Peptidomic Identification of Serum Peptides Diagnosing Preeclampsia

Qiaojun Wen,David K Stevenson,Ting Yang,Xuefeng B Ling,Guojun Sheng,Atul J Butte,Linda Y Liu,Cantas Alev,Shuaibin Wu,Yan-Ling Wang

doi:10.1371/journal.pone.0065571

Qiaojun Wen, David K Stevenson + Show 8 more

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https://doi.org/10.1371/journal.pone.0065571

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Journal: PloS one	Publication Date: Jun 19, 2013
Citations: 64	License type: CC BY 4.0

Affiliation: Stanford University

Abstract

We sought to identify serological markers capable of diagnosing preeclampsia (PE). We performed serum peptide analysis (liquid chromatography mass spectrometry) of 62 unique samples from 31 PE patients and 31 healthy pregnant controls, with two-thirds used as a training set and the other third as a testing set. Differential serum peptide profiling identified 52 significant serum peptides, and a 19-peptide panel collectively discriminating PE in training sets (n = 21 PE, n = 21 control; specificity = 85.7% and sensitivity = 100%) and testing sets (n = 10 PE, n = 10 control; specificity = 80% and sensitivity = 100%). The panel peptides were derived from 6 different protein precursors: 13 from fibrinogen alpha (FGA), 1 from alpha-1-antitrypsin (A1AT), 1 from apolipoprotein L1 (APO-L1), 1 from inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4), 2 from kininogen-1 (KNG1), and 1 from thymosin beta-4 (TMSB4). We concluded that serum peptides can accurately discriminate active PE. Measurement of a 19-peptide panel could be performed quickly and in a quantitative mass spectrometric platform available in clinical laboratories. This serum peptide panel quantification could provide clinical utility in predicting PE or differential diagnosis of PE from confounding chronic hypertension.

Highlights

Preeclampsia (PE) complicates about 5% of all pregnancies worldwide and is a major cause of maternal, fetal and neonatal morbidity and mortality, especially in developing nations [1,2]
Sample Qualification with sFlt-1 and PIGF Analysis Elevated soluble sFlt-1 and decreased PIGF levels are suggested in the pathogenesis of PE [15,16,17,18,19,20,21], and the sFlt-1/PIGF ratio has been proposed as a useful index in the diagnosis and management of PE [22,23]
The differential 52 serum peptides are derived from proteins known to be involved in the pathophysiology of PE, e.g. A1AT, apolipoprotein L1 (APO-L1), fibrinogen alpha (FGA), inhibitor heavy chain H4 (ITIH4), KNG1, SERPINA1 in acute inflammatory and defense response; APO-A4, APO-C3, APO-E, and APOL1 in lipid metabolism; C3, C4A, FGA, and SERPINA1 in the activation of complement and coagulation responses

Summary

Introduction

Preeclampsia (PE) complicates about 5% of all pregnancies worldwide and is a major cause of maternal, fetal and neonatal morbidity and mortality, especially in developing nations [1,2]. It is a potentially dangerous complication of the second half of pregnancy, labor, or early period after delivery, characterized by hypertension, abnormal amounts of protein in the urine, and other systemic disturbances. Mass spectrometry-based profiling of naturally occurring peptides can provide an extensive inventory of serum peptides derived from either high-abundant endogenous circulating proteins or cell and tissue proteins [10] These peptides are usually soluble, and stable from endogenous proteases or peptidases, and can be directly used for liquid chromatographymass spectrometry (LC/MS) analysis without additional manipulation (e.g. tryptic digests). A serum peptidomics based approach has not been attempted for the discovery of PE biomarkers

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