the identification ability of

Summary Background Polymorphic variants within human melanocortin‐3 receptor gene (MC3R) gene have been associated with obesity. However, its influence on infancy and early childhood adiposity has not been reported before. Objectives We assessed associations between genotype at polymorphic sites within MC3R with early childhood adiposity and interaction with early childhood appetitive traits. Methods We studied 1090 singletons in an Asian mother–offspring cohort genotyped for MC3R and in a subgroup (n = 422) who had completed Child Eating Behaviour Questionnaires (CEBQ) at 12 months. Children were followed from birth to 48 months, and up to 10 measurements of body mass index and five measures of triceps and subscapular skin‐folds were obtained. Results Independent of potential confounders, each additional MC3R minor allele copy was associated with greater body mass index standard deviation score [B{95% confidence interval}: 0.004 units/month {0.001,0.007}; p = 0.007], triceps [0.009 mm/month {0.001,0.02}; p = 0.021] and subscapular skin‐fold [0.008 mm/month {0.002,0.01}; p = 0.011] gain velocity in the first 48 months. Each additional MC3R minor allele copy was also associated with increased odds of overweight [odds ratio {95% confidence interval}: 1.48{1.17–1.88}] and obesity [1.58{1.10–2.28}] in the first 48 months. Every additional copy of MC3R minor allele was positively associated with ‘slowness‐in‐eating’ appetitive trait [0.24{0.06,0.39}, p = 0.006]; however, the relationship between ‘slowness‐in‐eating’ with adiposity gain was not statistically significant. Conclusions Our findings support the role of MC3R genetic variants in adiposity gain during early childhood.

UNLABELLED Limited research exists on how different oil types and time of addition affect starch digestibility of rice. This study aimed to assess the starch digestibility of white and red rice prepared with 2 oil types: vegetable oil (unsaturated fat) and ghee (clarified butter, saturated fat) added at 3 different time points during the cooking process ("before": frying raw rice in oil before boiling, "during": adding oil during boiling, and "after": stir-frying cooked rice in oil). Red rice produced a slower digestion rate than white rice. White rice digestibility was not affected by oil type, but was affected by addition time of oil. Adding oil "after" (stir-frying) to white or red rice resulted in higher slowly digestible starch. Red rice cooked using ghee showed the lowest amount of glucose release during in vitro digestion. The addition of ghee "during" (that is boiling with ghee) or "before" (that is frying rice raw with ghee then boiling) cooking showed potential for attenuating the postprandial glycemic response and increasing resistant starch content. This is the first report to show healthier ways of preparing rice. White rice with oil added "after" (stir-fried) may provide a source of sustained glucose and stabilize blood glucose levels. Boiling red rice with ghee or cooking red rice with ghee pilaf-style may provide beneficial effects on postprandial blood glucose and insulin concentrations, and improve colonic health. The encouraging results of the present study justify extending it to an in vivo investigation to conclusively determine the effect of time of addition of fat when rice is cooked on blood glucose homeostasis. PRACTICAL APPLICATION Rice is a predominant source of energy in most of Asia with excessive consumption of rice being implicated in the rise of type 2 diabetes. Stir-frying white rice can be a source of sustained glucose and provide a stabilizing effect on blood glucose levels. Boiling red rice with ghee or cooking red rice with ghee pilaf-style may provide beneficial effects on postprandial blood glucose and insulin concentrations. This suggests how a single technique of adding fat in the cooking of rice at certain time points may be a useful method in providing taste and lowering glycemia.

