X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis

UK-PBC Consortium, Japan-PBC-GWAS Consortium, Canadian-US PBC Consortium, Italian PBC Genetics Study Group (2021) X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis. Gastroenterology, 160 (7). 2483-2495.e26. ISSN 0016-5085

Full text not available from this repository.

Abstract

Background & Aims: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease.  Methods: We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals).  Results: Single-marker association analyses found approximately 100 loci displaying P < 5 × 10–4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10–6; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028–1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09–1.26; P = 9.93 × 10–8), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10–9; OR, 1.33; 95% CI, 1.21–1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively).  Conclusions: This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.

Item Type:	Article
Additional Information:	Publisher Copyright: © 2021 AGA Institute
Uncontrolled Keywords:	meta-analysis,superenhancer,x-wide association study,hepatology,gastroenterology ,/dk/atira/pure/subjectarea/asjc/2700/2721
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
Related URLs:	https://www.scopus.com/pages/publication...
Depositing User:	LivePure Connector
Date Deposited:	30 Jun 2026 14:19
Last Modified:	30 Jun 2026 15:22
URI:	https://ueaeprints.uea.ac.uk/id/eprint/103569
DOI:	10.1053/j.gastro.2021.02.061

Actions (login required)

View Item