Balaraman S1, Schafer J2, Wertelecki W2, Zymak N3, Yevtushok L3, Chambers C2, Miranda RC1, CIFASD
1Texas A&M Health Science Ctr, TX USA
2University of California, San Diego, CA USA
3Khmelnytsky and Rivne Diagnostic Centers and Omni-Net, Ukraine
Fetal alcohol exposure (FAE) is an important cause of neurodevelopmental disability. However, many FAE infants do not show associated craniofacial characteristics and consequently, remain undiagnosed, and risk developing secondary disabilities. Therefore, there is a pressing need for biomarkers to better identify FAE infants.
In a sheep model, we previously showed that miRNAs in maternal plasma were biomarkers for FAE. Therefore, we selected 68 prospectively identified pregnant women from a larger longitudinal cohort study in two clinics in Western Ukraine. Each woman provided a detailed history of alcohol use in the current pregnancy. Their subsequent live born infants were evaluated for physical and neurodevelopment features of FASD, between 6-12 months of age. These women represented heavily-exposed mothers with an FASD-affected child (HEa); heavily-exposed mothers with an apparently unaffected child (HEua); and low or unexposed mothers with an unaffected child (UE). Blood samples were collected at two time points in pregnancy from each woman: early to mid-gestation and in the third trimester.
We assessed 752 miRNAs in plasma samples using Exiqon, miRCURY miRNA RTPCR arrays. MiRNAs expressed in >70% of samples in at least one group were subjected to forward stepwise linear regression modeling, which identified 46 miRNAs that predicted group membership. This model accurately predicted group membership for the HEa and UE groups. However, membership in the HEua group overlapped with either HEa or UE groups. Next, 150 miRNAs in HEa and UE groups with the highest expression variance were subject to Random Forest Analysis, resulting in an overall classification error rate of 26.7%. These analyses show that plasma miRNAs discriminate between HEa and UE groups, but that HEua group members exhibit similarities to either HEa or UE groups.
Candidate miRNAs identified in both statistical analysis methods are predicted to control addiction pathways, as well as proteoglycan metabolism, stem cell pluripotency and other pathways, which are important for placenta and embryo growth. Collectively, these data support the use of maternal plasma miRNAs as biomarkers for FAE, and their potential use in identifying alcohol-exposed pregnancies that do not result in children with obvious alcohol-related physical features. Supported by U01AA014835, U24AA014811, R01AA013440 & NIH-ODS.
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