Enrichment of Genetic Variants in the Glucocorticoid Receptor Signalling Pathway in Autoimmune Hepatitis with Failure of Standard Treatment

Abstract

The standard treatment for autoimmune hepatitis (AIH) is predniso(lo)ne for remission induction, tapered and followed by azathioprine, which effectively controls the disease in the majority of patients. However, some patients prove to be unresponsive or non-tolerant and require alternative immunosuppressive regimens for disease control. We aimed to investigate whether these AIH patients who experience failure of standard treatment have a genomic basis for their problem in the form of pharmacogenetic variants. Fifty-six consecutive patients with AIH [41 female and 15 male; median age 42 years (12-76)] were retrospectively stratified according to being responders to standard therapy (n = 33) or patients with failure of standard therapy (n = 23). Their blood DNA was exome-captured and sequenced. Genomic variants were filtered and compared between the groups using Ingenuity Variant Analysis (3.1.20150407). The exome sequencing and data processing revealed glucocorticoid receptor signalling to be the most prominently affected pathway among the patients with failure of standard therapy (highly significant). Standard treatment failure was not associated with thiopurine S-methyltransferase variants or the HLA-DRB1*03 genotype. In conclusion, enrichment of variants related to glucocorticoid receptor signalling was a particular genomic trait of the AIH patients in whom standard treatment failed and alternative immunosuppression was required. If confirmed, a future application of this finding may be to identify prospective cases of failure of standard treatment already at diagnosis.

Evaluation and Study of Patho-Physiological Role of Glucocorticoid Receptor (Gr) Ligands in Acetaminophen-Induced Liver Injury in Mice

“…Glucocorticoid receptors exert their action through cellular effects and gene transcription. The signaling of glucocorticoids (GCs) is coupled to various pathways (Eriksen et al, 2017). Glucocorticoids act by binding to glucocorticoid receptors intracellularly.…”

Precision medicine for autoimmune hepatitis

“…It has been discovered that several mechanisms contribute to the great heterogeneity of glucocorticoid receptor protein among individuals, such as genetic polymorphisms in the glucocorticoid receptor gene . Recently, a study from Denmark found that the insensitivity to steroids in patients with AIH had a close association with genetic polymorphisms in the glucocorticoid receptor‐signaling pathway . Nevertheless, much more evidence is still needed to guide the clinical use of steroids according to the genetic polymorphisms of patients.…”