The genetics of complex cholestatic disorders

Abstract

Cholestatic liver diseases are caused by a range of hepatobiliary insults and involve complex interactions among environmental and genetic factors. Little is known about the pathogenic mechanisms of specific cholestatic diseases, which has limited our ability to manage patients with these disorders. However, recent genome-wide studies have provided insight into the pathogenesis of gallstones, primary biliary cirrhosis, and primary sclerosing cholangitis. A lithogenic variant in the gene that encodes the hepatobiliary transporter ABCG8 has been identified as a risk factor for gallstone disease; this variant has been associated with altered cholesterol excretion and metabolism. Other variants of genes encoding transporters that affect the composition of bile have been associated with cholestasis, namely ABCB11, which encodes the bile salt export pump, and ABCB4, which encodes hepatocanalicular phosphatidylcholine floppase. In contrast, studies have associated primary biliary cirrhosis and primary sclerosing cholangitis with genes encoding major histocompatibility complex proteins and identified loci associated with microbial sensing and immune regulatory pathways outside this region, such as genes encoding IL12, STAT4, IRF5, IL2 and its receptor (IL2R), CD28, and CD80. These discoveries have raised interest in the development of reagents that target these gene products. We review recent findings from genetic studies of patients with cholestatic liver disease. Future characterization of genetic variants in animal models, stratification of risk alleles by clinical course, and identification of interacting environmental factors will increase our understanding of these complex cholestatic diseases.

Figure 1

Interaction of genes and environment in complex cholestatic disease. (A) Variations in severity of disease manifestation are observed with different genotypic variants in the ABCB4 encoding the biliary phosphatidylcholine transporter. Heterozygous ABCB4 variants encompass mild phenotypes, whereas homozygous deficiency leads to more severe diseases (ie, biliary cirrhosis and chronic liver failure). Specific genotypes might also contribute to chronic cholestasis and/or modify disease progression in patients with PBC and PSC. (B) Venn diagram illustrating variants that have been confirmed in replication studies. The size of each circle reflects the estimated number of adults with gallstones in each continent. Previous studies showed that Latin American populations have the highest (~30%) incidence of gallstone disease, with intermediate frequency of the disease in Europe (15%–20%) and lowest relative frequency in Asia (5%–6%). (C) The gut microbiome is more predictive of type 2 diabetes than current candidate loci derived by GWAS. A comparison of data derived from candidate type 2 diabetes loci^, and a selection of genes derived from metagenomic analyses of the gut microbiome from individuals with type 2 diabetes shows a superior correlation with the microbiome (based on the original cited data). ICP, intrahepatic cholestasis of pregnancy.

Figure 2

Circus plot of associations of cholestasis candidate genes with other diseases. Many of the candidate genes associated with PBC and PSC have previously been linked with other immune-mediated disorders and few, if any, specifically associated with biliary disease. Candidate loci found in patients with gallstone disease are predominantly associated with bile contents, lipid metabolism, and risk of coronary artery disease. Each radial line represents a PBC, PSC, or gallstone locus, ordered by genomic position and labeled around the rim, and each circular line represents a phenotype, with all points on a line colored according to the phenotype key given. Points sit at the intersection of radial and circular lines and represent sharing of a PBC, PSC, or gallstone locus with a given phenotype. The location of each locus is recorded in Table 1 and is shown as shapes in this figure, with triangles indicating PBC-specific disease, squares indicating PSC-specific disease, and circles indicating gallstone disease. AnkS, ankylosing spondylitis; CAD, coronary artery disease; CelD, celiac disease; CholM, cholesterol metabolism; CroD, Crohn's disease; GD, Graves’ disease; GS, gallstone disease; IBD, inflammatory bowel disease; MS, multiple sclerosis; PID, primary immunodeficiency syndromes; Ps, psoriasis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SS, systemic sclerosis; T1D, type 1 diabetes; TrigM, triglyceride metabolism; UC, ulcerative colitis; Viti, vitiligo.

Figure 3

The putative role of IL-12 signaling in risk of PBC. IL-12 is a heterodimeric cytokine encoded by IL-12A and IL-12B, produced mainly by monocytes and macrophages, dendritic cells, and neutrophils. A strong role for IL-12 and related cytokines is implied in the pathogenesis of PBC by the identification of upstream and downstream mediators of IL-12 signaling as susceptibility loci in the PBC GWAS. CTLA-4, cytotoxic T-lymphocyte antigen 4; Foxp3, forkhead box P3; IFN-γ, interferon gamma; IκB, inhibitory κB; IRF-5, interferon regulatory factor 5; JAK, Janus kinase; NF-κB, nuclear factor κB; SOCS-1, suppressor of cytokine signaling; STAT, signal transducer and activator of transcription; TLR, toll-like receptor; TNFRSF, tumor necrosis factor receptor super-family; TYK2, tyrosine kinase 2.

Figure 4

Modeling of genetic influence in cholestatic liver diseases. The liver compartment comprises genes involved in hereditary cholestatic syndromes and gallstone disease (highlighted in red). The same loci and loci in the biliary compartment may also serve as modifiers in immune-mediated injury, as exemplified by the immunologic compartment. Susceptibility to cholestatic liver disease has also recently been shown to be associated with genetic factors influencing microbial community composition, as illustrated by the gut compartment that also involves the enterohepatic circulation of bile acids. Cyp7A1, cytochrome P450, family 7, subfamily A, polypeptide 1; NTCP, Na/taurocholate cotransporting polypep-tide; OATP, organic anion-transporting polypeptide; BSEP, bile salt export pump; MRP2, multidrug resistance-associated protein 2; MDR3, P-glycoprotein-3/multiple drug resistance-3; ABCG5/8, adenosine triphosphate–binding cassette subfamily G member 5/8 heterodimer; ATP8B1, adenosine triphosphatase, class I, type 8B, member 1; CYP3A, cytochrome P450, family 3, subfamily A; UGT, uridine diphosphate glucoseglycoprotein glucosyltransferases; SULT, sulfotransferases; GST, glutathione S-transferase; MRP3/4, multidrug resistance-associated protein 3/4; OST, organic solute transporter; F, FXR, farnesoid X receptor; S, SXR/PXR, steroid and xenobiotic receptor/pregnane X receptor; C, CAR, constitutive androstane receptor; CFTR, cystic fibrosis transmembrane conductance regulator; TGR5, G protein–coupled bile acid receptor 1; ASBT, apical sodium-dependent bile acid transporter; AE2, anion exchange protein 2; TCR, T-cell receptor; ANCA, anti-neutrophil cytoplasmic antibodies; FUT2, fucosyltransferase 2; IBABP, ileal bile acid binding protein; FGF19, fibroblast growth factor 19.