The Genomics/Genetics of Primary Biliary Cholangitis: The Case for a Functional SNP rs10893900 in ETS1/FLI1 and Review of the Literature

Mingming Zhang^#¹, Chan Wang^#², Yexi Huang¹, Lu Wang¹, Yaping Dai³, Yuzhang Jiang⁴, Chongxu Han⁵, Yuhua Gong⁶, Li Li⁷, Ye Tian⁸, Wenyan Tian⁹, Runhao Lin¹, Shuna Tong¹, Meilin Wang¹⁰, Xiong Ma¹¹, Fang Qiu², Zhexiong Lian¹², M Eric Gershwin¹³, Xingjuan Shi¹⁴, Weichang Chen¹⁵, Xiangdong Liu^{16

17}

Affiliations

¹ Key Laboratory of Developmental Genes and Human Diseases, School of Life Science and Technology, Southeast University, Nanjing, 210096, Jiangsu, China.
² Department of Laboratory Medicine, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, 210031, Jiangsu, China.
³ Department of Laboratory Medicine, The Fifth People's Hospital of Wuxi, Wuxi, Jiangsu, 214000, China.
⁴ Department of Laboratory Medicine, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, Jiangsu, 223300, China.
⁵ Department of Laboratory Medicine, Clinical Medical College, Subei People's Hospital, Yangzhou University, Yangzhou, 225001, Jiangsu, China.
⁶ Department of Laboratory Medicine, The Third People's Hospital of Zhenjiang, Zhenjiang, 212021, Jiangsu, China.
⁷ Department of Clinical Laboratory, ZhongDa Hospital, Southeast University, Nanjing, 210009, Jiangsu, China.
⁸ Department of Radiology & Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, Jiangsu, China.
⁹ Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu, China.
¹⁰ Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, Nanjing Medical University School of Public Health, Nanjing, 210029, Jiangsu, China.
¹¹ Department of Gastroenterology and Hepatology, Shanghai Institute of Digestive Diseases, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, 200001, China.
¹² Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, Guangdong, China.
¹³ Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, 95616, USA.
¹⁴ Key Laboratory of Developmental Genes and Human Diseases, School of Life Science and Technology, Southeast University, Nanjing, 210096, Jiangsu, China. xingjuanshi@seu.edu.cn.
¹⁵ Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu, China. weichangchen@126.com.
¹⁶ Key Laboratory of Developmental Genes and Human Diseases, School of Life Science and Technology, Southeast University, Nanjing, 210096, Jiangsu, China. xiangdongliu@seu.edu.cn.
¹⁷ College of Synthetic Biology Industry, Hunan University of Arts and Science, Changde, 415000, Hunan, China. xiangdongliu@seu.edu.cn.

^# Contributed equally.

PMID: 41144175
DOI: 10.1007/s12016-025-09102-w

Review

The Genomics/Genetics of Primary Biliary Cholangitis: The Case for a Functional SNP rs10893900 in ETS1/FLI1 and Review of the Literature

Mingming Zhang et al. Clin Rev Allergy Immunol. 2025.

. 2025 Oct 27;68(1):96.

doi: 10.1007/s12016-025-09102-w.

Authors

Affiliations

¹ Key Laboratory of Developmental Genes and Human Diseases, School of Life Science and Technology, Southeast University, Nanjing, 210096, Jiangsu, China.
² Department of Laboratory Medicine, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, 210031, Jiangsu, China.
³ Department of Laboratory Medicine, The Fifth People's Hospital of Wuxi, Wuxi, Jiangsu, 214000, China.
⁴ Department of Laboratory Medicine, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, Jiangsu, 223300, China.
⁵ Department of Laboratory Medicine, Clinical Medical College, Subei People's Hospital, Yangzhou University, Yangzhou, 225001, Jiangsu, China.
⁶ Department of Laboratory Medicine, The Third People's Hospital of Zhenjiang, Zhenjiang, 212021, Jiangsu, China.
⁷ Department of Clinical Laboratory, ZhongDa Hospital, Southeast University, Nanjing, 210009, Jiangsu, China.
⁸ Department of Radiology & Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, Jiangsu, China.
⁹ Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu, China.
¹⁰ Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, Nanjing Medical University School of Public Health, Nanjing, 210029, Jiangsu, China.
¹¹ Department of Gastroenterology and Hepatology, Shanghai Institute of Digestive Diseases, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, 200001, China.
¹² Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, Guangdong, China.
¹³ Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, 95616, USA.
¹⁴ Key Laboratory of Developmental Genes and Human Diseases, School of Life Science and Technology, Southeast University, Nanjing, 210096, Jiangsu, China. xingjuanshi@seu.edu.cn.
¹⁵ Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu, China. weichangchen@126.com.
¹⁶ Key Laboratory of Developmental Genes and Human Diseases, School of Life Science and Technology, Southeast University, Nanjing, 210096, Jiangsu, China. xiangdongliu@seu.edu.cn.
¹⁷ College of Synthetic Biology Industry, Hunan University of Arts and Science, Changde, 415000, Hunan, China. xiangdongliu@seu.edu.cn.

