Epigenome-Wide Association Study Reveals Methylation Loci Associated With Offspring Gestational Diabetes Mellitus Exposure and Maternal Methylome

Abstract

Objective: Gestational diabetes mellitus (GDM) is associated with a future offspring risk for the development of obesity and insulin resistance in Gestational diabetes mellitus (GDM) is associated with an increased risk of obesity and insulin resistance in offspring later in life, which might be explained by epigenetic changes in response to maternal hyperglycaemic exposure. Research Design and Methods:We explored the association of GDM exposure on maternal blood and newborn cord-blood methylation of 536 mother-offspring pairs from the prospective FinnGeDi cohort, using Illumina's methylationEPIC BeadChip 850K arrays. We assessed two hypotheses First, we tested for shared maternal and offspring epigenetic effects due to GDM exposure. Second, we tested whether GDM exposure and maternal methylation has an epigenetic effect on the offspring. Results:We did not find any epigenetic marks (differentially methylated CpG probes) with shared and consistent effects between mothers and offspring. After including maternal methylation in the model, we identified a single significant (FDR = 1.38 x 10 -2 ) CpG at the cg22790973 probe (TFCP2) associated with GDM. We identified seven additional FDR-significant interactions of maternal methylation and GDM status, with the strongest association at the same cg22790973 probe (TFCP2), plus cg03456133, cg24440941 (H3C6), cg20002843 (LOC127841), cg19107264, cg11493553 located in the UBE3C gene and cg17065901 in FAM13A, both susceptibility genes for type 2 diabetes and BMI and cg23355087, within the DLGAP2 gene, known to be involved in insulin resistance during pregnancy. Conclusion:Our study reveals the potential complexity of the epigenetic transmission between GDM mothers and their offspring, likely determined by not only GDM

Maternal Glycemic Dysregulation During Pregnancy and Neonatal Blood DNA Methylation: Meta-analyses of Epigenome-Wide Association Studies

“…Seven cohorts with cord blood DNAm and fasting glycemic data in midpregnancy participated in the meta-analyses ( Table 1 and Supplementary Material ). These cohorts were from Southeast Asia (Singapore: Growing Up in Singapore Towards healthy Outcomes [GUSTO] [ 14 ]), North America (Canada: Genetics of Glucose regulation in Gestation and Growth [Gen3G] [ 15 ], U.S.: Healthy Start [ 16 ]), and Europe (Finland: the Finnish Gestational Diabetes [FinnGeDi] Study [ 7 , 17 ] and Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction [PREDO] study [ 18 ], France: EDEN [ 19 ], and Belgium: the ENVIRonmental influence ON early AGEing [ENVIRONAGE] [ 20 ]). One cohort, in the Generation R Study ( 21 ) (the Netherlands), had nonfasting glycemic data (included in a secondary analysis).…”

DNA Methylation in Gestational Diabetes and its Predictive Value for Postpartum Glucose Disturbances

“…Global DNAm is altered during hyperglycemia ( 34 , 35 ), and increased global methylation in placental tissue has been associated with GDM ( 36 , 37 ). However, there are limited data describing DNAm in the peripheral blood of patients with GDM, and the results are inconclusive ( 16-19 , 21 , 22 , 38 , 39 ). Small sample sizes and the absence of reproducibility or confirmatory cohorts have been the main weaknesses in most studies ( 16-18 , 38 ).…”

“…In a recent study on Black South African women, global DNAm in peripheral blood was found not to be associated with GDM, which was contrary to the authors’ hypothesis ( 20 ). Two studies with larger cohorts have been recently published using the Infinium MethylationEPIC BeadChip ( 21 , 22 ), which covers 850 000 CpG sites. Fragoso-Bargas et al ( 22 ) identified 4 CpG sites associated with BMI and hyperglycemia in peripheral blood leukocytes of a subcohort of the EPI-PREG study; however, the data were not validated in an independent cohort.…”

“…Fragoso-Bargas et al ( 22 ) identified 4 CpG sites associated with BMI and hyperglycemia in peripheral blood leukocytes of a subcohort of the EPI-PREG study; however, the data were not validated in an independent cohort. Canouil et al ( 21 ) used the same array to assess maternal methylation in a group of the FinnGeDi prospective multicenter cohort, but failed to find any significant differentially methylated positions associated with GDM (after false discovery rate adjustment) in an epigenome-wide association study. In our exploratory study, we identified 7 putative genes associated with both hyper- and hypomethylated sites, and we validated these in a larger population, finding the same trend in 2 CpG sites: Cg03554962 ( LINC00917 ) and Cg05090351 ( CTBP2 ).…”

Cohort profile: Epigenetics in Pregnancy (EPIPREG) – population-based sample of European and South Asian pregnant women with epigenome-wide DNA methylation (850k) in peripheral blood leukocytes

“…One of the most studied epigenetic mechanisms is DNA methylation, which plays an important role in normal development, chromatin organization and gene expression [3]. Several studies have indicated that DNA methylation is associated with cardiovascular risk factors such as body mass index (BMI) [4][5][6][7], gestational diabetes (GDM) [8], type 2 diabetes (T2D) [9][10][11][12][13], lipid levels [14,15], hypertension [16,17], smoking [18][19][20][21][22] and alcohol intake [23][24][25], suggesting that cardiometabolic diseases have an epigenetic component.…”