DNA methylation risk score for type 2 diabetes is associated with gestational diabetes.

BACKGROUND: Gestational diabetes mellitus (GDM) and type 2 diabetes mellitus (T2DM) share many pathophysiological factors including genetics, but whether epigenetic marks are shared is unknown. We aimed to test whether a DNA methylation risk score (MRS) for T2DM was associated with GDM across ancestry and GDM criteria. METHODS: In two independent pregnancy cohorts, EPIPREG (n = 480) and EPIDG (n = 32), DNA methylation in peripheral blood leukocytes was measured at a gestational age of 28 ± 2. We constructed an MRS in EPIPREG and EPIDG based on CpG hits from a published epigenome-wide association study (EWAS) of T2DM. RESULTS: With mixed models logistic regression of EPIPREG and EPIDG, MRS for T2DM was associated with GDM: odd ratio (OR)[95% CI]: 1.3 [1.1-1.8], P = 0.002 for the unadjusted model, and 1.4 [1.1-1.7], P = 0.00014 for a model adjusted by age, pre-pregnant BMI, family history of diabetes and smoking status. Also, we found 6 CpGs through a meta-analysis (cg14020176, cg22650271, cg14870271, cg27243685, cg06378491, cg25130381) associated with GDM, and some of their methylation quantitative loci (mQTLs) were related to T2DM and GDM. CONCLUSION: For the first time, we show that DNA methylation marks for T2DM are also associated with GDM, suggesting shared epigenetic mechanisms between GDM and T2DM.

Cross-Ancestry DNA Methylation Marks of Insulin Resistance in Pregnancy: An Integrative Epigenome-Wide Association Study.

Although there are some epigenome-wide association studies (EWAS) of insulin resistance, for most of them authors did not replicate their findings, and most are focused on populations of European ancestry, limiting the generalizability. In the Epigenetics in Pregnancy (EPIPREG; n = 294 Europeans and 162 South Asians) study, we conducted an EWAS of insulin resistance in maternal peripheral blood leukocytes, with replication in the Born in Bradford (n = 879; n = 430 Europeans and 449 South Asians), Methyl Epigenome Network Association (MENA) (n = 320), and Botnia (n = 56) cohorts. In EPIPREG, we identified six CpG sites inversely associated with insulin resistance across ancestry, of which five were replicated in independent cohorts (cg02988288, cg19693031, and cg26974062 in TXNIP; cg06690548 in SLC7A11; and cg04861640 in ZSCAN26). From methylation quantitative trait loci analysis in EPIPREG, we identified gene variants related to all five replicated cross-ancestry CpG sites, which were associated with several cardiometabolic phenotypes. Mediation analyses suggested that the gene variants regulate insulin resistance through DNA methylation. To conclude, our cross-ancestry EWAS identified five CpG sites related to lower insulin resistance.

Epigenome-wide association study of serum folate in maternal peripheral blood leukocytes.

Aim: To perform an epigenome-wide association study (EWAS) of serum folate in maternal blood. Methods: Cross-ancestry (Europeans = 302, South Asians = 161) and ancestry-specific EWAS in the EPIPREG cohort were performed, followed by methyl quantitative trait loci analysis and association with cardiometabolic phenotypes. Replication was attempted using maternal folate intake and blood methylation data from the MoBa study and verified if the findings were significant in a previous EWAS of maternal serum folate in cord blood. Results & conclusion: cg19888088 (cross-ancestry) in EBF3, cg01952260 (Europeans) and cg07077240 (South Asians) in HERC3 were associated with serum folate. cg19888088 and cg01952260 were associated with diastolic blood pressure. cg07077240 was associated with variants in CASC15. The findings were not replicated and were not significant in cord blood.

Epigenetic signatures associated with maternal body mass index or gestational weight gain: a systematic review.

Maternal body mass index (BMI) and gestational weight gain (GWG) impacts both the mother's and the child's health, and epigenetic modifications have been suggested to mediate some of these effects in offspring. This systematic review aimed to summarize the current literature on associations between maternal BMI and GWG and epigenetic marks. We performed systematic searches in PubMed and EMBASE and manual searches of reference lists. We included 49 studies exploring the association between maternal BMI and/or GWG and DNA methylation or miRNA; 7 performed in maternal tissues, 13 in placental tissue and 38 in different offspring tissues. The most consistent findings were reported for the relationship between maternal BMI, in particular pre-pregnant BMI, and expression of miRNA Let-7d in both maternal blood and placental tissue, methylation of the gene HIF3A in umbilical cord blood and umbilical tissue, and with expression in the miR-210 target gene, BDNF in placental tissue and cord blood. Correspondingly, methylation of BDNF was also found in placental tissue and cord blood. The current evidence suggests that maternal BMI is associated with some epigenetic signatures in the mother, the placenta and her offspring, which could indicate that some of the effects proposed by the Developmental Origins of Health and Disease-hypothesis may be mediated by epigenetic marks. In conclusion, there is a need for large, well-designed studies and meta-analyses that can clarify the relationship between BMI, GWG and epigenetic changes.

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.

Pregnancy is a valuable model to study the association between DNA methylation and several cardiometabolic traits, due to its direct potential to influence mother's and child's health. Epigenetics in Pregnancy (EPIPREG) is a population-based sample with the aim to study associations between DNA-methylation in pregnancy and cardiometabolic traits in South Asian and European pregnant women and their offspring. This cohort profile paper aims to present our sample with genetic and epigenetic data and invite researchers with similar cohorts to collaborative projects, such as replication of ours or their results and meta-analysis. In EPIPREG we have quantified epigenome-wide DNA methylation in maternal peripheral blood leukocytes in gestational week 28±1 in Europeans (n = 312) and South Asians (n = 168) that participated in the population-based cohort STORK Groruddalen, in Norway. DNA methylation was measured with Infinium MethylationEPIC BeadChip (850k sites), with technical validation of four CpG sites using bisulphite pyrosequencing in a subset (n = 30). The sample is well characterized with few missing data on e.g. genotype, universal screening for gestational diabetes, objectively measured physical activity, bioelectrical impedance, anthropometrics, biochemical measurements, and a biobank with maternal serum and plasma, urine, placenta tissue. In the offspring, we have repeated ultrasounds during pregnancy, cord blood, and anthropometrics up to 4 years of age. We have quantified DNA methylation in peripheral blood leukocytes in nearly all eligible women from the STORK Groruddalen study, to minimize the risk of selection bias. Genetic principal components distinctly separated Europeans and South Asian women, which fully corresponded with the self-reported ethnicity. Technical validation of 4 CpG sites from the methylation bead chip showed good agreement with bisulfite pyrosequencing. We plan to study associations between DNA methylation and cardiometabolic traits and outcomes.