Integrated GWAS and mRNA Microarray Analysis Identified IFNG and CD40L as the Central Upstream Regulators in Primary Biliary Cholangitis

Abstract

Genome-wide association studies (GWASs) in European and East Asian populations have identified more than 40 disease-susceptibility genes in primary biliary cholangitis (PBC). The aim of this study is to computationally identify disease pathways, upstream regulators, and therapeutic targets in PBC through integrated GWAS and messenger RNA (mRNA) microarray analysis. Disease pathways and upstream regulators were analyzed with ingenuity pathway analysis in data set 1 for GWASs (1,920 patients with PBC and 1,770 controls), which included 261 annotated genes derived from 6,760 single-nucleotide polymorphisms (P < 0.00001), and data set 2 for mRNA microarray analysis of liver biopsy specimens (36 patients with PBC and 5 normal controls), which included 1,574 genes with fold change >2 versus controls (P < 0.05). Hierarchical cluster analysis and categorization of cell type-specific genes were performed for data set 2. There were 27 genes, 10 pathways, and 149 upstream regulators that overlapped between data sets 1 and 2. All 10 pathways were immune-related. The most significant common upstream regulators associated with PBC disease susceptibility identified were interferon-gamma (IFNG) and CD40 ligand (CD40L). Hierarchical cluster analysis of data set 2 revealed two distinct groups of patients with PBC by disease activity. The most significant upstream regulators associated with disease activity were IFNG and CD40L. Several molecules expressed in B cells, T cells, Kupffer cells, and natural killer-like cells were identified as potential therapeutic targets in PBC with reference to a recently reported list of cell type-specific gene expression in the liver. Conclusion: Our integrated analysis using GWAS and mRNA microarray data sets predicted that IFNG and CD40L are the central upstream regulators in both disease susceptibility and activity of PBC and identified potential downstream therapeutic targets. (Hepatology Communications 2020;4:724-738). P rimary biliary cholangitis (PBC) is a rare chronic autoimmune cholestatic liver disease that predominantly affects middle-aged females. PBC is characterized by lymphocytic cholangitis and gradual destruction of the small intrahepatic bile ducts, which leads to fibrosis, cirrhosis, and

An emerging spectrum of variants and clinical features in KCNMA1-linked channelopathy

“…Interestingly, one variant in the channel's ß subunit (KCNMB1) has been repeatedly shown to exert a protective effect against cardiovascular disease [89][90][91][92][93][94]. KCNMA1 has also been implicated in inflammatory pathology, including angioedema in response to specific antihypertensives [95], chronic rhinosinusitis [96], and primary biliary cholangitis [97]. GWAS has further uncovered KCNMA1-linked variations in drug and nutrient metabolism, including selenium [98], thiopurine chemotherapy [99,100], and ranibizumab for age-related macular degeneration [101].…”

Interferon-induced protein with tetratricopeptide repeats 3 may be a key factor in primary biliary cholangitis

“…Accumulating evidences suggest that IFN pathways may participate in the pathogenesis of PBC 20 – 24 , however, there has been no report regarding IFIT3 in PBC to our knowledge. Recent integrated analysis using GWAS, and mRNA microarray data sets predicted that IFNG and CD40L are the central upstream regulators in both disease susceptibility and activity of PBC 24 . The interplay of types I and II IFN is also implicated as a cause of human PBC 23 and a murine model of autoimmune cholangitis 22 .…”

“…IFIT3 is an IFN-induced antiviral protein acting as an inhibitor of cellular and viral processes, cell migration, proliferation, signaling, and viral replication 17 – 19 . A participation of IFN pathways in the pathogenesis of PBC was previously reported 20 – 24 , so we selected IFIT3 for further examination.…”

Peroxisome Proliferator-Activated Receptors Regulate Hepatic Immunity and Assist in the Treatment of Primary Biliary Cholangitis

“…The mechanism underlying the high levels of IgM and its role in PBC remains unclear. Genomic and miRNA analyses have indicated that IFNγ and CD40L are central upstream regulators of PBC ( 132 ). One study also found that reduced methylation of the CD40L promoter in CD4 + T cells was inversely associated with IgM levels in PBC ( 133 ).…”