Association of primary biliary cirrhosis with variants in the CLEC16A, SOCS1, SPIB and SIAE immunomodulatory genes

Hirschfield, G M; Xie, G; Lu, E; Sun, Y; Juran, B D; Chellappa, V; Coltescu, C; Mason, A L; Milkiewicz, P; Myers, R P; Odin, J A; Luketic, V A; Bacon, B; Bodenheimer, H; Liakina, V; Vincent, C; Levy, C; Pillai, S; Lazaridis, K N; Amos, C I; Siminovitch, K A

doi:10.1038/gene.2011.89

Cited by 85Liver Diseases and ImmunityGenetic Associations and EpidemiologyPediatric Hepatobiliary Diseases and Treatments

Association of primary biliary cirrhosis with variants in the CLEC16A, SOCS1, SPIB and SIAE immunomodulatory genes

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Hirschfield, G M, Xie, G, Lu, E, Sun, Y, Juran, B D, Chellappa, V, Coltescu, C, Mason, A L +13 more·2012·Genes & Immunity

DOI 10.1038/gene.2011.89PMC PMC3360983

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Abstract

We fine mapped two primary biliary cirrhosis (PBC) risk loci, CLEC16A (C-type lectin domain family 16 member A)-suppressor of cytokine signaling 1 (SOCS1) and Spi-B protein (SPIB) and sequenced a locus, sialic acid acetylesterase (SIAE), proposed to harbor autoimmunity-associated mutations. In all, 1450 PBC cases and 2957 healthy controls were genotyped for 84 single-nucleotide polymorphisms (SNPs) across the CLEC16A-SOCS1 and SPIB loci. All 10 exons of the SIAE gene were resequenced in 381 cases and point substitutions of unknown significance assayed for activity and secretion. Fine mapping identified 26 SNPs across the CLEC16A-SOCS1 and 11 SNPs across the SPIB locus with significant association to PBC, the strongest signals at the CLEC16A-SOCS1 locus emanating from a SOCS1 intergenic SNP (rs243325; P=9.91 × 10(-9)) and at the SPIB locus from a SPIB intronic SNP (rs34944112; P=3.65 × 10(-9)). Among the associated SNPs at the CLEC16A-SOCS1 locus, two within the CLEC16A gene as well as one SOCS1 SNP (rs243325) remained significant after conditional logistic regression and contributed independently to risk. Sequencing of the SIAE gene and functional assays of newly identified variants revealed six patients with functional non-synonymous SIAE mutations (Fisher's P=9 × 10(-4) vs controls) We demonstrate independent effects on risk of PBC for CLEC16A, SOCS1 and SPIB variants, while identifying functionally defective SIAE variants as potential factors in risk for PBC.

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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 [52]
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Alleles of the CLEC16A gene confer risk for autoimmune diseases including type 1 diabetes, multiple sclerosis, primary adrenal insufficiency, primary biliary cirrhosis, alopecia areata, juvenile idiopathic arthritis and rheumatoid arthritis.
“Genome-wide association studies (GWAS) demonstrate that alleles of the CLEC16A gene (also KIAA0350) confer risk for autoimmune diseases including type 1 diabetes, multiple sclerosis, primary adrenal insufficiency, primary biliary cirrhosis, alopecia areata, juvenile idiopathic arthritis and rheumatoid arthritis1234567.”
From Clec16a is Critical for Autolysosome Function and Purkinje Cell Survival (2016) · cites this paper as [3]
The Introduction (page unavailable) identifies CLEC16A, also called KIAA0350, within a locus associated with type 1 diabetes, multiple sclerosis and primary biliary cirrhosis; it also reports variants within CLEC16A that contribute to PBC risk. Our copy does not link CLEC16A alleles to primary adrenal insufficiency, alopecia areata, juvenile idiopathic arthritis or rheumatoid arthritis. Its mention of rheumatoid arthritis concerns other immune-related loci or SIAE, not specifically CLEC16A. (LLM, conf=0.88)
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Authors: Hirschfield, G. M., Xie, G., Lu, E., Sun, Y., Juran, B. D., Chellappa, V, Coltescu, C., Mason, A. L., Milkiewicz, P., Myers, R. P., Odin, J. A., Luketic, V. A., Bacon, B., Bodenheimer, H., Liakina, V, Vincent, C., Levy, C., Pillai, S., Lazaridis, K. N., Amos, C. I., & Siminovitch, K. A.
Affiliations: Toronto Western Hospital (CA)
The University of Texas MD Anderson Cancer Center (US)
Mount Sinai Hospital (CA)
Mayo Clinic (US)
Harvard University (US)
University of Alberta (CA)
Pomeranian Medical University (PL)
University of Calgary (CA)
Icahn School of Medicine at Mount Sinai (US)
Virginia Commonwealth University (US)
Saint Louis University (US)
Albert Einstein College of Medicine (US)
Vilnius University (LT)
Hôpital Saint-Luc (CA)
University of Miami (US)
Corresponding author: Siminovitch, K A
ORCID: Hirschfield, G M
Sun, Y
Mason, A L
Milkiewicz, P
Odin, J A
Liakina, V
Vincent, C
Levy, C
Pillai, S
Venue: Genes & Immunity
Publisher: Springer Science and Business Media LLC
Published: 2012-01-19
Volume: 13
Issue: 4
Pages: 328-335
ISSN: 1466-4879 (ISSN-L)
1476-5470
DOI: 10.1038/gene.2011.89
PMC: PMC3360983
OpenAlex: W2046079073
Cited by: 85
References: 27
Citations by year: 2025: 3 · 2024: 4 · 2023: 6 · 2022: 5 · 2021: 3 · 2020: 7 · 2019: 5 · 2018: 7 · 2017: 6 · 2016: 5 · 2015: 7 · 2014: 9 · 2013: 12 · 2012: 6
FWCI: 6.90
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Genes and Immunity (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
Funders: American Gastroenterological Association
Canada Research Chairs
National Institutes of Health (1rc2hl103010-01)
Health Canada
Canadian Institutes of Health Research (MOP74621)
National Heart, Lung, and Blood Institute (RC2HL102925, RC2HL102926, RC2HL102923, UC2HL102924, RC2HL-103010, UC2HL102925, UC2HL102923, UC2HL103010, RC2HL102924, UC2HL102926)
National Institute of Allergy and Infectious Diseases (AI076505, AI064930, R01AI064930, R01AI090867, R01AI076505)
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK080670, R01 DK 80670)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (RC1AR058481, AR058481)
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, CLEC16A, SOCS1, Spi-B, SIAE, single nucleotide polymorphisms, genetic association, fine mapping, autoimmunity, immunomodulatory genes, non-synonymous variants
MeSH terms: Suppressor of Cytokine Signaling 1 Protein, Acetylesterase, Alleles, Chromosome Mapping, DNA-Binding Proteins, Haplotypes, Humans, Liver Cirrhosis, Biliary, Monosaccharide Transport Proteins, Risk Factors, Transcription Factors, Logistic Models, Case-Control Studies, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Lectins, C-Type, Suppressor of Cytokine Signaling Proteins, Genetic Loci, Enzyme Assays

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Association of primary biliary cirrhosis with variants in the CLEC16A, SOCS1, SPIB and SIAE immunomodulatory genes

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