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Novel epigenetic link between gestational diabetes mellitus and macrosomia.

ABSTRACT: Background & objectives: Examine maternal gestational diabetes mellitus (GDM), macrosomia and DNA methylation in candidate genes IGF1, IGF2, H19, ARHGRF11, MEST, NR3C1, ADIPOQ and RETN. Materials & methods: A total of 1145 children (572 GDM cases and 573 controls) from the Tianjin GDM study, including 177 with macrosomia, had blood DNA collection at median age 5.9 (range: 3.1-10.0). We used logistic regression to screen for associations with GDM and model macrosomia on 37 CpGs, and performed mediation analysis. Results: One CpG was associated with macrosomia at false discovery rate (FDR) <0.05 (cg14428359 in MEST); two (cg19466922 in MEST and cg26263166 in IGF2) were associated at p < 0.05 but mediated 26 and 13%, respectively. Conclusion: MEST and IGF2 were previously identified for potential involvement in fetal growth and development (Trial Registration number: NCT01554358 [ClinicalTrials.gov]).

SUBMITTER: Joyce BT

PROVIDER: S-EPMC8371577 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Novel epigenetic link between gestational diabetes mellitus and macrosomia.

Joyce Brian T BT Liu Huikun H Wang Leishen L Wang Jun J Zheng Yinan Y Nannini Drew D Drong Alex A Shiau Stephanie S Li Weiqin W Leng Junhong J Shen Yun Y Gao Ru R Baccarelli Andrea A Hu Gang G Hou Lifang L

Epigenomics 20210802 15

Background & objectives: Examine maternal gestational diabetes mellitus (GDM), macrosomia and DNA methylation in candidate genes IGF1, IGF2, H19, ARHGRF11, MEST, NR3C1, ADIPOQ and RETN. Materials & methods: A total of 1145 children (572 GDM cases and 573 controls) from the Tianjin GDM study, including 177 with macrosomia, had blood DNA collection at median age 5.9 (range: 3.1-10.0). We used logistic regression to screen for as ...[more]

PMID: 34337972

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Project description:IntroductionGestational diabetes mellitus (GDM), a metabolism-related pregnancy complication, is significantly associated with an increased risk of macrosomia. We hypothesized that maternal circulating metabolic biomarkers differed between women with GDM and macrosomia (GDM-M) and women with GDM and normal neonatal weight (GDM-N), and had good prediction performance for GDM-M.MethodsPlasma samples from 44 GDM-M and 44 GDM-N were analyzed using Olink Proseek multiplex metabolism assay targeting 92 biomarkers. Combined different clinical characteristics and Olink markers, LASSO regression was used to optimize variable selection, and Logistic regression was applied to build a predictive model. Nomogram was developed based on the selected variables visually. Receiver operating characteristic (ROC) curve, calibration plot, and clinical impact curve were used to validate the model.ResultsWe found 4 metabolism-related biomarkers differing between groups [CLUL1 (Clusterin-like protein 1), VCAN (Versican core protein), FCRL1 (Fc receptor-like protein 1), RNASE3 (Eosinophil cationic protein), FDR < 0.05]. Based on the different clinical characteristics and Olink markers, a total of nine predictors, namely pre-pregnancy body mass index (BMI), weight gain at 24 gestational weeks (gw), parity, oral glucose tolerance test (OGTT) 2 h glucose at 24 gw, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) at 24 gw, and plasma expression of CLUL1, VCAN and RNASE3 at 24 gw, were identified by LASSO regression. The model constructed using these 9 predictors displayed good prediction performance for GDM-M, with an area under the ROC of 0.970 (sensitivity = 0.955, specificity = 0.886), and was well calibrated (P Hosmer-Lemeshow test = 0.897).ConclusionThe Model included pre-pregnancy BMI, weight gain at 24 gw, parity, OGTT 2 h glucose at 24 gw, HDL and LDL at 24 gw, and plasma expression of CLUL1, VCAN and RNASE3 at 24 gw had good prediction performance for predicting macrosomia in women with GDM.

