Proteomic identification of novel plasma biomarkers associated with spontaneous preterm birth in women with preterm labor without infection/inflammation

Abstract

Objective We sought to identify plasma biomarkers associated with spontaneous preterm birth (SPTB, delivery within 21 days of sampling) in women with preterm labor (PTL) without intra-amniotic infection/inflammation (IAI) using label-free quantitative proteomic analysis, as well as to elucidate specific protein pathways involved in these cases. Methods This was a retrospective cohort study comprising 104 singleton pregnant women with PTL (24–32 weeks) who underwent amniocentesis and demonstrated no evidence of IAI. Analysis of pooled plasma samples collected from SPTB cases and term birth (TB) controls (n = 10 for each group) was performed using label-free quantitative mass spectrometry for proteome profiling in a nested case-control study design. Eight candidate proteins of interest were validated by ELISA-based assay and a clot-based assay in the total cohort. Results Ninety-one proteins were differentially expressed (P < 0.05) in plasma samples obtained from SPTB cases, of which 53 (58.2%) were upregulated and 38 (41.8%) were downregulated when compared to TD controls. A validation study confirmed that plasma from women who delivered spontaneously within 21 days of sampling contained significantly higher levels of coagulation factor Ⅴ and lower levels of S100 calcium binding protein A9 (S100A9), especially the former which was independent of baseline variables. The top-ranked pathways related to the 91 differentially expressed proteins were liver-X-receptor/retinoid X receptor (RXR) activation, acute phase response signaling, farnesoid X receptor/RXR activation, coagulation system, and complement system. Conclusions Proteomic analyses in this study identified potential novel biomarkers (i.e., coagulation factor V and S100A9) and potential protein pathways in plasma associated with SPTB in the absence of IAI in women with PTL. The present findings provide novel insights into the molecular pathogenesis and therapeutic targets specific for idiopathic SPTB.

Proteomic analysis of plasma to identify novel biomarkers for intra-amniotic infection and/or inflammation in preterm premature rupture of membranes

“…In the present study, IPA revealed the most significant canonical pathways associated with the 17 DEPs identified in maternal plasma potentially involved in MIAC/IAI. Overall, the five top signaling pathways identified are parallel to those associated with SPTD development, as reported in previous proteomics studies on patients at risk for preterm delivery [62][63][64][65] . APR is a complex systemic inflammatory reaction triggered by various factors, including local infection/inflammation, trauma, and tissue damage 66 .…”

“…The discrepancy concerning the results of LRP1 between the shotgun proteomics and ELISA data can be generally found in other proteomics-based biomarker discovery and verification studies 19,62,64,[86][87][88] , but this disagreement may be attributed to (i) sample types evaluated (pooled vs. individual samples), (ii) somewhat loose threshold used in the present study as selection criteria for DEPs (fold change of LFQ intensities > 1.3 or < 0.77), and (iii) inherent disadvantages of the ELISA method, including cross-reactivity of the antibodies with non-target antigens, high-dose hook effect, and that the target proteins might be denatured during ELISA processing and thus their epitopes cannot be detected by the secondary antibodies 89,90 .…”

Associations of serum keratin 1 with thyroid function and immunity in Graves’ disease

“…The divergence between the two techniques may also have contributed to the discrepancy. Moreover, only 34 HT patients were included in the study; recruiting more HT patients could have further validated the data and made our results more convincing and valuable [ 33 – 35 ].…”

Capture-recapture for -omics data meta-analysis

“…After the final exclusions, 12 datasets from 10 studies remained, with details shown in Supplementary Table S1 [20,[41][42][43][44][45][46][47][48][49]. The studies cover a range of sampling time points, inclusion criteria, different protein identification techniques, different tissues and fractions (maternal plasma, amniotic fluid, placental tissues); although we excluded several studies which collected neonatal samples after birth, reasoning that these likely reflect consequences rather than causes of preterm delivery.…”