Decidual/placental and first trimester plasma levels of hsa-miR-199a-3p|hsa-miR-199b-3p and hsa-miR-3150b-3p are associated with insulin secretion in pregnancy

Amelie Taschereau¹Frédérique White²Catherine Allard³Andrea G Edlow⁴François Aguet⁵Kristin G Ardlie⁵Jose C Florez^5,6,7,8Pierre-Étienne Jacques^2,3,9S. Ananth Karumanchi¹⁰Camille E Powe^4,5,6,8Luigi Bouchard^11,12,3Marie-France Hivert^13,3,6*

• ¹Biochemistry and Functional Genomics, Université de Sherbrooke, Sherbrooke, Canada
• ²Département de Biologie, Université de Sherbrooke, Sherbrooke, Canada
• ³Centre de recherche du Centre hospitalier universitaire de Sherbrooke (CRCHUS), Sherbrooke, Canada
• ⁴Department of Obstetrics and Gynecology, Massachusetts General Hospital, and Harvard Medical School, Boston, United States
• ⁵Broad Institute of MIT and Harvard, Cambridge, United States
• ⁶Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital, Boston, United States
• ⁷Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States
• ⁸Department of Medicine, Harvard Medical School, Boston, United States
• ⁹Institut de recherche sur le cancer de l’Université de Sherbrooke (IRCUS), Sherbrooke, Canada
• ¹⁰Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States
• ¹¹Department of Biochemistry and Functional Genomics, Université de Sherbrooke, Sherbrooke, Canada
• ¹²Department of Medical Biology, CIUSSS of Saguenay-Lac-Saint-Jean, Saguenay, Saguenay, Canada
• ¹³Department of Population Medicine, Harvard Medical School, Harvard Pilgrim Health Care Institute, Boston, United States

Background/Aims: The placenta expresses and releases specific microRNAs (miRNAs) into the maternal circulation that may influence insulin secretion during pregnancy. We hypothesized that specific decidual/placental miRNAs are associated with maternal insulin secretion during pregnancy.In the Genetics of Glucose regulation in Gestation and Growth (Gen3G) prospective cohort, we estimated maternal insulin secretion using the Stumvoll first phase index derived from an oral glucose tolerance test at ~26 weeks of gestation. We quantified miRNAs by small RNA sequencing in placenta (N=435) and first trimester plasma (=422) samples. We used the Limma R package to identify miRNAs associated with the Stumvoll index (P<0.05). We adjusted models for Matsuda index, gravidity, maternal age, newborn sex, gestational age at sampling (first trimester plasma sampling or delivery for placenta samples), and for technical covariates (batch and run for plasma, surrogate variables for placenta).Stumvoll first phase index of 1112.9 [905.4 -1284.5] in pregnancy. We identified 30 decidual/placental and 93 first trimester plasma miRNAs nominally associated with the Stumvoll first phase estimate (P<0.05). Lower insulin secretion was associated with lower levels of has-miR-199a-3p|has-miR-199b-3p (b=1.47 [0.10, 2.69] in placenta and b= 4.22 [0.70, 7.67] in plasma), and with higher levels of has-miR-3150b-3p (b= -6.97 [-14.39, 0.40] in placenta and b= -9.19 [-18.38, -0.60] in plasma).We identified hsa-miR-199a-3p|hsa-miR-199b-3p and hsa-miR-3150b-3p as differentially expressed in placenta and circulating levels associated with insulin secretion in pregnancy. Hsa-miR-199a-3p may regulate insulin secretion by modulating the expression of Ecadherin and components of the Notch signalling pathway; hsa-miR-3150b-3p may influence glucose-induced insulin secretion through interaction with phospholipase A2.