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Cited by 55Liver Diseases and ImmunityGenetic Associations and EpidemiologyPediatric Hepatobiliary Diseases and Treatments

X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis

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Asselta, Rosanna, Paraboschi, Elvezia M., Gerussi, Alessio, Cordell, Heather J., Mells, George F., Sandford, Richard N., Jones, David E., Nakamura, Minoru +581 more·2021·Gastroenterology
DOI 10.1053/j.gastro.2021.02.061PMC PMC8169555
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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.

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  • An X-chromosome-wide association study revealed a novel genomic locus that marks a superenhancer regulating FOXP3, a crucial transcription factor in the development and function of regulatory T (Treg) cells.

    “An X-chromosome-wide association study revealed a novel genomic locus that marks a superenhancer regulating FOXP3, a crucial transcription factor in the development and function of regulatory T (Treg) cells.23”

    From Primary biliary cholangitis. (2024) · cites this paper as [23]

    The Results identify a genome-wide significant X-chromosome locus containing a superenhancer and list FOXP3 among its predicted targets. The Discussion describes FOXP3 as a marker of Treg cells, but says the enhancer is only possibly involved in FOXP3 regulation and notes that functional studies are lacking. The claim overstates that proposed regulatory link as established. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • More than 60 non-HLA susceptibility regions have been identified in PBC pathogenesis.

    “In addition to the human leukocyte antigen (HLA) locus, more than 60 non-HLA susceptibility regions have been identified in PBC pathogenesis, including tumor necrosis factor superfamily member 15 (TNFSF15), Interleukin 12 A (IL12A), Interleukin 12 receptor (IL12R), Nuclear Factor Kappa B Subunit 1 (NFKB1) and other immune-associated genes6–11.”

    From A regulatory variant at 19p13.3 is associated with primary biliary cholangitis risk and ARID3A expression (2023) · cites this paper as [10]

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References 64 · Cited by 55

Research works printed but not linked: 3

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Authors
Asselta, R., Paraboschi, E. M., Gerussi, A., Cordell, H. J., Mells, G. F., Sandford, R. N., Jones, D. E., 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, K. A., Walker, E., Xie, G., Mason, A., Myers, R., Peltekian, K., Ghent, C., Atkinson, E., Juran, B., Lazaridis, K., Lu, Y., Gu, X., Jing, K., Amos, C., Affronti, A., Brunetto, M., Coco, B., Spinzi, G., Elia, G., Ferrari, C., Lleo, A., Muratori, L., Muratori, P., Portincasa, P., Colli, A., Bruno, S., Colloredo, G., Azzaroli, F., Andreone, P., Bragazzi, M., Alvaro, D., Cardinale, V., Cazzagon, N., Rigamonti, C., Floreani, A., Rosina, F., Ciaccio, A., Cristoferi, L., D’Amato, D., Malinverno, F., Mancuso, C., Massironi, S., Milani, C., O’Donnell, S. E., Ronca, V., Barisani, D., Lampertico, P., Donato, F., Fagiuoli, S., Almasio, P. 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E., Seldin, M. F., & Invernizzi, P.
Affiliations
  • Humanitas University (IT)
  • Azienda Ospedaliera San Gerardo (IT)
  • Newcastle University (GB)
  • University of Cambridge (GB)
  • Nagasaki Medical Center (JP)
  • National Center for Global Health and Medicine (JP)
  • The University of Tokyo (JP)
  • Kyoto University (JP)
  • Teikyo University (JP)
  • Shanghai Jiao Tong University (CN)
  • Qingdao University (CN)
  • Southeast University (CN)
  • University of Toronto (CA)
  • Mount Sinai Hospital (CA)
  • University of California, Davis (US)
  • University of Milano-Bicocca (IT)
Corresponding author
  • Ghent, Cameron
  • Floreani, Annarosa
  • Colombo, Massimo
ORCID
Venue
Gastroenterology
Publisher
Elsevier BV
Published
2021-06
Volume
160
Issue
7
Pages
2483-2495.e26
ISSN
0016-5085 (ISSN-L)
DOI
10.1053/j.gastro.2021.02.061
PMC
PMC8169555
OpenAlex
W3135320785
Cited by
55
References
64
Citations by year
2026: 6 · 2025: 12 · 2024: 11 · 2023: 12 · 2022: 10 · 2021: 4
FWCI
5.15
Type
journal article
Language
en
Open access
Licence
Locations
  • Gastroenterology (publishedVersion)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (publishedVersion, other-oa)
  • PubMed Central (acceptedVersion)
  • CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion, cc-by-nc-nd)
  • ArTS Archivio della ricerca di Trieste (University of Trieste https://www.units.it/) (submittedVersion, cc-by-nc-nd)
  • BOA (University of Milano-Bicocca) (submittedVersion, cc-by-nc-nd)
  • Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Florence Research (University of Florence) (submittedVersion)
  • CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion)
  • IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
  • Nova Science Publishers (Nova Science Publishers, Inc.) (submittedVersion)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, other-oa)
  • Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
  • Università Politecnica delle Marche (Università Politecnica delle Marche) (submittedVersion)
  • Royal Devon and Exeter Research Repository (Royal Devon and Exeter) (submittedVersion, public-domain)
  • Spiral (Imperial College London) (submittedVersion, cc-by-nc-nd)
  • UEA Digital Repository (University of East Anglia) (submittedVersion)
  • Padua Research Archive (University of Padova) (submittedVersion, cc-by-nc-nd)
  • Newcastle University ePrints (Newcastle Univesity)
Funders
  • Japan Society for the Promotion of Science
  • National Natural Science Foundation of China-Yunnan Joint Fund
  • Japan Agency for Medical Research and Development
  • National Institutes of Health
  • Ministero della Salute
Topics
  • Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Surgery › Pediatric Hepatobiliary Diseases and Treatments
Keywords
primary biliary cirrhosis, X chromosome, sex differences, autoimmune liver disease, OTUD5, Foxp3, super-enhancers, linkage disequilibrium blocks, PQBP1, PIM2, SLC35A2, regulatory T cells, genetic susceptibility
MeSH terms
Mitochondrial Precursor Protein Import Complex Proteins, UDP-Galactose Translocators, Adult, Carrier Proteins, DNA-Binding Proteins, Female, Humans, Liver Cirrhosis, Biliary, Male, Monosaccharide Transport Proteins, Endopeptidases, Proto-Oncogene Proteins, Linkage Disequilibrium, Odds Ratio, Protein Serine-Threonine Kinases, Cell Lineage, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Chromosomes, Human, X, White People, Asian People, Shal Potassium Channels, Forkhead Transcription Factors, Genome-Wide Association Study, Genetic Loci

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