Circulating early- and mid-pregnancy microRNAs and risk of gestational diabetes

Abstract

Aims Epigenetic regulators, including microRNAs(miRNAs), are implicated in type 2 diabetes, but evidence linking circulating miRNAs in pregnancy and risk of gestational diabetes(GDM) is sparse. Potential modifiers, including pre-pregnancy overweight/obesity and offspring sex, are unexamined. We hypothesized that circulating levels of early-mid-pregnancy(range 7-23 weeks of gestation) candidate miRNAs are related to subsequent development of GDM. We also hypothesized that miRNA-GDM associations might vary by pre-pregnancy body-mass index(ppBMI) or offspring sex. Methods In a case-control analysis(36 GDM cases/80 controls) from the Omega study, a prospective cohort study of pregnancy complications, we measured early–mid-pregnancy plasma levels of 10 miRNAs chosen for potential roles in pregnancy course and complications(miR-126-3p, -155-5p, -21-3p, -146b-5p, -210-3p, -222-3p, -223-3p, -517-5p, -518a-3p, and 29a-3p) using qRT-PCR. Logistic regression models adjusted for gestational age at blood draw (GA) were fit to compare circulating miRNAs between cases and controls. We repeated analyses among overweight/obese(ppBMI≥25kg/m2) or lean(ppBMI<25kg/m2) women, and women with male or female offspring separately. Results Mean age was 34.3 years(cases) and 32.9 years(controls). GA-adjusted miR-155-5p(β=0.260/p=0.028) and - 21-3p(β=0.316/p=0.005) levels were positively associated with GDM. MiR-146b-5p(β=0.266/p=0.068) and miR-517-5p(β=0.196/p=0.074) were borderline. Associations of miR-21-3p and miR-210-3p with GDM were observed among overweight/obese but not lean women. Associations of six miRNAs(miR-155-5p, -21-3p, - 146b-5p, -223-3p, -517-5p, and -29a-3p) with GDM were present only among women carrying male fetuses(all p<0.05). Conclusions Circulating early–mid-pregnancy miRNAs are associated with GDM, particularly among women who are overweight/obese pre-pregnancy or pregnant with male offspring. This area has potential to clarify mechanisms underlying GDM pathogenesis and identify at-risk mothers earlier in pregnancy.

Diabetes Mellitus and Cardiovascular Risk Assessment in Mothers with a History of Gestational Diabetes Mellitus Based on Postpartal Expression Profile of MicroRNAs Associated with Diabetes Mellitus and Cardiovascular and Cerebrovascular Diseases

“…However, most of microRNAs, which were the subjects of our interest, have not yet been observed by other investigators to be dysregulated in maternal circulation (peripheral blood, plasma, or serum samples) of women with clinically established GDM or before the onset of GDM [20,21,37,80,92,143,149,[172][173][174][175][176]. So, it is feasible that epigenetic profiles of a series of microRNAs have also been changing with time by force of various circumstances as a result of the interaction between genetic and environmental factors [177].…”

“…Moreover, a set of circulating microRNAs associated with cardiovascular/cerebrovascular diseases (miR-16-5p, miR-17-5p, miR-20a-5p, miR-29a-3p, miR-125b-5p, and miR-195-5p) was reported by several independent studies [20,21,80,92,143,172,173] to be upregulated during various gestational ages in serum or plasma of mothers with already-diagnosed GDM or mothers who were destined to develop GDM later during pregnancy. The data resulting from these prenatally ongoing studies and interaction network analysis [20,21,80,92,98,125,143,172,173] may support our current finding referring to upregulated expression profile of these particular microRNAs in whole peripheral blood of women with a prior exposure to GDM.…”

“…Ischemia/reperfusion-induced cardiac injury [76], cardiac cachexia, heart failure [77], atrial fibrillation [78], diffuse myocardial fibrosis in hypertrophic cardiomyopathy [30], coronary artery disease [79], pulmonary arterial hypertension [74], gestational diabetes mellitus [80], diabetes mellitus [13,23,81,82] [83] Hypertension [84], hypoxia-induced pulmonary hypertension [85], myocardial ischemia/reperfusion injury, acute myocardial infarction [84], ischemic dilated cardiomyopathy [66], obesity, regulation of insulin sensitivity [86], T1DM [87] hsa-miR-125b-5p 11q24.1 21q21.1 [88] Acute ischemic stroke [89], acute myocardial infarction [90,91], ischemic dilated cardiomyopathy [66], ascending aortic aneurysm [49], gestational diabetes mellitus [92], T1DM [93,94], T2DM [95] hsa-miR-126-3p 9q34.3 [96] Acute myocardial infarction [72], T2DM [53,97], T2DM with major cardiovascular events [53], gestational diabetes mellitus [98] hsa-miR-130b-3p 22q11.21 Hypertriglyceridemia [99,100], intracranial aneurysms [101], hyperacute cerebral infarction [102], T2DM [52,103,104], gestationa...…”

The role of genetics and epigenetics in the pathogenesis of gestational diabetes mellitus

“…A study by Wander et al. (), which included 116 women, revealed that miR‐155‐5p and miR‐21‐3p plasma levels in the early stages of pregnancy are connected with higher risk of GDM. The miRNAs miR‐21‐3p and miR‐210‐3p also showed association with GDM, but only in overweight women.…”

Circulating RNAs as predictive markers for the progression of type 2 diabetes

“…31,32 MiR-210-3p has been previously shown to be involved in adipogenesis, is differentially expressed in visceral adipose tissues in obese T2DM individuals, and is associated with gestational diabetes in obese women. [33][34][35][36] Using validated miRNA targets, we explored the possible biological processes/pathways that might be affected by the dysregulated miRNAs. A number of signal transduction related processes that play important roles in T2DM pathophysiology, including the insulin signaling pathway, mTOR signaling pathway, TGF-β signaling pathway, and VEGF signaling pathway [37][38][39][40] were enriched in this analysis.…”