Objective Low glycemic index (GI) foods have been suggested to minimize large fluctuations in blood glucose levels and reduce food intake. However, the majority of studies have been conducted on Caucasian populations with limited data on Asians. The objective of this study was to investigate how the provision of a low GI breakfast and afternoon snack affected daily blood glucose profiles and food intake. Materials and methods In a randomized, controlled crossover non blind design, 11 healthy Chinese male adults (body mass index 22.4 ± 1.3 kg m−2) attended two sessions where they consumed either a high or low GI breakfast and afternoon snack, and a standardized buffet lunch. Daily changes in glycemic response (GR) were measured using the Medtronic MiniMed (Northridge, CA) iPro™2 continuous glucose monitoring system (CGMS). The GR was further calculated to obtain the incremental area under the curve (IAUC). Glycemic variability was calculated as mean amplitude of glycemic excursion (MAGE) and energy intake (kcal) was measured quantitatively at the buffet lunch. Results Compared to the high GI intervention, the low GI intervention significantly reduced the GR following breakfast (p = 0.02), lunch (p = 0.02) and dinner (p = 0.05). The low GI treatment showed a reduction in daily AUC (p = 0.03). There was a significant reduction in IAUC after a low GI breakfast compared to the high GI breakfast (p = 0.03). The low GI breakfast resulted in a significantly lower food intake at lunch and a resulting decreased energy intake of 285 kcal (p = 0.02). The MAGE was significantly lower during the entire low GI treatment (p = 0.03). Conclusions Consumption of a low GI breakfast and afternoon snack was capable of attenuating 24-h blood glucose profiles, minimize glycemic excursions and reduce food intake in healthy Asian males. This simple dietary intervention may be an acceptable approach in improving overall glycemia and energy balance in Asians. Clinical trial registration number NCT02340507, Highlights • The impact of low and high glycemic index foods on 24 h blood glucose profile. • The CGMS provides detailed information on how diets affect longer term glycemia. • Low GI breakfast and afternoon snack minimize large blood glucose fluctuations. • Low GI foods reduce glycemic variability and total energy intake.

Early life environments interact with genotype to determine stable phenotypic outcomes. Here we examined the influence of a variant in the brain-derived neurotropic factor (BDNF) gene (Val66Met), which underlies synaptic plasticity throughout the central nervous system, on the degree to which antenatal maternal anxiety associated with neonatal DNA methylation. We also examined the association between neonatal DNA methylation and brain substructure volume, as a function of BDNF genotype. Infant, but not maternal, BDNF genotype dramatically influences the association of antenatal anxiety on the epigenome at birth as well as that between the epigenome and neonatal brain structure. There was a greater impact of antenatal maternal anxiety on the DNA methylation of infants with the methionine (Met)/Met compared to both Met/valine (Val) and Val/Val genotypes. There were significantly more cytosine–phosphate–guanine sites where methylation levels covaried with right amygdala volume among Met/Met compared with both Met/Val and Val/Val carriers. In contrast, more cytosine–phosphate–guanine sites covaried with left hippocampus volume in Val/Val infants compared with infants of the Met/Val or Met/Met genotype. Thus, antenatal Maternal Anxiety × BDNF Val66Met Polymorphism interactions at the level of the epigenome are reflected differently in the structure of the amygdala and the hippocampus. These findings suggest that BDNF genotype regulates the sensitivity of the methylome to early environment and that differential susceptibility to specific environmental conditions may be both tissue and function specific.

Accounting for cellular heterogeneity is essential in neonatal epigenome-wide association studies (EWAS) performed on heterogeneous tissues, such as umbilical cord tissue (CT) or cord blood (CB). Using a reference-panel-based statistical approach, the cell type composition of heterogeneous tissues can be estimated by comparison of whole tissue DNA methylation profiles with cell type-specific DNA methylation signatures. Currently, there is no adequate DNA methylation reference panel for CT, and existing CB panels have been generated on lower coverage Infinium HumanMethylation450 arrays. In this study, we generate a reference panel for CT and improve available CB panels by using the higher coverage Infinium MethylationEPIC arrays. We performed DNA methylation profiling of 9 cell types isolated from CT and CB samples from 14 neonates. In addition to these cell types, we profiled DNA methylation of unfractionated CT and CB. Cell type composition of these unfractionated tissue samples, as estimated by our reference panels, was in agreement with that obtained by flow cytometry. Expectedly, DNA methylation profiles from CT and CB were distinct, reflecting their mesenchymal and hematopoietic stem cell origins. Variable CpGs from both unfractionated CT and its isolated cell types were more likely to be located in open seas and intronic regions than those in CB. Cell type specific CpGs in CT were enriched in intercellular matrix pathways, while those from CB were enriched in immune-related pathways. This study provides an open source reference panel for estimation and adjustment of cellular heterogeneity in CT and CB, and broadens the scope of tissue utilization assessed in future neonatal EWAS studies.

Multiple myeloma is an incurable hematological malignancy that relies on drug combinations for first and secondary lines of treatment. The inclusion of proteasome inhibitors, such as bortezomib, into these combination regimens has improved median survival. Resistance to bortezomib, however, is a common occurrence that ultimately contributes to treatment failure, and there remains a need to identify improved drug combinations. We developed the quadratic phenotypic optimization platform (QPOP) to optimize treatment combinations selected from a candidate pool of 114 approved drugs. QPOP uses quadratic surfaces to model the biological effects of drug combinations to identify effective drug combinations without reference to molecular mechanisms or predetermined drug synergy data. Applying QPOP to bortezomib-resistant multiple myeloma cell lines determined the drug combinations that collectively optimized treatment efficacy. We found that these combinations acted by reversing the DNA methylation and tumor suppressor silencing that often occur after acquired bortezomib resistance in multiple myeloma. Successive application of QPOP on a xenograft mouse model further optimized the dosages of each drug within a given combination while minimizing overall toxicity in vivo, and application of QPOP to ex vivo multiple myeloma patient samples optimized drug combinations in patient-specific contexts.

