Systematic Review of Micro-RNA Expression in Pre-Eclampsia Identifies a Number of Common Pathways Associated with the Disease

Abstract

Background: Pre-eclampsia (PE) is a complex, multi-systemic condition of pregnancy which greatly impacts maternal and perinatal morbidity and mortality. MicroRNAs (miRs) are differentially expressed in PE and may be important in helping to understand the condition and its pathogenesis.

Methods: Case-control studies investigating expression of miRs in PE were collected through a systematic literature search. Data was extracted and compared from 58 studies to identify the most promising miRs associated with PE pathogenesis and identify areas of methodology which could account for often conflicting results.

Results: Some of the most frequently differentially expressed miRs in PE include miR-210, miR-223 and miR-126/126* which associate strongly with the etiological domains of hypoxia, immunology and angiogenesis. Members of the miR-515 family belonging to the imprinted chromosome 19 miR cluster with putative roles in trophoblast invasion were also found to be differentially expressed. Certain miRs appear to associate with more severe forms of PE such as miR-210 and the immune-related miR-181a and miR-15 families. Patterns of miR expression may help pinpoint key pathways (e.g. IL-6/miR-223/STAT3) and aid in untangling the heterogeneous nature of PE. The detectable presence of many PE-associated miRs in antenatal circulatory samples suggests their usefulness as predictive biomarkers. Further progress in ascertaining the clinical value of miRs and in understanding how they might contribute to pathogenesis is predicated upon resolving current methodological challenges in studies. These include differences in diagnostic criteria, cohort characteristics, sampling technique, RNA isolation and platform-dependent variation in miR profiling.

Conclusion: Reviewing studies of PE-associated miRs has revealed their potential as informants of underlying target genes and pathways relating to PE pathogenesis. However, the incongruity in results across current studies hampers their capacity to be useful biomarkers of the condition.

Fig 1. Flow chart denoting the search procedure for this systematic review.

This process was repeated multiple times between September 2015 and December 2015.

Fig 2. Charts depicting the included screening and candidate studies split by sample type.

Some individual studies examined miR expression in multiple sample types.

Fig 3. Flow chart depicting the systematic comparison of miRs across studies.

Input data was collected from all studies included within the systematic review.

Fig 4. Direction of expression of the most frequently discovered differentially expressed miRs.

Border colour represents consensus direction of change across all screening studies for the top 10 miRs.

Fig 5. Collection of base miR groups containing putatively related, differentially expressed members across all included screening studies.

Group which consisted solely of the same repeated exact miR entity (e.g. miR-181a) were removed. The miRs were grouped together into families using mirBASE and miRNAVISA. See S1 File for a full list of specific miRs belonging to these groups and study references.

Fig 6. Sample size groups used across all included screening studies.

Fig 7. RNA extraction and isolation methods used across all included screening studies.

Fig 8. Overlapping results from SOLiD-based NGS screening studies.

a) Profiling in placental samples with similar methodologies b) Profiling in circulatory (plasma/serum) samples c) Profiling across all sample types.

Fig 9. Internal controls used for qRT-PCR (both array-based and stem-loop) across screening and candidate studies mainly consisted of the small nuclear RNA, U6.