TY - JOUR
T1 - Serum Proteomics Uncovers Biomarkers of Clinical Portal Hypertension in Children With Biliary Atresia
AU - Osborn, Julie
AU - Mourya, Reena
AU - Thanekar, Unmesha
AU - Su, Weizhe
AU - Fei, Lin
AU - Shivakumar, Pranavkumar
AU - Bezerra, Jorge A.
N1 - Funding Information:
Supported by the National Institute of Diabetes and Digestive and Kidney Diseases (grants DK83781, DK64008, DK62497, and DK78392 to J.A.B. with use of the Clinical Component and Integrative Morphology Cores of the Digestive Health Center) and National Institutes of Health Pediatric Gastroenterology and Nutrition Training grant T32 DK007727‐27 to J.O. (PI: Lee Armistead Denson).
Funding Information:
Serum samples were obtained as an ancillary study of the NIDDK-funded ChiLDReN (DK-62497). We thank the Scientific Data Coordinating Center for managing all studies and providing data and specimens and the principal investigators and clinical research coordinators of the ChiLDReN centers for patient recruitment and acquisition of tissue and data. The contents of the article do not necessarily reflect the opinions or views of the NIDDK, ChiLDReN, or ChiLDReN investigators.
Publisher Copyright:
© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.
PY - 2022/5
Y1 - 2022/5
N2 - Children with biliary atresia (BA) often develop portal hypertension (PHT) and its complications, which are associated with high morbidity and mortality. The goal of this study was to identify serum biomarkers of PHT by using large-scale proteomics. We applied the slow off-rate modified aptamer scan (SOMAscan) to measure 1,305 proteins in serum samples of children with BA with and without clinical evidence of PHT in validation and discovery cohorts enrolled in the Biliary Atresia Study of Infants and Children. Serum proteomics data was analyzed using logistic regression to identify protein(s) with an area under the receiver operating characteristic curve (AUROC) ≥ 0.90. Immunostaining was used to characterize the cellular localization of the new biomarker proteins in liver tissues. We identified nine proteins in the discovery cohort (n = 40 subjects) and five proteins in the validation cohort (n = 80 subjects) that individually or in combination predicted clinical PHT with AUROCs ≥ 0.90. Merging the two cohorts, we found that semaphorin 6B (SEMA6B) alone and three other protein combinations (SEMA6B+secreted frizzle protein 3 [SFRP3], SEMA6B+COMM domain containing 7 [COMMD7], and vascular cell adhesion molecule 1 [VCAM1]+BMX nonreceptor tyrosine kinase [BMX]) had AUROCs ≥ 0.90 in both cohorts, with high positive- and negative-predictive values. Immunostaining of the new protein biomarkers showed increased expression in hepatic endothelial cells, cholangiocytes, and immune cells within portal triads in BA livers with clinical PHT compared to healthy livers. Conclusion: Large-scale proteomics identified SEMA6B, SFRP3, COMMD7, BMX, and VCAM1 as biomarkers highly associated with clinical PHT in BA. The expression of the biomarkers in hepatic epithelial, endothelial, and immune cells support their potential role in the pathophysiology of PHT.
AB - Children with biliary atresia (BA) often develop portal hypertension (PHT) and its complications, which are associated with high morbidity and mortality. The goal of this study was to identify serum biomarkers of PHT by using large-scale proteomics. We applied the slow off-rate modified aptamer scan (SOMAscan) to measure 1,305 proteins in serum samples of children with BA with and without clinical evidence of PHT in validation and discovery cohorts enrolled in the Biliary Atresia Study of Infants and Children. Serum proteomics data was analyzed using logistic regression to identify protein(s) with an area under the receiver operating characteristic curve (AUROC) ≥ 0.90. Immunostaining was used to characterize the cellular localization of the new biomarker proteins in liver tissues. We identified nine proteins in the discovery cohort (n = 40 subjects) and five proteins in the validation cohort (n = 80 subjects) that individually or in combination predicted clinical PHT with AUROCs ≥ 0.90. Merging the two cohorts, we found that semaphorin 6B (SEMA6B) alone and three other protein combinations (SEMA6B+secreted frizzle protein 3 [SFRP3], SEMA6B+COMM domain containing 7 [COMMD7], and vascular cell adhesion molecule 1 [VCAM1]+BMX nonreceptor tyrosine kinase [BMX]) had AUROCs ≥ 0.90 in both cohorts, with high positive- and negative-predictive values. Immunostaining of the new protein biomarkers showed increased expression in hepatic endothelial cells, cholangiocytes, and immune cells within portal triads in BA livers with clinical PHT compared to healthy livers. Conclusion: Large-scale proteomics identified SEMA6B, SFRP3, COMMD7, BMX, and VCAM1 as biomarkers highly associated with clinical PHT in BA. The expression of the biomarkers in hepatic epithelial, endothelial, and immune cells support their potential role in the pathophysiology of PHT.
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U2 - 10.1002/hep4.1878
DO - 10.1002/hep4.1878
M3 - Article
C2 - 34962102
AN - SCOPUS:85122042053
SN - 2471-254X
VL - 6
SP - 995
EP - 1004
JO - Hepatology Communications
JF - Hepatology Communications
IS - 5
ER -