Background: Traditional nutrition scoring cannot be applied in Intensive care units (ICU).NUTRIC (NUTrition RIsk in Critically ill) score is an ICU-specific nutrition risk assessment which has not been validated in Asian patients. Setting: Observational study in a university-affiliated tertiary hospital during October913-September914 with adult patients staying more than 24hours in medical ICU. Methods: Demographics, body mass index (BMI), mechanical ventilation (MV), vasopressor use, renal replacement therapy (RRT) and components of NUTRIC score (except interleukin 6) were obtained from ICU database. We calculated nutritional adequacy (calorie received/calorie recommended) during MV (maximum 12days) from nasogastric tube or parenteral feeding data. Results: 401 patients (male 62%, mean age 60±16.3years, mean BMI 23.9±6.2kg/m 2 ) were included. In univariate analysis BMI, modified NUTRIC (mNUTRIC) score, MV, vasopressor use and RRT were associated with 28day mortality. Patients on MV (273,68%) had median nutritional adequacy of 0.44(IQR 0.15-0.70). Effect modification between low vs high mNUTRIC score is shown. Conclusion: In an Asian ICU population, mNUTRIC score is independently associated with 28day mortality. Increased nutritional adequacy may improve predicted 28day mortality in high mNUTRIC group.

Interindividual variability in the epigenome has gained tremendous attention for its potential in pathophysiological investigation, disease diagnosis, and evaluation of clinical intervention. DNA methylation is the most studied epigenetic mark in epigenome-wide association studies (EWAS) as it can be detected from limited starting material. Infinium 450K methylation array is the most popular platform for high-throughput profiling of this mark in clinical samples, as it is cost-effective and requires small amounts of DNA. However, this method suffers from low genome coverage and errors introduced by probe cross-hybridization. Whole-genome bisulfite sequencing can overcome these limitations but elevates the costs tremendously. Methyl-Capture Sequencing (MC Seq) is an attractive intermediate solution to increase the methylome coverage in large sample sets. Here we first demonstrate that MC Seq can be employed using DNA amounts comparable to the amounts used for Infinium 450K. Second, to provide guidance when choosing between the 2 platforms for EWAS, we evaluate and compare MC Seq and Infinium 450K in terms of coverage, technical variation, and concordance of methylation calls in clinical samples. Last, since the focus in EWAS is to study interindividual variation, we demonstrate the utility of MC Seq in studying interindividual variation in subjects from different ethnicities.

We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 x 10(-11) to 5.0 x 10(-21)). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 x 10(-6)). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.

Aim: Determine if the association of HIF3A DNA methylation with weight and adiposity is detectable early in life. Material & methods: We determined HIF3A genotype and DNA methylation patterns (on hybridization arrays) in DNA extracted from umbilical cords of 991 infants. Methylation levels at three CpGs in the HIF3A first intron were related to neonatal and infant anthropometry and to genotype at nearby polymorphic sites. Results & conclusion: Higher methylation levels at three previously described HIF3A CpGs were associated with greater infant weight and adiposity. The effect sizes were slightly smaller than those reported for adult BMI. There was also an interaction within cis-genotype. The association between higher DNA methylation at HIF3A and increased adiposity is present in neonates. In this study, no particular prenatal factor strongly influenced HIF3A hypermethylation. Our data nonetheless suggest shared prenatal influences on HIF3A methylation and adiposity.

