First Trimester Plasma MicroRNA Levels Predict Risk of Developing Gestational Diabetes Mellitus

Abstract

AimsOur objective is to identify first-trimester plasmatic miRNAs associated with and predictive of GDM.MethodsWe quantified miRNA using next-generation sequencing in discovery (Gen3G: n = 443/GDM = 56) and replication (3D: n = 139/GDM = 76) cohorts. We have diagnosed GDM using a 75-g oral glucose tolerance test and the IADPSG criteria. We applied stepwise logistic regression analysis among replicated miRNAs to build prediction models.ResultsWe identified 17 miRNAs associated with GDM development in both cohorts. The prediction performance of hsa-miR-517a-3p|hsa-miR-517b-3p, hsa-miR-218-5p, and hsa-let7a-3p was slightly better than GDM classic risk factors (age, BMI, familial history of type 2 diabetes, history of GDM or macrosomia, and HbA1c) (AUC 0.78 vs. 0.75). MiRNAs and GDM classic risk factors together further improved the prediction values [AUC 0.84 (95% CI 0.73–0.94)]. These results were replicated in 3D, although weaker predictive values were obtained. We suggest very low and higher risk GDM thresholds, which could be used to identify women who could do without a diagnostic test for GDM and women most likely to benefit from an early GDM prevention program.ConclusionsIn summary, three miRNAs combined with classic GDM risk factors provide excellent prediction values, potentially strong enough to improve early detection and prevention of GDM.

The role of ncRNA regulatory mechanisms in diseases—case on gestational diabetes

“…In a study using next-generation sequencing to identify plasma miRNA markers in patients with GDM in early pregnancy, 17 miRNAs associated with GDM development were identified, which may be involved in the regulation of lipid metabolism and insulin sensitivity (IS). Among them, three miRNAs, hsa-miR-517a-3p|hsa-miR-517b-3p, hsa-miR-218-5p and hsa-let7a-3p, have comparable predictive ability to traditional GDM risk factors [ 54 ]. Another study observed that plasma miRNAs from 18 patients with early pregnancy GDM predicted IS in the late second trimester of pregnancy [ 55 ].…”

Genetics and Epigenetics: Implications for the Life Course of Gestational Diabetes

“…Given their stability in blood and other body fluids, the utility of miRNAs as non-invasive biomarkers has been examined, including for GDM. An increasing area of interest is identifying circulating miRNAs that are present early in pregnancy and associated with the development of GDM and using these miRNAs to help predict the development of GDM [ 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 ]. To date, many of the studies that have been performed have been small with limited power and have used different approaches to identify relevant miRNAs.…”

“…Together, studies seeking to identify miRNAs in the first trimester and early second trimester of pregnancy have identified 37 miRNAs associated with the development of GDM ( Table 3 ) [ 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 ]. However, most of these miRNAs were specific to a single study and not reproduced in other studies.…”

“…Circulating miRNAs present in the first and early second trimester have demonstrated the potential utility of miRNAs in predicting who will progress to GDM, as shown by their inclusion in models for prediction of GDM and reflected by the area under the ROC curve [ 115 , 116 , 117 , 119 ]. Juchnika et al used age-, BMI-, and gestational age-matched women who progressed to GDM or maintained normoglycemia to demonstrate that each of three miRNAs, miR-16-5p, -144-3p, and 142-3p, resulted in an area under the ROC curve between 0.756 to 0.868 [ 116 ].…”

“…Finally, Legare et al included three miRNAs, miR-517a-3p/517b-3p, -218-3p, and -7a-3p, in a predictive model that included maternal age, BMI, family history of type 2 diabetes, history of GDM, and hemoglobin A1c. The inclusion of the miRNAs increased the area under the ROC curve from 0.754 to 0.841 [ 115 ]. Importantly, these results were validated in an independent cohort.…”