^# Contributed equally.

PMID: 41144175
DOI: 10.1007/s12016-025-09102-w

Abstract

ETS1 and FLI1 exhibit distinct roles in immunoregulation and autoimmune pathogenesis. Previous transethnic genome-wide meta-analyses incorporating our Han Chinese population established significant associations between ETS1 single-nucleotide polymorphisms (SNPs) and susceptibility to primary biliary cholangitis (PBC). In our earlier genome-wide association study (GWAS), ten SNPs within the ETS1 and FLI1 loci demonstrated modest yet suggestive associations with PBC susceptibility in the Han Chinese population. To validate these putative risk loci, we conducted an independent replication study of rs10893900 and rs2246290 using a separate Han Chinese PBC cohort. A meta-analysis combining data from two stages identified rs10893900 as a genome-wide significant variant (P = 4.55 × 10^-8, OR = 1.19, 95% CI = 1.12-1.27). Subsequent functional characterization identified rs10893900 as a susceptibility-associated functional variant. Based on the literature review, we summarized ETS1 variants' susceptibility to human autoimmune diseases, including SLE, RA, and PBC, and evaluated these variants in silico analysis. Importantly, our research implicates the importance of ETS1 involving JAK-STAT signaling pathway, expanding the understanding of pathological mechanisms of PBC.

Keywords: E26 transformation specific-1; Friend leukemia integration 1; Han Chinese; Primary biliary cholangitis; Single-nucleotide polymorphism.

PubMed Disclaimer

Conflict of interest statement

Declarations. Conflict of interest: The authors declare no competing interests.

References

1. Selmi C, Invernizzi P, Keeffe EB, Coppel RL, Podda M, Rossaro L et al (2004) Epidemiology and pathogenesis of primary biliary cirrhosis. J Clin Gastroenterol 38:264–271. https://doi.org/10.1097/00004836-200403000-00013 - DOI - PubMed
1. Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D, Vierling JM, Adams D, Alpini G et al (2019) The challenges of primary biliary cholangitis: what is new and what needs to be done. J Autoimmun 105:102328. https://doi.org/10.1016/j.jaut.2019.102328 - DOI - PubMed
1. Hirschfield GM, Siminovitch KA (2015) Genetics in PBC: what do the “risk genes” teach us? Clin Rev Allergy Immunol 48:176–181. https://doi.org/10.1007/s12016-014-8419-x - DOI - PubMed
1. Liu X, Invernizzi P, Lu Y, Kosoy R, Lu Y, Bianchi I et al (2010) Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis. Nat Genet 42:658–660. https://doi.org/10.1038/ng.627 - DOI - PubMed - PMC
1. Hirschfield GM, Liu X, Xu C, Lu Y, Xie G, Lu Y et al (2009) Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. N Engl J Med 360:2544–2555. https://doi.org/10.1056/NEJMoa0810440 - DOI - PubMed - PMC

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

The Genomics/Genetics of Primary Biliary Cholangitis: The Case for a Functional SNP rs10893900 in ETS1/FLI1 and Review of the Literature

Affiliations

The Genomics/Genetics of Primary Biliary Cholangitis: The Case for a Functional SNP rs10893900 in ETS1/FLI1 and Review of the Literature

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous