A Genetic Score Associates With Pioglitazone Response in Patients With Non-alcoholic Steatohepatitis

Abstract

Pioglitazone is used effectively to treat non-alcoholic steatohepatitis (NASH), but there is marked variability in response. This study examined whether genetic variation contributes to pioglitazone response variability in patients with NASH. This genetic substudy includes 55 participants of a randomized controlled trial designed to determine the efficacy of long-term pioglitazone treatment in patients with NASH. The primary outcome of the clinical trial was defined as ≥2-point reduction in the non-alcoholic fatty liver disease activity score (NAS). In this substudy, single nucleotide polymorphisms (SNPs) in putative candidate genes were tested for association with primary and secondary outcomes. A genetic response score was constructed based on the sum of response alleles for selected genes. The genetic response score was significantly associated with achievement of the primary outcome (odds ratio 1.74; 95% CI 1.27–2.54; p = 0.0015). ADORA1 rs903361 associated with resolution of NASH (p = 0.0005) and change in the ballooning score among Caucasian and Hispanic patients (p = 0.0005). LPL rs10099160 was significantly associated with change in ALT (p = 0.0005). The CYP2C8∗3 allele, which confers faster pioglitazone clearance in allele carriers, was associated with change in fibrosis score (p = 0.026). This study identified key genetic factors that explain some of the inter-individual variability in response to pioglitazone among patients with NASH.

A Pilot Genome‐Wide Analysis Study Identifies Loci Associated With Response to Obeticholic Acid in Patients With NASH

“…Understanding the host genetic factors that may influence response to a certain therapeutic agent may therefore allow a more effective and personalized delivery of therapy to patients with NASH who have a high chance of response. It may also spare patients with a low chance of response the exposure to a therapeutic agent that they may not respond to and also spare them the side effects of such agent …”

“…It may also spare patients with a low chance of response the exposure to a therapeutic agent that they may not respond to and also spare them the side effects of such agent. (25,26) In this study, we identified several genetic variants associated with NASH resolution and fibrosis improvement in participants in the FLINT trial. To our knowledge, except for variants in MAPK10, which were previously reported to be associated with liver enzymes levels in another GWAS, (27) the other variants and nearby genes identified in this study had not been previously reported to be associated with NASH or with response of liver disease to therapeutic agents ( Supporting Table S5).…”

Gender differences in the efficacy of pioglitazone treatment in nonalcoholic fatty liver disease patients with abnormal glucose metabolism

“…CYP2C8 is a critical enzyme in the metabolism of pioglitazone, and the CYP2C8 genotype could be a potential factor for the sex difference. Carriers of the CYP2C8*3 allele have faster metabolism rate of pioglitazone and have less improvement in liver brosis after pioglitazone intervention (p = 0.026) [40] . However, it has not been reported whether there are gender differences in the expression of CYP2C8 in humans, and only one study found that the mRNA and protein levels of CYP2C8 in the liver of white individuals were independent of gender [41] .…”

Combination therapy for non-alcoholic steatohepatitis: rationale, opportunities and challenges

“…Kawaguchi-Suzuki et al reported that a single nucleotide polymorphism rs903361 in the ADORA1 gene was associated with resolution of NASH in patients treated with pioglitazone. 69 Recently, a genome-wide analysis study identified several loci associated with response to obeticholic acid in patients with NASH. 70 More research in this field is needed before we see the introduction of predictive biomarkers in NASH.…”