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      Proteomics Mapping of Cord Blood Identifies Haptoglobin “Switch-On” Pattern as Biomarker of Early-Onset Neonatal Sepsis in Preterm Newborns

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          Abstract

          Background

          Intra-amniotic infection and/or inflammation (IAI) are important causes of preterm birth and early-onset neonatal sepsis (EONS). A prompt and accurate diagnosis of EONS is critical for improved neonatal outcomes. We sought to explore the cord blood proteome and identify biomarkers and functional protein networks characterizing EONS in preterm newborns.

          Methodology/Principal Findings

          We studied a prospective cohort of 180 premature newborns delivered May 2004-September 2009. A proteomics discovery phase employing two-dimensional differential gel electrophoresis (2D-DIGE) and mass spectrometry identified 19 differentially-expressed proteins in cord blood of newborns with culture-confirmed EONS (n = 3) versus GA-matched controls (n = 3). Ontological classifications of the proteins included transfer/carrier, immunity/defense, protease/extracellular matrix. The 1 st-level external validation conducted in the remaining 174 samples confirmed elevated haptoglobin and haptoglobin-related protein immunoreactivity (Hp&HpRP) in newborns with EONS (presumed and culture-confirmed) independent of GA at birth and birthweight (P<0.001). Western blot concurred in determining that EONS babies had conspicuous Hp&HpRP bands in cord blood (“switch-on pattern”) as opposed to non-EONS newborns who had near-absent “switch-off pattern” ( P<0.001). Fetal Hp phenotype independently impacted Hp&HpRP. A Bayesian latent-class analysis (LCA) was further used for unbiased classification of all 180 cases based on probability of “antenatal IAI exposure” as latent variable. This was then subjected to 2 nd-level validation against indicators of adverse short-term neonatal outcome. The optimal LCA algorithm combined Hp&HpRP switch pattern (most input), interleukin-6 and neonatal hematological indices yielding two non-overlapping newborn clusters with low (≤20%) versus high (≥70%) probability of IAI exposure. This approach reclassified ∼30% of clinical EONS diagnoses lowering the number needed to harm and increasing the odds ratios for several adverse outcomes including intra-ventricular hemorrhage.

          Conclusions/Significance

          Antenatal exposure to IAI results in precocious switch-on of Hp&HpRP expression. As EONS biomarker, cord blood Hp&HpRP has potential to improve the selection of newborns for prompt and targeted treatment at birth.

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          Most cited references87

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          DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status.

          A complex combination of adult health-related disorders can originate from developmental events that occur in utero. The periconceptional period may also be programmable. We report on the effects of restricting the supply of specific B vitamins (i.e., B(12) and folate) and methionine, within normal physiological ranges, from the periconceptional diet of mature female sheep. We hypothesized this would lead to epigenetic modifications to DNA methylation in the preovulatory oocyte and/or preimplantation embryo, with long-term health implications for offspring. DNA methylation is a key epigenetic contributor to maintenance of gene silencing that relies on a dietary supply of methyl groups. We observed no effects on pregnancy establishment or birth weight, but this modest early dietary intervention led to adult offspring that were both heavier and fatter, elicited altered immune responses to antigenic challenge, were insulin-resistant, and had elevated blood pressure-effects that were most obvious in males. The altered methylation status of 4% of 1,400 CpG islands examined by restriction landmark genome scanning in the fetal liver revealed compelling evidence of a widespread epigenetic mechanism associated with this nutritionally programmed effect. Intriguingly, more than half of the affected loci were specific to males. The data provide the first evidence that clinically relevant reductions in specific dietary inputs to the methionine/folate cycles during the periconceptional period can lead to widespread epigenetic alterations to DNA methylation in offspring, and modify adult health-related phenotypes.
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            The International Protein Index: an integrated database for proteomics experiments.

            Despite the complete determination of the genome sequence of several higher eukaryotes, their proteomes remain relatively poorly defined. Information about proteins identified by different experimental and computational methods is stored in different databases, meaning that no single resource offers full coverage of known and predicted proteins. IPI (the International Protein Index) has been developed to address these issues and offers complete nonredundant data sets representing the human, mouse and rat proteomes, built from the Swiss-Prot, TrEMBL, Ensembl and RefSeq databases.
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              Biological and clinical significance of haptoglobin polymorphism in humans.

              Haptoglobin is a hemoglobin-binding protein expressed by a genetic polymorphism as three major phenotypes: 1-1, 2-1, and 2-2. Most attention has been paid to determining haptoglobin phenotype as a genetic fingerprint used in forensic medicine. More recently, several functional differences between haptoglobin phenotypes have been demonstrated that appear to have important biological and clinical consequences. Haptoglobin polymorphism is associated with the prevalence and clinical evolution of many inflammatory diseases, including infections, atherosclerosis, and autoimmune disorders. These effects are explained by a phenotype-dependent modulation of oxidative stress and prostaglandin synthesis. Recent evidence is growing that haptoglobin is involved in the immune response as well. The strong genetic pressure favoring the 2-2 phenotype suggests an important role of haptoglobin in human pathology.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                10 October 2011
                : 6
                : 10
                : e26111
                Affiliations
                [1 ]Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University, School of Medicine, New Haven, Connecticut, United States of America
                [2 ]Department of Pediatrics, Division of Perinatal Medicine Yale University, School of Medicine, New Haven, Connecticut, United States of America
                [3 ]Department of Periodontics, Case Western Reserve University, School of Dental Medicine, Cleveland, Ohio, United States of America
                University of Florida, United States of America
                Author notes

                Conceived and designed the experiments: CSB IAB. Performed the experiments: CSB IAB GZ. Analyzed the data: CSB IAB GZ VB ATD UAN MB SSA-R. Contributed reagents/materials/analysis tools: CSB IAB. Wrote the paper: CSB VB ATD UAN SSA-R CMP ST GZ MB YWH IAB. Neonatal follow-up: MB VB. Microbiological expertise: YWH.

                Article
                PONE-D-11-11382
                10.1371/journal.pone.0026111
                3189953
                22028810
                49f8f69b-9b9a-48e0-a94e-6cdd304e9188
                Buhimschi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 17 June 2011
                : 19 September 2011
                Page count
                Pages: 15
                Categories
                Research Article
                Biology
                Biochemistry
                Blood Chemistry
                Computational Biology
                Molecular Genetics
                Gene Expression
                Genetics
                Gene Expression
                Molecular Cell Biology
                Cellular Types
                Blood Cells
                Gene Expression
                Population Biology
                Epidemiology
                Genetic Epidemiology
                Proteomics
                Medicine
                Clinical Immunology
                Immunomodulation
                Clinical Research Design
                Modeling
                Critical Care and Emergency Medicine
                Sepsis
                Diagnostic Medicine
                Pathology
                General Pathology
                Biomarkers
                Epidemiology
                Genetic Epidemiology
                Global Health
                Infectious Diseases
                Infectious Disease Modeling
                Obstetrics and Gynecology
                Pregnancy
                Pregnancy Complications
                Preterm Labor
                Pediatrics
                Neonatalology

                Uncategorized
                Uncategorized

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