A regulatory variant at 19p13.3 is associated with primary biliary cholangitis risk and ARID3A expression

You Li, Zhiqiang Li, Ruiling Chen, Min Lian, Hanxiao Wang, Yiran Wei, Zhengrui You, Jun Zhang, Bo Li, Yikang Li, Bingyuan Huang, Yong Chen, Qiaoyan Liu, Zhuwan Lyu, Xueying Liang, Qi Miao, Xiao Xiao, Qixia Wang, Jingyuan Fang, YongYong Shi, Xiangdong Liu, Michael F. Seldin, M. Eric Gershwin (), Ruqi Tang () and Xiong Ma ()
Additional contact information
You Li: School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease
Zhiqiang Li: Shanghai Jiao Tong University
Ruiling Chen: School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease
Min Lian: School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease
Hanxiao Wang: School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease
Yiran Wei: School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease
Zhengrui You: School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease
Jun Zhang: School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease
Bo Li: School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease
Yikang Li: School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease
Bingyuan Huang: School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease
Yong Chen: School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease
Qiaoyan Liu: School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease
Zhuwan Lyu: School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease
Xueying Liang: School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease
Qi Miao: School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease
Xiao Xiao: School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease
Qixia Wang: School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease
Jingyuan Fang: School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease
YongYong Shi: Shanghai Jiao Tong University
Xiangdong Liu: Southeast University
Michael F. Seldin: University of California at Davis
M. Eric Gershwin: University of California at Davis
Ruqi Tang: School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease
Xiong Ma: School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Genome-wide association studies have identified 19p13.3 locus associated with primary biliary cholangitis (PBC). Here we aim to identify causative variant(s) and initiate efforts to define the mechanism by which the 19p13.3 locus variant(s) contributes to the pathogenesis of PBC. A genome-wide meta-analysis of 1931 PBC subjects and 7852 controls in two Han Chinese cohorts confirms the strong association between 19p13.3 locus and PBC. By integrating functional annotations, luciferase reporter assay and allele-specific chromatin immunoprecipitation, we prioritize rs2238574, an AT-Rich Interaction Domain 3A (ARID3A) intronic variant, as a potential causal variant at 19p13.3 locus. The risk allele of rs2238574 shows higher binding affinity of transcription factors, leading to an increased enhancer activity in myeloid cells. Genome-editing demonstrates the regulatory effect of rs2238574 on ARID3A expression through allele-specific enhancer activity. Furthermore, knock-down of ARID3A inhibits myeloid differentiation and activation pathway, and overexpression of the gene has the opposite effect. Finally, we find ARID3A expression and rs2238574 genotypes linked to disease severity in PBC. Our work provides several lines of evidence that a non-coding variant regulates ARID3A expression, presenting a mechanistic basis for association of 19p13.3 locus with the susceptibility to PBC.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-37213-5 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37213-5

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-37213-5

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().