How genetic risk contributes to autoimmune liver disease

Abstract

Genome-wide association studies (GWAS) for autoimmune hepatitis (AIH) and GWAS/genome-wide meta-analyses (GWMA) for primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) have been successful over the past decade, identifying about 100 susceptibility loci in the human genome, with strong associations with the HLA locus and many susceptibility variants outside the HLA locus with relatively low risk. However, identifying causative variants and genes and determining their effects on liver cells and their immunological microenvironment is far from trivial. Polygenic risk scores (PRSs) based on current genome-wide data have limited potential to predict individual disease risk. Interestingly, results of mediated expression score regression analysis provide evidence that a substantial portion of gene expression at susceptibility loci is mediated by genetic risk variants, in contrast to many other complex diseases. Genome- and transcriptome-wide comparisons between AIH, PBC, and PSC could help to better delineate the shared inherited component of autoimmune liver diseases (AILDs), and statistical fine-mapping, chromosome X-wide association testing, and genome-wide in silico drug screening approaches recently applied to GWMA data from PBC could potentially be successfully applied to AIH and PSC. Initial successes through single-cell RNA sequencing (scRNA-seq) experiments in PBC and PSC now raise high hopes for understanding the impact of genetic risk variants in the context of liver-resident immune cells and liver cell subpopulations, and for bridging the gap between genetics and disease.

Metabolic heterogeneity caused by HLA-DRB1*04:05 and protective effect of inosine on autoimmune hepatitis

“…Although HLA alleles are considered to confer the risk for various autoimmune diseases, the precise mechanism remains unclear. Some studies have demonstrated that autoantigens encoded by HLA genes are expressed on the cell surface and presented to immune cells, which activates the downstream immune process (26). Thus, Chinese AIH patients with DRB1*04:05 have typical clinical traits, probably because of the proteins presented by HLA-DRB1*04:05.…”

Artificial intelligence for precision medicine in autoimmune liver disease

“…For all three conditions, single-nucleotide polymorphisms (SNPs) within the human leukocyte antigen region have a significant role in shaping their genetic risk (71-73); yet, several non-HLA variants have been described for PBC (74) and PSC (73), and more recently also for AIH (75). The discussion of the large topic of missing heritability is out of the scope of this review (76); however, it is worth mentioning that large portions of the heritability of AIH, PBC, and PSC are yet to be characterized (77). Whole-exome and whole-genome sequencing have clearly revealed that the identification of rare predisposing variants with large effect size is useful to fill this gap of knowledge (78,79).…”

“…Evidence in AiLD is scanty, mostly available for PSC, where autosomal-like patterns of inheritance have been identified in some families (80, 81), although it is likely that AiLDs derive in most cases from the interaction of some environmental triggers on the ground of a predisposing genetic background mostly composed of common variants. That said, the utility of PRSs, which are typically based on common variants, in AiLD is still a matter of debate (77).…”

Causal association between autoimmune liver disease and Sjögren's syndrome: A Mendelian randomization study

“…Autoimmune liver disease (AILD) is a rare chronic immunemediated liver injury disease, mainly comprising the following three type. 1 Primary biliary cholangitis (PBC) is a type of autoimmune liver disease characterized by autoimmune-mediated destruction of the intrahepatic bile duct epithelium and chronic biliary stasis. Its histological feature is the accumulation of lymphocytes or granulomas within the portal tracts, infiltrating and damaging the epithelial cells of the bile ducts, leading to immune inflammation.…”