Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 1/2023

Open Access 01-12-2023 | Primary Biliary Cholangitis | Research

Integrative bioinformatics analysis and experimental validation of key biomarkers for risk stratification in primary biliary cholangitis

Authors: Siyuan Tian, Yinan Hu, Miao Zhang, Kemei Wang, Guanya Guo, Bo Li, Yulong Shang, Ying Han

Published in: Arthritis Research & Therapy | Issue 1/2023

Login to get access

Abstract

Background

Primary biliary cholangitis (PBC) is an autoimmune liver disease, whose etiology is yet to be fully elucidated. Currently, ursodeoxycholic acid (UDCA) is the only first-line drug. However, 40% of PBC patients respond poorly to it and carry a potential risk of disease progression. So, in this study, we aimed to explore new biomarkers for risk stratification in PBC patients to enhance treatment.

Methods

We first downloaded the clinical characteristics and microarray datasets of PBC patients from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified and subjected to enrichment analysis. Hub genes were further validated in multiple public datasets and PBC mouse model. Furthermore, we also verified the expression of the hub genes and developed a predictive model in our clinical specimens.

Results

A total of 166 DEGs were identified in the GSE79850 dataset, including 95 upregulated and 71 downregulated genes. Enrichment analysis indicated that DEGs were significantly enriched in inflammatory or immune-related process. Among these DEGs, 15 risk-related genes were recognized and further validated in the GSE119600 cohort. Then, TXNIP, CD44, ENTPD1, and PDGFRB were identified as candidate hub genes. Finally, we proceeded to the next screening with these four genes in our serum samples and developed a three-gene panel. The gene panel could effectively identify those patients at risk of disease progression, yielding an AUC of 0.777 (95% CI, 0.657–0.870).