International audience; Individuals who are born small for gestational age (SGA) have a risk to develop various metabolic diseases during their life course. The biological memory of the prenatal state of growth restricted individuals may be reflected in epigenetic alterations in stem cell populations. Mesenchymal stem cells (MSCs) from the Wharton's jelly of umbilical cord tissue are multipotent, and we generated primary umbilical cord MSC isolates from SGA and normal neonates, which were subsequently differentiated into adipocytes. We established chromatin state maps for histone marks H3K27 acetylation and H3K27 trimethylation and tested whether enrichment of these marks was associated with gene expression changes. After validating gene expression levels for 10 significant chromatin immunoprecipitation sequencing candidate genes, we selected acyl-coenzyme A synthetase 1 (ACSL1) for further investigations due to its key roles in lipid metabolism. The ACSL1 gene was found to be highly associated with histone acetylation in adipocytes differentiated from MSCs with SGA background. In SGA-derived adipocytes, the ACSL1 expression level was also found to be associated with increased lipid loading as well as higher insulin sensitivity. ACSL1 depletion led to changes in expression of candidate genes such as proinflammatory chemokines and down-regulated both, the amount of cellular lipids and glucose uptake. Increased ACSL1, as well as modulated downstream candidate gene expression, may reflect the obese state, as detected in mice fed a high-fat diet. In summary, we believe that ACSL1 is a programmable mediator of insulin sensitivity and cellular lipid content and adipocytes differentiated from Wharton's jelly MSCs recapitulate important physiological characteristics of SGA individuals.

Limited research exists on how different oil types and time of addition affect starch digestibility of rice. This study aimed to assess the starch digestibility of white and red rice prepared with 2 oil types: vegetable oil (unsaturated fat) and ghee (clarified butter, saturated fat) added at 3 different time points during the cooking process ("before": frying raw rice in oil before boiling, "during": adding oil during boiling, and "after": stir-frying cooked rice in oil). Red rice produced a slower digestion rate than white rice. White rice digestibility was not affected by oil type, but was affected by addition time of oil. Adding oil "after" (stir-frying) to white or red rice resulted in higher slowly digestible starch. Red rice cooked using ghee showed the lowest amount of glucose release during in vitro digestion. The addition of ghee "during" (that is boiling with ghee) or "before" (that is frying rice raw with ghee then boiling) cooking showed potential for attenuating the postprandial glycemic response and increasing resistant starch content. This is the first report to show healthier ways of preparing rice. White rice with oil added "after" (stir-fried) may provide a source of sustained glucose and stabilize blood glucose levels. Boiling red rice with ghee or cooking red rice with ghee pilaf-style may provide beneficial effects on postprandial blood glucose and insulin concentrations, and improve colonic health. The encouraging results of the present study justify extending it to an in vivo investigation to conclusively determine the effect of time of addition of fat when rice is cooked on blood glucose homeostasis.Rice is a predominant source of energy in most of Asia with excessive consumption of rice being implicated in the rise of type 2 diabetes. Stir-frying white rice can be a source of sustained glucose and provide a stabilizing effect on blood glucose levels. Boiling red rice with ghee or cooking red rice with ghee pilaf-style may provide beneficial effects on postprandial blood glucose and insulin concentrations. This suggests how a single technique of adding fat in the cooking of rice at certain time points may be a useful method in providing taste and lowering glycemia.

STUDY QUESTION Are molecular pathways reflecting the biology of small for gestational age (SGA) neonates preserved in umbilical cord-derived mesenchymal stem cells (MSCs)? SUMMARY ANSWER MSCs from SGA newborns were found to express an altered EGR-1-dependent gene network involved in the regulation of cell proliferation and oxidative stress. WHAT IS KNOWN ALREADY Individuals with suboptimal intrauterine development are at greater risk of metabolic diseases such as type II diabetes, obesity and cardiovascular disease. STUDY DESIGN, SIZE, DURATION Umbilical cords (n = 283) from the GUSTO (growing up in Singapore towards healthy outcomes) birth cohort study, and primary MSC isolates established from SGA and matched control cases (n = 6 per group), were subjected to gene expression analysis and candidate genes were studied for functional validation. PARTICIPANTS/MATERIALS, SETTING, METHODS Umbilical cord specimens were derived from babies born at the National University Hospital (NUH) in Singapore. Local ethical approval was obtained. MSC isolates were established in Wharton's jelly and molecular analysis was conducted by gene expression microarrays and RT-PCR. Cells from SGA and control groups were compared in the presence and absence of insulin and candidate gene function was studied via siRNA-mediated gene knockdown and over-expression experiments in MSCs. MAIN RESULTS AND THE ROLE OF CHANCE Using repeated measure ANOVAs, proliferation rates of MSCs isolated from SGA neonates were found to be significantly increased (P < 0.01). In the absence of insulin, EGR-1 levels were found to be significantly reduced in the group of SGA-derived MSCs, whereas EGR-1 expression was found to be up-regulated in the same group in the presence of insulin (P < 0.01). EGR-1 was found to induce expression of COX-2 in the SGA group (P < 0.01) and both, EGR-1 and COX-2 stimulated glucose uptake in MSCs (P < 0.01). EGR-1 and COX-2 levels were associated in whole umbilical cords (n = 283, P < 0.01) and EGR-1 positively correlated with abdominal circumference and birthweight (n = 91, P < 0.01 and n = 91, P < 0.01). LIMITATIONS, REASONS FOR CAUTION Cell models may not entirely reflect the physiology of the host and patient follow-up studies will be necessary for further clinical validation. WIDER IMPLICATIONS OF THE FINDINGS Our study suggests that Wharton's jelly-derived MSCs are useful in identifying pathways specific for fetal growth restriction. STUDY FUNDING/COMPETING INTERESTS This work is supported by the Translational Clinical Research (TCR) Flagship Program on Developmental Pathways to Metabolic Disease funded by the National Research Foundation (NRF) and administered by the National Medical Research Council (NMRC), Singapore- NMRC/TCR/004-NUS/2008'. SICS Investigators are supported through the Agency for Science Technology and Research (A*STAR) funding. No potential conflicts of interest relevant to this article were reported.