Project description:IntroductionExosomes are cell-derived vesicles that are present in many biological fluids. Exosomal RNAs in cord blood may allow intercellular communication between mother and fetus. We aimed to establish exosomal RNA expression profiles in cord blood from patients with gestational diabetes mellitus and macrosomia (GDM-M) and evaluate their prediction performance.MethodsWe used microarray technology to establish the differential messenger RNA (mRNA), long non-coding RNA (lncRNA), and circular RNA (circRNA) expression profiles in cord blood exosomes from 3 patients with GDM-M compared with 3 patients with GDM and normal neonatal weight, followed by qPCR validation in an additional 40 patients with GDM. Logistic regression, receiver operating characteristic (ROC) curves, and graphical nomogram were applied to evaluate the performance of exosomal RNA (in peripheral blood) in macrosomia prediction.ResultsA total of 98 mRNAs, 372 lncRNAs, and 452 circRNAs were differentially expressed in cord blood exosomes from patients with GDM-M. Pathway analysis based on screening data showed that the differential genes were associated with Phosphatidylinositol 3'-kinase (PI3acK)-Akt signaling pathway, Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway, Transforming growth factor (TGF)-beta signaling pathway, insulin resistance, glycerolipid metabolism, fatty acid degradation, and mammalian target of rapamycin (mTOR) signaling pathway. After validation by qPCR, the expressions of GDF3, PROM1, AC006064.4, lnc-HPS6-1:1, and circ_0014635 were significantly increased and the expression of lnc-ZFHX3-7:1 was significantly decreased in cord blood exosomes of an additional 20 patients with GDM-M. The risk prediction performance of the expression of these validated genes (in peripheral blood exosomes) for GDM-related macrosomia was also evaluated. Only GDF3 expression and AC006064.4 expression showed well prediction performance [area under the curve (AUC) = 0.78 and 0.74, respectively]. Excitingly, the model including maternal age, fasting plasma glucose, 2-h plasma glucose, GDF3 expression, and AC006064.4 expression in peripheral blood exosomes had better prediction performance with an AUC of 0.86 (95% CI = 0.75-0.97).ConclusionThese results showed that exosomal RNAs are aberrantly expressed in the cord blood of patients with GDM-M and highlighted the importance of exosomal RNAs in peripheral blood for GDM-M prediction.

Project description:Gestational diabetes mellitus (GDM) is the most common metabolic disorder in pregnancy. GDM is associated with serious maternal and fetal complications, in particular, fetal macrosomia and large for gestational age (LGA), which predisposes to a higher risk of childhood obesity and type 2 diabetes mellitus later in life. Early prediction and diagnosis of GDM leads to early interventions such as diet and lifestyle, which could mitigate the maternal and fetal complications associated with GDM. Glycated haemoglobin A1c (HbA1c) has been widely used for monitoring, screening for and diagnosing diabetes and prediabetes. Increasing evidence has also showed that HbA1c could indicate fetal glucose supply. Thus, we hypothesise that the HbA1c level at around 24 to 28 weeks may predict the development of fetal macrosomia or an LGA baby in women with GDM, which could be useful for better prevention of fetal macrosomia and LGA. We searched MEDLINE, EMBASE, Cochrane and Google Scholar databases from inception to November 2022 for relevant studies that reported at least one HbA1c level during 24-28 weeks of pregnancy and fetal macrosomia or an LGA baby. We excluded studies that were not published in the English language. No other search filters were applied during the search. Two independent reviewers selected eligible studies for meta-analysis. Two independent reviewers performed data collection and analyses. The PROSPERO registration number is CRD42018086175. A total of 23 studies were included in this systematic review. Of these, 8 papers reported data of 17,711 women with GDM that allowed for inclusion in a meta-analysis. The obtained results demonstrated the prevalence of fetal macrosomia was 7.4% and of LGA, 13.36%. Meta-analyses showed that the estimated pooled risk ratio (RR) for LGA in women with high HbA1c values compared to normal or low values was 1.70 (95% CI: 1.23-2.35), p = 0.001; and the pooled RR for fetal macrosomia was 1.45 (95% CI: 0.80 to 2.63), p = 0.215. Further research is needed to evaluate the utility of HbA1c levels in predicting the delivery of a baby with fetal macrosomia or LGA in pregnant women.

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Novel epigenetic link between gestational diabetes mellitus and macrosomia.

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Novel epigenetic link between gestational diabetes mellitus and macrosomia.

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