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Proteomic Analysis of Maternal Serum in Down Syndrome: Identification of Novel Protein Biomarkers

Srinivasa R. Nagalla,*^‡ Jacob A. Canick,^§^# Thomas Jacob, Kimberly A. Schneider, Ashok P. Reddy, Archana Thomas, Surendra Dasari,^‡ Xinfang Lu,^‡ Jodi A. Lapidus,^† Geralyn M. Lambert-Messerlian,^§^# Michael G. Gravett, Charles T. Roberts, Jr.,^‡ David Luthy,^# Fergal D. Malone,⁺^# and Mary E. D'Alton⁺^#

Departments of Pediatrics and Public Health and Preventive Medicine, Oregon Health and Science University, Portland, Oregon 97239, Brown University School of Medicine, Providence, Rhode Island 02903, ProteoGenix, Inc., Portland, Oregon 97213, Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington 98101, Swedish Medical Center, Seattle, Washington 98122, and Columbia University College of Physicians and Surgeons, New York, New York 10032

J. Proteome Res., 2007, 6 (4), pp 1245–1257

DOI: 10.1021/pr060539h

Publication Date (Web): March 21, 2007

To whom correspondence should be addressed. E-mail: nagallas@ohsu.edu; tel, (503)494-1928; fax, (503)494-4821.

‡

Department of Pediatrics, Oregon Health and Science University.

ProteoGenix, Inc.

Brown University School of Medicine.

First- and Second-Trimester Evaluation at Risk (FASTER) Research Consortium.

†

Department Public Health and Preventive Medicine, Oregon Health and Science University.

University of Washington.

Columbia University College of Physicians and Surgeons.

Abstract

Down syndrome (DS) is the most prevalent chromosomal disorder, accounting for significant morbidity and mortality. Definitive diagnosis requires invasive amniocentesis, and current maternal serum-based testing requires a false-positive rate of about 5% to detect 85% of affected pregnancies. We have performed a comprehensive proteomic analysis to identify potential serum biomarkers to detect DS. First- and second-trimester maternal serum samples of DS and gestational age-matched controls were analyzed using multiple, complementary proteomic approaches, including fluorescence 2-dimensional gel electrophoresis (2D-DIGE), 2-dimensional liquid chromatography-chromatofocusing (2D-CF), multidimensional protein identification technology (MudPIT; LC/LC−MS/MS), and MALDI-TOF−MS peptide profiling. In total, 28 and 26 proteins were differentially present in first- and second-trimester samples, respectively. Of these, 19 were specific for the first trimester and 16 for the second trimester, and 10 were differentially present in both trimesters. Analysis of MALDI-TOF−MS peptide profiles with pattern-recognition software also discriminated between DS and controls in both trimesters, with an average recognition capability approaching 96%. A majority of the biomarkers identified are serum glycoproteins that may play a role in cellular differentiation and growth of fetus. Further characterization and quantification of these markers in a larger cohort of subjects may provide the basis for new tests for improved DS screening.

Keywords: Aneuploidy • Prenatal Screening • Chrom • Pregnancy

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