Conclusions

In summary, combining bioinformatics analysis and experiment validation, we identified TXNIP, CD44, and ENTPD1 as promising biomarkers for risk stratification in PBC patients.
Appendix
Available only for authorised users
Literature
1.
Lleo A, Wang G-Q, Gershwin ME, Hirschfield GM. Primary biliary cholangitis. The Lancet. 2020;396(10266):1915–26.CrossRef
2.
Gulamhusein AF, Hirschfield GM. Primary biliary cholangitis: pathogenesis and therapeutic opportunities. Nat Rev Gastroenterol Hepatol. 2020;17(2):93–110.CrossRefPubMed
3.
Younossi Z, Bernstein D, Shiffman M, Kwo P, Kim W, Kowdley K, et al. Diagnosis and management of primary biliary cholangitis. Am J Gastroenterol. 2019;114(1):48–63.CrossRefPubMed
4.
Lv T, Chen S, Li M, Zhang D, Kong Y, Jia J. Regional variation and temporal trend of primary biliary cholangitis epidemiology: a systematic review and meta-analysis. J Gastroenterol Hepatol. 2021;36(6):1423–34.CrossRefPubMed
5.
Carey E, Ali A, Lindor K. Primary biliary cirrhosis. Lancet (London, England). 2015;386(10003):1565–75.CrossRefPubMed
6.
Lindor KD, Bowlus CL, Boyer J, Levy C, Mayo M. Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases. Hepatology. 2019;69(1):394–419.CrossRefPubMed
7.
European Association for the Study of the L. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol. 2009;51(2):237–67.
8.
Shah RA, Kowdley KV. Current and potential treatments for primary biliary cholangitis. Lancet Gastroenterol Hepatol. 2020;5(3):306–15.CrossRefPubMed
9.
Grover VP, Southern L, Dyson JK, Kim JU, Crossey MM, Wylezinska-Arridge M, et al. Early primary biliary cholangitis is characterised by brain abnormalities on cerebral magnetic resonance imaging. Aliment Pharmacol Ther. 2016;44(9):936–45.CrossRefPubMedPubMedCentral
10.
European Association for the Study of the Liver. Electronic address eee, European Association for the Study of the L. EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis. J Hepatol. 2017;67(1):145–72.
11.
Corpechot C, Chazouilleres O, Rousseau A, Le Gruyer A, Habersetzer F, Mathurin P, et al. A placebo-controlled trial of bezafibrate in primary biliary cholangitis. N Engl J Med. 2018;378(23):2171–81.CrossRefPubMed
12.
Pares A, Caballeria L, Rodes J. Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic acid. Gastroenterology. 2006;130(3):715–20.CrossRefPubMed
13.
Kumagi T, Guindi M, Fischer SE, Arenovich T, Abdalian R, Coltescu C, et al. Baseline ductopenia and treatment response predict long-term histological progression in primary biliary cirrhosis. Am J Gastroenterol. 2010;105(10):2186–94.CrossRefPubMed
14.
Corpechot C, Abenavoli L, Rabahi N, Chretien Y, Andreani T, Johanet C, et al. Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology. 2008;48(3):871–7.CrossRefPubMed
15.
ter Borg PC, Schalm SW, Hansen BE, van Buuren HR, Dutch PBCSG. Prognosis of ursodeoxycholic acid-treated patients with primary biliary cirrhosis. Results of a 10-yr cohort study involving 297 patients. Am J Gastroenterol. 2006;101(9):2044–50.
16.
Nakamura M, Shimizu-Yoshida Y, Takii Y, Komori A, Yokoyama T, Ueki T, et al. Antibody titer to gp210-C terminal peptide as a clinical parameter for monitoring primary biliary cirrhosis. J Hepatol. 2005;42(3):386–92.CrossRefPubMed
17.
Mytilinaiou MG, Meyer W, Scheper T, Rigopoulou EI, Probst C, Koutsoumpas AL, et al. Diagnostic and clinical utility of antibodies against the nuclear body promyelocytic leukaemia and Sp100 antigens in patients with primary biliary cirrhosis. Clin Chim Acta. 2012;413(15–16):1211–6.CrossRefPubMed
18.
Lammers WJ, van Buuren HR, Hirschfield GM, Janssen HL, Invernizzi P, Mason AL, et al. Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow-up study. Gastroenterology. 2014;147(6):1338–49 e5; quiz e15.
19.
Tian S, Liu Y, Sun K, Zhou X, Ma S, Zhang M, et al. A nomogram based on pretreatment clinical parameters for the prediction of inadequate biochemical response in primary biliary cholangitis. J Clin Lab Anal. 2020;34(11): e23501.CrossRefPubMedPubMedCentral
20.
Zaitsev A, Chelushkin M, Dyikanov D, Cheremushkin I, Shpak B, Nomie K, et al. Precise reconstruction of the TME using bulk RNA-seq and a machine learning algorithm trained on artificial transcriptomes. Cancer Cell. 2022;40(8):879–94 e16.
21.
Huang B, Lyu Z, Qian Q, Chen Y, Zhang J, Li B, et al. NUDT1 promotes the accumulation and longevity of CD103+ TRM cells in primary biliary cholangitis. J Hepatol. 2022;77(5):1311–24.
22.
Muller AL, Casar C, Preti M, Krzikalla D, Gottwick C, Averhoff P, et al. Inflammatory type 2 conventional dendritic cells contribute to murine and human cholangitis. J Hepatol. 2022;77(6):1532–44.
23.
Chatila WK, Kim JK, Walch H, Marco MR, Chen CT, Wu F, et al. Genomic and transcriptomic determinants of response to neoadjuvant therapy in rectal cancer. Nat Med. 2022;28(8):1646–55.CrossRefPubMedPubMedCentral
24.
Banales JM, Saez E, Uriz M, Sarvide S, Urribarri AD, Splinter P, et al. Up-regulation of microRNA 506 leads to decreased Cl-/HCO3- anion exchanger 2 expression in biliary epithelium of patients with primary biliary cirrhosis. Hepatology. 2012;56(2):687–97.CrossRefPubMed
25.
Nakagawa R, Muroyama R, Saeki C, Goto K, Kaise Y, Koike K, et al. miR-425 regulates inflammatory cytokine production in CD4(+) T cells via N-Ras upregulation in primary biliary cholangitis. J Hepatol. 2017;66(6):1223–30.CrossRefPubMed
26.
Hardie C, Green K, Jopson L, Millar B, Innes B, Pagan S, et al. Early molecular stratification of high-risk primary biliary cholangitis. EBioMedicine. 2016;14:65–73.CrossRefPubMedPubMedCentral