Integrating the genotype with epigenetic marks holds the promise of better understanding the biology that underlies the complex interactions of inherited and environmental components that define the developmental origins of a range of disorders. The quality of the in utero environment significantly influences health over the lifecourse. Epigenetics, and in particular DNA methylation marks, have been postulated as a mechanism for the enduring effects of the prenatal environment. Accordingly, neonate methylomes contain molecular memory of the individual in utero experience. However, interindividual variation in methylation can also be a consequence of DNA sequence polymorphisms that result in methylation quantitative trait loci (methQTLs) and, potentially, the interaction between fixed genetic variation and environmental influences. We surveyed the genotypes and DNA methylomes of 237 neonates and found 1423 punctuate regions of the methylome that were highly variable across individuals, termed variably methylated regions (VMRs), against a backdrop of homogeneity. MethQTLs were readily detected in neonatal methylomes, and genotype alone best explained ∼25% of the VMRs. We found that the best explanation for 75% of VMRs was the interaction of genotype with different in utero environments, including maternal smoking, maternal depression, maternal BMI, infant birth weight, gestational age, and birth order. Our study sheds new light on the complex relationship between biological inheritance as represented by genotype and individual prenatal experience and suggests the importance of considering both fixed genetic variation and environmental factors in interpreting epigenetic variation. Published version

Background Obesity is an escalating health problem worldwide, and hence the causes underlying its development are of primary importance to public health. There is growing evidence that suboptimal intrauterine environment can perturb the metabolic programing of the growing fetus, thereby increasing the risk of developing obesity in later life. However, the link between early exposures in the womb, genetic susceptibility, and perturbed epigenome on metabolic health is not well understood. In this study, we shed more light on this aspect by performing a comprehensive analysis on the effects of variation in prenatal environment, neonatal methylome, and genotype on birth weight and adiposity in early childhood. Methods In a prospective mother-offspring cohort (N = 987), we interrogated the effects of 30 variables that influence the prenatal environment, umbilical cord DNA methylation, and genotype on offspring weight and adiposity, over the period from birth to 48 months. This is an interim analysis on an ongoing cohort study. Results Eleven of 30 prenatal environments, including maternal adiposity, smoking, blood glucose and plasma unsaturated fatty acid levels, were associated with birth weight. Polygenic risk scores derived from genetic association studies on adult adiposity were also associated with birth weight and child adiposity, indicating an overlap between the genetic pathways influencing metabolic health in early and later life. Neonatal methylation markers from seven gene loci (ANK3, CDKN2B, CACNA1G, IGDCC4, P4HA3, ZNF423 and MIRLET7BHG) were significantly associated with birth weight, with a subset of these in genes previously implicated in metabolic pathways in humans and in animal models. Methylation levels at three of seven birth weight-linked loci showed significant association with prenatal environment, but none were affected by polygenic risk score. Six of these birth weight-linked loci continued to show a longitudinal association with offspring size and/or adiposity in early childhood. Conclusions This study provides further evidence that developmental pathways to adiposity begin before birth and are influenced by environmental, genetic and epigenetic factors. These pathways can have a lasting effect on offspring size, adiposity and future metabolic outcomes, and offer new opportunities for risk stratification and prevention of obesity. Clinical Trial Registration This birth cohort is a prospective observational study, designed to study the developmental origins of health and disease, and was retrospectively registered on 1 July 2010 under the identifier NCT01174875. Electronic supplementary material The online version of this article (doi:10.1186/s12916-017-0800-1) contains supplementary material, which is available to authorized users.