7
IRUS Total
Downloads
  Altmetric

X chromosome contribution to the genetic architecture of primary biliary cholangitis.

File Description SizeFormat 
PBC_Study_Final_2021.docxAccepted version398.77 kBMicrosoft WordView/Open
Title: X chromosome contribution to the genetic architecture of primary biliary cholangitis.
Authors: Asselta, R
Paraboschi, EM
Gerussi, A
Cordell, HJ
Mells, GF
Sandford, RN
Jones, DE
Nakamura, M
Ueno, K
Hitomi, Y
Kawashima, M
Nishida, N
Tokunaga, K
Nagasaki, M
Tanaka, A
Tang, R
Li, Z
Shi, Y
Liu, X
Xiong, M
Hirschfield, G
Siminovitch, KA
Canadian-US PBC Consortium
Italian PBC Genetics Study Group
UK-PBC Consortium
Japan PBC-GWAS Consortium
Carbone, M
Cardamone, G
Duga, S
Gershwin, ME
Seldin, MF
Invernizzi, P
Item Type: Journal Article
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.
Issue Date: Jun-2021
Date of Acceptance: 25-Feb-2021
URI: http://hdl.handle.net/10044/1/90806
DOI: 10.1053/j.gastro.2021.02.061
ISSN: 0016-5085
Publisher: WB Saunders
Start Page: 2483
End Page: 2495.e26
Journal / Book Title: Gastroenterology
Volume: 160
Issue: 7
Copyright Statement: © 2021 Elsevier Ltd. All rights reserved. This manuscript is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licence http://creativecommons.org/licenses/by-nc-nd/4.0/
Sponsor/Funder: LiveR North
Funder's Grant Number: BH160790
Keywords: Meta-analysis
Superenhancer
X-Wide Association Study
Canadian-US PBC Consortium
Italian PBC Genetics Study Group
UK-PBC Consortium
Japan PBC-GWAS Consortium
Meta-analysis
Superenhancer
X-Wide Association Study
1103 Clinical Sciences
1109 Neurosciences
1114 Paediatrics and Reproductive Medicine
Gastroenterology & Hepatology
Publication Status: Published
Conference Place: United States
Online Publication Date: 2021-03-04
Appears in Collections:Electrical and Electronic Engineering



This item is licensed under a Creative Commons License Creative Commons