Association of IL12A Expression Quantitative Trait Loci (eQTL) With Primary Biliary Cirrhosis in a Chinese Han Population

Li, Ping; Lu, Guanting; Cui, Ying; Wu, Ziyan; Chen, Si; Li, Jing; Wen, Xiaozhong; Zhang, Haoze; Mu, Shijie; Zhang, Fengchun; Li, Yongzhe

doi:10.1097/md.0000000000003665

Cited by 5 publications

(5 citation statements)

References 43 publications

(50 reference statements)

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“…More recently, specific PBC populations have been found to have diminished IL-12A production [24], and a clinical trial using the IL-12 inhibitor ustekinumab showed no efficacy [25], suggesting that patients may lack IL-12 activity. Epidemiological studies also indicate that PBC patients may lack immune function with both an increased prevalence of infectious diseases, such as tonsillitis and urinary tract infection, and an increased prevalence of cancers, such as lymphoma, thyroid, kidney, and breast cancer [7,26,27].…”

Section: Pbc: Genes Vs Environmentmentioning

confidence: 99%

Linking Human Betaretrovirus with Autoimmunity and Liver Disease in Patients with Primary Biliary Cholangitis

Syed

Penner

Mason

2022

Viruses

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Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by the production of diagnostic antimitochondrial antibodies (AMA) reactive to the pyruvate dehydrogenase complex. A human betaretrovirus (HBRV) resembling mouse mammary tumor virus has been characterized in patients with PBC. However, linking the viral infection with the disease is not a straight-forward process because PBC is a complex multifactorial disease influenced by genetic, hormonal, autoimmune, environmental, and other factors. Currently, PBC is assumed to have an autoimmune etiology, but the evidence is lacking to support this conjecture. In this review, we describe different approaches connecting HBRV with PBC. Initially, we used co-cultivation of HBRV with biliary epithelial cells to trigger the PBC-specific phenotype with cell surface expression of cryptic mitochondrial autoantigens linked with antimitochondrial antibody expression. Subsequently, we have derived layers of proof to support the role of betaretrovirus infection in mouse models of autoimmune biliary disease with spontaneous AMA production and in patients with PBC. Using Hill’s criteria, we provide an overview of how betaretrovirus infection may trigger autoimmunity and propagate biliary disease. Ultimately, the demonstration that disease can be cured with antiviral therapy may sway the argument toward an infectious disease etiology in an analogous fashion that was used to link H. pylori with peptic ulcer disease.

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Section: Pbc: Genes Vs Environmentmentioning

confidence: 99%

Linking Human Betaretrovirus with Autoimmunity and Liver Disease in Patients with Primary Biliary Cholangitis

Syed

Penner

Mason

2022

Viruses

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“…The statistical analysis was primarily carried out as previously reported. [ 18 19 ] A PLINK tool set (Broad Institute, MA, USA) was used to conduct the association analysis. [ 20 ] The Chi-square test was applied to compare allele frequencies between case and control groups under dominant and recessive models.…”

Section: Ethodsmentioning

confidence: 99%

Variants in the Promoter Region of HLA-DQA1 were Associated with Idiopathic Membranous Nephropathy in a Chinese Han Population

Qin

Liu

Lyu

et al. 2017

Chinese Medical Journal

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Background:Idiopathic membranous nephropathy (IMN) is an autoimmune disease and the leading cause of adult nephritic syndrome. HLA-DQA1 had been identified to be associated with IMN in Europeans and the result was replicated in Chinese Han population. In this study, six single nucleotide polymorphisms (SNPs) in the promoter of HLA-DQA1 and other two SNPs with IgA nephropathy were included for the association analysis.Methods:The SNPs were genotyped in 509 patients and 601 controls by the MassArray iPLEX. The quantification of anti-phospholipase A2 receptor (PLA2R) antibodies in sera of IMN patients was performed by anti-PLA2R ELISA (IgG) kit.Results:After analysis, four SNPs were significantly associated with IMN, with rs2187668 and rs28383345 as the top two signals (P = 8.42×10-5 and 2.48×10-5, respectively). Even under dominant model, the two SNPs were still significantly associated with IMN (P = 3.50×10-3 for rs28383345 and P = 6.55×10-5 for rs2187668). After conditional study with rs2187668, rs28383345 was the only variant significantly correlated with IMN after Bonferroni correction (P = 0.016). The minor alleles of the two SNPs were also mutually exclusive in our cohort. This indicated that the two SNPs were independently associated with IMN in Chinese Han population. Levels of anti-PLA2R autoantibodies were correlated with the genotypes of the two SNPs, but not significantly (P>0.05).Conclusions:Our results revealed that a novel independent variant in the promoter of HLA-DQA1 was associated with IMN in Chinese Han population. The locus possessed regulatory role according to the data of RegulomeDB. The exact role of the SNPs on the expression of HLA-DQA1 needs further investigation.

