Plasma microRNA Interindividual Variability in Healthy Individuals, Pregnant Women, and an Individual with a Stably Altered Neuroendocrine Phenotype

Author:

Max Klaas E.A.1ORCID,Wang Victoria R.1,Chang Michael S.1,Liau Jonathan1,Weiss Zachary R.2,Morgan Stephanie2,Li Jenny1,Bogardus Kimberly A.1,Morozov Pavel1,Suryawanshi Hemant12,Akat Kemal M.13ORCID,Ben-Dov Iddo Z.4ORCID,Hurley Arlene M.5,Dowd Kathleen5,Williams Zev2,Tuschl Thomas1

Affiliation:

1. Rockefeller University, Laboratory for RNA Molecular Biology, New York, NY

2. Department of Obstetrics and Gynecology, Columbia University Medical Center, Columbia University Irving Medical Center, New York, NY

3. Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN

4. Department of Nephrology, Hadassah–Hebrew University Medical Center, Jerusalem, IL

5. Clinical Research Facilitation Office, Rockefeller University, New York, NY

Abstract

Abstract Background Extracellular RNAs (exRNAs) in biofluids are amenable to quantitative analysis and proposed as noninvasive biomarkers for monitoring organ function. Cell-lineage-specific microRNAs (miRNAs) are present in plasma as soluble ribonucleoproteins or enclosed in exRNA carriers and transported through the vasculature. However, more extensive studies of healthy individuals are needed to gain insights into the variability of plasma miRNA abundance and composition. Methods The exRNA composition of platelet-depleted plasma collected twice from 236 healthy individuals was characterized by small RNA sequencing. Plasma of pregnant women featuring dramatically increased placental miRNAs and samples from subject P12 with noticeably increased epithelial- and neuroendocrine-origin miRNAs were included for comparison. The miRNA content of 10 000g and 100 000g pellet fractions of plasma generated by ultracentrifugation was also determined. Data analysis methods included Pearson correlation, differential gene expression, and unsupervised clustering. Results The abundance changes for more variable miRNAs in plasma of normal individuals correlated between coexpressed cell-lineage-specific miRNAs of the liver, neuroendocrine organs, epithelial cells, and muscle. ExRNA of pellet fractions contained <2% of total plasma miRNA with modest enrichment of lineage-specific and variable miRNAs compared to supernatant. The abundance fold changes of miRNAs observed in pregnancy and P12 compared to normal exceeded interquartile variability of healthy individuals. The neuroendocrine miRNA signature of P12 persisted for more than 4 years and was absent in other individuals. Conclusions This study defines the framework and effect size for screening of extensive plasma collections for miRNA phenotypes and biomarker discovery.

Funder

National Institutes of Health (NIH) Extracellular RNA Communication (ERC) Program

Publisher

Oxford University Press (OUP)

Subject

Biochemistry (medical),Clinical Biochemistry

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