Substantially Altered Expression Profile of Diabetes/Cardiovascular/Cerebrovascular Disease Associated microRNAs in Children Descending from Pregnancy Complicated by Gestational Diabetes Mellitus-One of Several Possible Reasons for an Increased Cardiovascular Risk

Abstract

Gestational diabetes mellitus (GDM), one of the major pregnancy-related complications, characterized as a transitory form of diabetes induced by insulin resistance accompanied by a low/absent pancreatic beta-cell compensatory adaptation to the increased insulin demand, causes the acute, long-term, and transgenerational health complications. The aim of the study was to assess if alterations in gene expression of microRNAs associated with diabetes/cardiovascular/cerebrovascular diseases are present in whole peripheral blood of children aged 3-11 years descending from GDM complicated pregnancies. A substantially altered microRNA expression profile was found in children descending from GDM complicated pregnancies. Almost all microRNAs with the exception of miR-92a-3p, miR-155-5p, and miR-210-3p were upregulated. The microRNA expression profile also differed between children after normal and GDM complicated pregnancies in relation to the presence of overweight/obesity, prehypertension/hypertension, and/or valve problems and heart defects. Always, screening based on the combination of microRNAs was superior over using individual microRNAs, since at 10.0% false positive rate it was able to identify a large proportion of children with an aberrant microRNA expression profile (88.14% regardless of clinical findings, 75.41% with normal clinical findings, and 96.49% with abnormal clinical findings). In addition, the higher incidence of valve problems and heart defects was found in children with a prior exposure to GDM. The extensive file of predicted targets of all microRNAs aberrantly expressed in children descending from GDM complicated pregnancies indicates that a large group of these genes is involved in ontologies of diabetes/cardiovascular/cerebrovascular diseases. In general, children with a prior exposure to GDM are at higher risk of later development of diabetes mellitus and cardiovascular/cerebrovascular diseases, and would benefit from dispensarisation as well as implementation of primary prevention strategies.

Keywords: BMI; bioinformatics; cardiovascular risk; children; echocardiography; gestational diabetes mellitus; miRWalk2.0 database; microRNA expression; prehypertension/hypertension; screening.

Figure 1

Workflow of the study.

Figure 2

Aberrant microRNA expression profile in children descending from GDM complicated pregnancies irrespective of the clinical findings (overweight/obesity, prehypertension/hypertension, and/or valve problems and heart defects). (A) Upregulation of miR-1-3p was observed in children descending from GDM complicated pregnancies when the comparison to the controls irrespective of the clinical findings was performed. Concerning individual microRNAs, miR-1-3p showed the highest accuracy for the identification of children at a higher risk of later development of diabetes mellitus and/or cardiovascular/cerebrovascular diseases. (B) Combined screening of microRNAs in the identification of children prenatally exposed to GDM at an increased risk of later development of diabetes mellitus and/or cardiovascular/cerebrovascular diseases. Screening based on the combination of microRNAs with a good sensitivity (miR-1-3p, miR-16-5p, miR-17-5p, miR-20a-5p, miR-20b-5p, miR-21-5p, miR-26a-5p, miR-29a-3p, miR-103a-3p, miR-125b-5p, miR-126-3p, miR-133a-3p, miR-143-3p, miR-181a-5p, miR-195-5p, miR-210-3p, miR-221-3p, miR-499a-5p, and miR-574-3p) showed the highest accuracy for the identification of children at a higher risk of later development of diabetes mellitus and/or cardiovascular/cerebrovascular diseases. GDM: Gestational diabetes mellitus.

Figure 3

Aberrant microRNA expression profile in children descending from GDM complicated pregnancies with normal clinical findings. (A) Upregulation of miR-1-3p was observed in children descending from GDM complicated pregnancies with normal clinical findings, when the comparison to the controls with normal clinical findings was performed. Concerning individual microRNAs, miR-1-3p showed the highest accuracy for the identification of children at a higher risk of later development of diabetes mellitus and/or cardiovascular/cerebrovascular diseases. (B) Combined screening of microRNAs in the identification of children prenatally exposed to GDM with normal clinical findings at an increased risk of later development of diabetes mellitus and/or cardiovascular/cerebrovascular diseases. Screening based on the combination of microRNAs with a good sensitivity (miR-1-3p, miR-17-5p, miR-20a-5p, miR-20b-5p, miR-21-5p, miR-23a-3p, miR-29a-3p, miR-100-5p, miR-103a-3p, miR-125b-5p, miR-126-3p, miR-133a-3p, miR-143-3p, miR-181a-5p, miR-195-5p, miR-221-3p, miR-499a-5p, and miR-574-3p) showed the highest accuracy for the identification of children prenatally exposed to GDM with normal clinical findings at a higher risk of later development of diabetes mellitus and/or cardiovascular/cerebrovascular diseases. The comparison to the controls with normal clinical findings was performed. NP: Normal pregnancies; GDM: Gestational diabetes mellitus.

Figure 4

Aberrant microRNA expression profile in children descending from GDM complicated pregnancies with abnormal clinical findings. (A) Upregulation of miR-1-3p was observed in children descending from GDM complicated pregnancies with abnormal clinical findings, when the comparison to the controls with normal clinical findings was performed. Concerning individual microRNAs, miR-1-3p showed the highest accuracy for the identification of children at a higher risk of later development of diabetes mellitus and/or cardiovascular/cerebrovascular diseases. (B) Combined screening of microRNAs in the identification of children prenatally exposed to GDM with abnormal clinical findings at an increased risk of later development of diabetes mellitus and/or cardiovascular/cerebrovascular diseases. Screening based on the combination of microRNAs with a good sensitivity (miR-1-3p, miR-17-5p, miR-20a-5p, miR-20b-5p, miR-21-5p, miR-29a-3p, miR-92a-3p, miR-103a-3p, miR-126-3p, miR-133a-3p, miR-143-3p, miR-181a-5p, miR-195-5p, miR-221-3p, and miR-499a-5p) showed the highest accuracy for the identification of children prenatally exposed to GDM with abnormal clinical findings at a higher risk of later development of diabetes mellitus and/or cardiovascular/cerebrovascular diseases. The comparison to the controls with normal clinical findings was performed. NP: Normal pregnancies; GDM: Gestational diabetes mellitus.