27.
Ostrowski J, Goryca K, Lazowska I, Rogowska A, Paziewska A, Dabrowska M, et al. Common functional alterations identified in blood transcriptome of autoimmune cholestatic liver and inflammatory bowel diseases. Sci Rep. 2019;9(1):7190.CrossRefPubMedPubMedCentral
28.
Oertelt S, Lian ZX, Cheng CM, Chuang YH, Padgett KA, He XS, et al. Anti-mitochondrial antibodies and primary biliary cirrhosis in TGF-beta receptor II dominant-negative mice. J Immunol. 2006;177(3):1655–60.CrossRefPubMed
29.
Gorelik L, Flavell RA. Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity. 2000;12(2):171–81.CrossRefPubMed
30.
31.
Nevens F, Andreone P, Mazzella G, Strasser SI, Bowlus C, Invernizzi P, et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med. 2016;375(7):631–43.CrossRefPubMed
32.
Oertelt S, Lian Z, Cheng C, Chuang Y, Padgett K, He X, et al. Anti-mitochondrial antibodies and primary biliary cirrhosis in TGF-beta receptor II dominant-negative mice. J Immunol. 2006;177(3):1655–60.
33.
Kennedy L, Carpino G, Owen T, Ceci L, Kundu D, Meadows V, et al. Secretin alleviates biliary and liver injury during late-stage primary biliary cholangitis via restoration of secretory processes. J Hepatol. 2023;78(1):99–113.CrossRefPubMed
34.
Carbone M, Sharp S, Flack S, Paximadas D, Spiess K, Adgey C, et al. The UK-PBC risk scores: Derivation and validation of a scoring system for long-term prediction of end-stage liver disease in primary biliary cholangitis. Hepatology. 2016;63(3):930–50.CrossRefPubMed
35.
Lammers W, Hirschfield G, Corpechot C, Nevens F, Lindor K, Janssen H, et al. Development and validation of a scoring system to predict outcomes of patients with primary biliary cirrhosis receiving ursodeoxycholic acid therapy. Gastroenterology. 2015;149(7):1804–12.e4.CrossRefPubMed
36.
Zhang L, Shi T, Shi X, Wang L, Yang Y, Liu B, et al. Early biochemical response to ursodeoxycholic acid and long-term prognosis of primary biliary cirrhosis: results of a 14-year cohort study. Hepatology. 2013;58(1):264–72.CrossRefPubMed
37.
Barron-Millar B, Ogle L, Mells G, Flack S, Badrock J, Sandford R, et al. The serum proteome and ursodeoxycholic acid response in primary biliary cholangitis. Hepatology. 2021;74(6):3269–83.CrossRefPubMed
38.
Sakamoto T, Morishita A, Nomura T, Tani J, Miyoshi H, Yoneyama H, et al. Identification of microRNA profiles associated with refractory primary biliary cirrhosis. Mol Med Rep. 2016;14(4):3350–6.CrossRefPubMed
39.
Wunsch E, Krawczyk M, Milkiewicz M, Trottier J, Barbier O, Neurath M, et al. Serum autotaxin is a marker of the severity of liver injury and overall survival in patients with cholestatic liver diseases. Sci Rep. 2016;6:30847.CrossRefPubMedPubMedCentral
40.
Joshita S, Umemura T, Usami Y, Yamashita Y, Norman G, Sugiura A, et al. Serum autotaxin is a useful disease progression marker in patients with primary biliary cholangitis. Sci Rep. 2018;8(1):8159.CrossRefPubMedPubMedCentral
41.
Selmi C, Meda F, Kasangian A, Invernizzi P, Tian Z, Lian Z, et al. Experimental evidence on the immunopathogenesis of primary biliary cirrhosis. Cell Mol Immunol. 2010;7(1):1–10.CrossRefPubMed
42.
43.
44.
Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011;469(7329):221–5.CrossRefPubMed
45.
Frissen M, Liao L, Schneider KM, Djudjaj S, Haybaeck J, Wree A, et al. Bidirectional role of NLRP3 during acute and chronic cholestatic liver injury. Hepatology. 2021;73(5):1836–54.CrossRefPubMed
46.
47.
Savio LEB, Robson SC, Longhi MS. Ectonucleotidase modulation of lymphocyte function in gut and liver. Front Cell Dev Biol. 2020;8: 621760.CrossRefPubMed
48.
Asimah Q. Rafi-Janajreh DC, Rudolf Schmits, TakW. Mak, Randolph L. Grayson, D. Phillip Sponenberg, Mitzi Nagarkatti and Prakash S. Nagarkatti. Evidence for the involvement of CD44 in endothelial cell injury and induction of vascular leak syndrome by IL-2. J Immunol. 1999;163(3):1619–27.
49.
Fu Q, Hou L, Xiao P, Guo C, Chen Y, Liu X. CD44 deficiency leads to decreased proinflammatory cytokine production in lung induced by PCV2 in mice. Res Vet Sci. 2014;97(3):498–504.CrossRefPubMed
Metadata
Title
Integrative bioinformatics analysis and experimental validation of key biomarkers for risk stratification in primary biliary cholangitis
Authors
Siyuan Tian
Yinan Hu
Miao Zhang
Kemei Wang
Guanya Guo
Bo Li
Yulong Shang
Ying Han
Publication date
01-12-2023
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 1/2023
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/s13075-023-03163-y

Other articles of this Issue 1/2023

Arthritis Research & Therapy 1/2023 Go to the issue

Research

Risk factors for avascular necrosis in patients with systemic lupus erythematosus: a multi-center cohort study of Chinese SLE Treatment and Research Group (CSTAR) Registry XXII

Correction

Correction: Association between periodontitis and temporomandibular joint disorders

Research

Equine osteoarthritis modifies fatty acid signatures in synovial fluid and its extracellular vesicles

Correction

Correction: Factors associated with discontinuation of biologics in patients with inflammatory arthritis in remission: data from the BIOBADASER registry

Research

Quantitative proteomic screening uncovers candidate diagnostic and monitoring serum biomarkers of ankylosing spondylitis

Research

Assessment of anti-malondialdehyde-acetaldehyde antibody frequencies in rheumatoid arthritis with new data from two independent cohorts, meta-analysis, and meta-regression
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits