Primary Biliary Cirrhosis Associated with HLA, IL12A, and IL12RB2 Variants
Open accessAbstract
BACKGROUND: Primary biliary cirrhosis is a chronic granulomatous cholangitis, characteristically associated with antimitochondrial antibodies. Twin and family aggregation data suggest that there is a significant genetic predisposition to primary biliary cirrhosis, but the susceptibility loci are unknown. METHODS: To identify genetic loci conferring a risk for primary biliary cirrhosis, we carried out a genomewide association analysis in which DNA samples from 2072 Canadian and U.S. subjects (536 patients with primary biliary cirrhosis and 1536 controls) were genotyped for more than 300,000 single-nucleotide polymorphisms (SNPs). Sixteen of the SNPs most strongly associated with primary biliary cirrhosis were genotyped in two independent replication sets. We carried out fine-mapping studies across three loci associated with primary biliary cirrhosis. RESULTS: We found significant associations between primary biliary cirrhosis and 13 loci across the HLA class II region; the HLA-DQB1 locus (encoding the major histocompatibility complex class II, DQ beta chain 1) had the strongest association (P=1.78x10(-19); odds ratio for patients vs. controls, 1.75). Primary biliary cirrhosis was also significantly and reproducibly associated with two SNPs at the IL12A locus (encoding interleukin-12alpha), rs6441286 (P=2.42x10(-14); odds ratio, 1.54) and rs574808 (P=1.88x10(-13); odds ratio, 1.54), and one SNP at the IL12RB2 locus (encoding interleukin-12 receptor beta2), rs3790567 (P=2.76x10(-11); odds ratio, 1.51). Fine-mapping analysis showed that a five-allele haplotype in the 3' flank of IL12A was significantly associated with primary biliary cirrhosis (P=1.15x10(-34)). We found a modest genomewide association (P<5.0x10(-5)) with the risk of disease for SNPs at the STAT4 locus (encoding signal transducer and activator of transcription 4) and the CTLA4 locus (encoding cytotoxic T-lymphocyte-associated protein 4) and 10 other loci. CONCLUSIONS: Our data show significant associations between primary biliary cirrhosis and common genetic variants at the HLA class II, IL12A, and IL12RB2 loci and suggest that the interleukin-12 immunoregulatory signaling axis is relevant to the pathophysiology of primary biliary cirrhosis. (ClinicalTrials.gov number, NCT00242125.)
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Genetic risks for PBC span key immune-regulatory pathways, including IL-12 and JAK-STAT signalling, and the HLA locus.
“This parallels the understanding of the genetic risks for PBC that span key immune-regulatory pathways, including interleukin (IL)-12 and Janus kinase/signal transducer and activator of transcription (JAK-STAT) signalling, as well as the human leukocyte antigen (HLA) locus [23,24].”
From EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis. (2017) · cites this paper as [23]
The presence of genetic susceptibility is supported by the increased concordance rate in monozygotic twins and confirmed by the identification of significant numbers of associated genetic loci in GWAS and other large-scale genetic approaches.
“The presence of genetic susceptibility is supported by the increased concordance rate in monozygotic twins44 and confirmed by the identification of significant numbers of associated genetic loci in Genome Wide Association Studies (GWAS) and other large-scale, high-quality genetic approaches.45–54”
From The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines (2018) · cites this paper as [45]
Non-HLA risk alleles in primary biliary cholangitis exhibit differences geographically and ethnically.
“Non-HLA risk alleles in primary biliary cholangitis also exhibit differences geographically and ethnically: IL-12A and IL-12RB2 in Canadian and North American patients; CCL20 and IL-12B in European patients; TNFSF15, POU2AF1, and PRKCB in Japanese patients; and IL-21, IL-21R, STAT4, CD28/ CTLA4/ICOS, CD58, ARID3A, and IL16 in Chinese patients.[13][14][15][16][17]”
From Primary biliary cholangitis. (2024) · cites this paper as [14]
Treatment with obeticholic acid was associated with decreases in the levels of IgM, IgA, IgG, interleukin-12, TNF-α, and high-sensitivity CRP, findings that suggest potential disease modification.
“the results showed that treatment with obeticholic acid was associated with decreases in the levels of IgM (which is classically elevated in patients with primary biliary cholangitis), 7,8 IgA, IgG, interleukin-12, 27 TNF-α, 28 and high-sensitivity CRP, findings that suggest potential disease modification”
From A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis (2016) · cites this paper as [27]
Gene variants in HLA or IL-12 signaling have been associated with PBC, and most patients display autoreactive antibodies against mitochondrial antigens and subsequent failure of biliary transporters, e.g., anion exchange protein 2 (AE2).
“Gene variants in HLA or IL-12 signaling have been associated with PBC, and most patients display autoreactive antibodies against mitochondrial antigens and subsequent failure of biliary transporters, e.g., anion exchange protein 2 (AE2) [177–179].”
From Inflammation and immunity in liver homeostasis and disease: a nexus of hepatocytes, nonparenchymal cells and immune cells (2025) · cites this paper as [178]
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 [6]
Another regulatory archaic variant, rs12531711, modifies the expression of TNPO3 in brain and is associated with multiple auto-immune phenotypes.
“Another regulatory archaic variant, rs12531711 (hg19, chr7:128617466), modifies the expression of TNPO3 in brain and is associated with multiple auto-immune phenotypes [26–35]”
From Functional implications of Neandertal introgression in modern humans (2017) · cites this paper as [29]
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Self-citation
- Authors
- Hirschfield, G. M., Liu, X., Xu, C., Lu, Y., Xie, G., Lu, Y., Gu, X., Walker, E. J., Jing, K., Juran, B. D., Mason, A. L., Myers, R. P., Peltekian, K. M., Ghent, C. N., Coltescu, C., Atkinson, E. J., Heathcote, E. J., Lazaridis, K. N., Amos, C. I., & Siminovitch, K. A.
- Affiliations
- University of Toronto (CA)
- University of Alberta (CA)
- The University of Texas MD Anderson Cancer Center (US)
- Mayo Clinic (US)
- University of Calgary (CA)
- Dalhousie University (CA)
- London Health Sciences Centre (CA)
- Toronto Western Hospital (CA)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2009-06-11
- Volume
- 360
- Issue
- 24
- Pages
- 2544-2555
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC2857316
- OpenAlex
- W1981904875
- Cited by
- 594
- References
- 40
- Citations by year
- 2026: 8 · 2025: 18 · 2024: 21 · 2023: 16 · 2022: 15 · 2021: 23 · 2020: 23 · 2019: 28 · 2018: 45 · 2017: 34 · 2016: 36 · 2015: 42 · 2014: 45 · 2013: 57 · 2012: 56
- FWCI
- 39.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- ScholarWorks @ UTRGV (The University of Texas Rio Grande Valley) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- American Gastroenterological Association
- Canadian Association for the Study of the Liver
- Canadian Liver Foundation
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R03DK078527, R01DK080670, R01 DK 80670, R03 DK78527, K23 DK68290, K23DK068290)
- 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, HLA-DQB1, IL12A, IL12RB2, STAT4, CTLA-4, genetic susceptibility, single nucleotide polymorphisms, HLA class II, IL-12, haplotype association, antimitochondrial antibodies, autoimmune liver disease, fine mapping
- MeSH terms
- Genes, MHC Class II, Genotype, HLA Antigens, HLA-DQ Antigens, Humans, Liver Cirrhosis, Biliary, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Receptors, Interleukin-12, Interleukin-12 Receptor beta 2 Subunit, Interleukin-23, Interleukin-12 Subunit p35, Genome-Wide Association Study, HLA-DQ beta-Chains
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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