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]).

Lay abstract

Many women who get gestational diabetes during pregnancy go on to give birth to larger (macrosomic) babies. These babies then grow up to have greater risk of being overweight or obese, and all the health concerns this entails. We sought to examine whether epigenetic factors could help explain this link, by examining the blood of some children whose mothers were enrolled in a gestational diabetes study in China. We identified three sites on two different genes as being associated with both gestational diabetes and macrosomia. The way these genes work suggest a mechanism for how they contribute to macrosomia, providing a promising new avenue for future research, early detection and precision prevention (Trial Registration number: NCT01554358 [ClinicalTrials.gov]).

Keywords::

• epigenetic epidemiology
• epigenetics
• macrosomia
• metabolic diseases
• pediatrics

Financial & competing interests disclosure

This study was supported by grants from the European Foundation for the Study of Diabetes (EFSD)/Chinese Diabetes Society (CDS)/Lilly programme for Collaborative Research between China and Europe, and the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK100790). This project also used core facilities supported by the NORC Center Grant P30 DK072476, and the COBRE Center Grant P30 GM118430. G Hu was partly supported by the grant from the National Institute of General Medical Sciences (U54GM104940). A Baccarelli was partially supported by a grant from the National Institute of Environmental Health Studies (P30ES009089). L Hou was partially supported by the American Heart Association Children’s Strategically Focused Research Network. BT Joyce was partially supported by an American Heart Association Career Development Award (Grant number 19CDA34630050). H Liu was supported by the Natural Science Foundation of Tianjin, China (19JCYBJC28000). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

This study was approved by the Human Subjects Committee of the Tianjin Women’s and Children’s Health Center, and all participants provided written informed consent. This original trial is registered with ClinicalTrials.gov, number NCT01554358.

Data sharing statement

The authors certify that this manuscript reports the secondary analysis of clinical trial data that have been shared with them, and that the use of this shared data is in accordance with the terms (if any) agreed upon their receipt. The source of this data is: Tianjin Gestational Diabetes Prevention Program (NCT01554358).

Additional information

Funding

This study was supported by grants from the European Foundation for the Study of Diabetes (EFSD)/Chinese Diabetes Society (CDS)/Lilly programme for Collaborative Research between China and Europe, and the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK100790). This project also used core facilities supported by the NORC Center Grant P30 DK072476, and the COBRE Center Grant P30 GM118430. G Hu was partly supported by the grant from the National Institute of General Medical Sciences (U54GM104940). A Baccarelli was partially supported by a grant from the National Institute of Environmental Health Studies (P30ES009089). L Hou was partially supported by the American Heart Association Children’s Strategically Focused Research Network. BT Joyce was partially supported by an American Heart Association Career Development Award (Grant number 19CDA34630050). H Liu was supported by the Natural Science Foundation of Tianjin, China (19JCYBJC28000). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.