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“…Several recent GWAS have shown that some non- HLA genes, such as STAT4 SNPs ( rs10168266 , rs11889341 , rs7574865 , rs8179673 , rs10181656 )[27], ESR2 rs1256030 T allele[28], CLEC16A, SOCS1, SPIB and SIAE genes[29], may also be significant risk factors for the progression of PBC. One study demonstrated that the downregulated expression of IL-12A in lymphoblastoid cell lines obtained from Han Chinese were markedly associated with the risk alleles of rs4679868 and rs6441286 ( P = 0.0031 and 0.0073, respectively)[30]. Furthermore, the risk alleles of the 2 SNPs were observably related to a decreased expression of SCHIP1 gene that is 91.5 kb, located upstream of IL-12A and associated with susceptibility to celiac disease[30].…”

Section: Risk Factorsmentioning

confidence: 99%

“…One study demonstrated that the downregulated expression of IL-12A in lymphoblastoid cell lines obtained from Han Chinese were markedly associated with the risk alleles of rs4679868 and rs6441286 ( P = 0.0031 and 0.0073, respectively)[30]. Furthermore, the risk alleles of the 2 SNPs were observably related to a decreased expression of SCHIP1 gene that is 91.5 kb, located upstream of IL-12A and associated with susceptibility to celiac disease[30]. These data have disclosed the IL-12/JAK-STAT signaling pathway as a pivotal etiologic factor for PBC.…”

Section: Risk Factorsmentioning

confidence: 99%

Recent advances in the diagnosis and treatment of primary biliary cholangitis

Huang¹

2016

WJH

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Primary biliary cholangitis (PBC), formerly referred to as primary biliary cirrhosis, is an infrequent progressive intrahepatic cholestatic autoimmune illness that can evolve into hepatic fibrosis, hepatic cirrhosis, hepatic failure, and, in some cases, hepatocellular carcinoma. The disease itself is characterized by T-lymphocyte-mediated chronic non-suppurative destructive cholangitis and elevated serum levels of extremely specific anti-mitochondrial autoantibodies (AMAs). In this article, we will not only review epidemiology, risk factors, natural history, predictive scores, radiologic approaches (e.g., acoustic radiation force impulse imaging, vibration controlled transient elastography, and magnetic resonance elastography), clinical features, serological characteristics covering biochemical markers, immunoglobulins, infections markers, biomarkers, predictive fibrosis marker, specific antibodies (including AMAs such as AMA-M2), anti-nuclear autoantibodies [such as anti-multiple nuclear dot autoantibodies (anti-sp100, PML, NDP52, anti-sp140), anti-rim-like/membranous anti-nuclear autoantibodies (anti-gp210, anti-p62), anti-centromere autoantibodies, and some of the novel autoantibodies], histopathological characteristics of PBC, diagnostic advances, and anti-diastole of PBC. Furthermore, this review emphasizes the recent advances in research of PBC in terms of therapies, including ursodeoxycholic acid, budesonide, methotrexate, obeticholic acid, cyclosporine A, fibrates such as bezafibrate and fenofibrate, rituximab, mesenchymal stem cells transplant, and hepatic transplant. Currently, hepatic transplant remains the only optimal choice with acknowledged treatment efficiency for end-stage PBC patients.

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Association of IL12A Expression Quantitative Trait Loci (eQTL) With Primary Biliary Cirrhosis in a Chinese Han Population

Abstract: Supplemental Digital Content is available in the text

Cited by 5 publications

References 43 publications

Linking Human Betaretrovirus with Autoimmunity and Liver Disease in Patients with Primary Biliary Cholangitis

Linking Human Betaretrovirus with Autoimmunity and Liver Disease in Patients with Primary Biliary Cholangitis

Variants in the Promoter Region of HLA-DQA1 were Associated with Idiopathic Membranous Nephropathy in a Chinese Han Population

Recent advances in the diagnosis and treatment of primary biliary cholangitis

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