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.
Highlights
Clinical guidelines support the use of pioglitazone as a pharmacological agent to manage biopsy-proven non-alcoholic steatohepatitis or NASH (Chalasani et al, 2017)
Plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentration, as well as plasma CK-18 concentration, decreased significantly with pioglitazone treatment compared to baseline levels (Table 2)
We examined multiple single nucleotide polymorphism (SNP) selected on the basis of reported associations with TZD response in patients with diabetes, and we replicated similar effects of polymorphisms in patients treated with pioglitazone for NASH
Summary
Clinical guidelines support the use of pioglitazone as a pharmacological agent to manage biopsy-proven non-alcoholic steatohepatitis or NASH (Chalasani et al, 2017). Pioglitazone is a PPAR-γ agonist that belongs to the thiazolidinedione (TZD) class of antidiabetic drugs (Cariou et al, 2012). PPAR-γ is highly expressed in adipose tissue, and TZDs are thought to work primarily through PPAR-γ in adipocytes (Cariou et al, 2012). PPAR-γ is expressed in non-parenchymal cells such as Kupffer and stellate cells, Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CK-18, cytokeratin-18; CYP, cytochrome P450; DNA, deoxyribonucleic acid; MAF, minor allele frequency; NAFLD, non-alcoholic fatty liver disease; NAS, NAFLD activity score; NASH, non-alcoholic steatohepatitis; OR, odds ratio; PPAR-γ, peroxisome proliferator-activated receptor-γ; SNP, single nucleotide polymorphism; TZD, thiazolidinedione; 95% CI, 95% confidence interval. The exact mechanism is not clear, the immune-modulatory and antiinflammatory effects of PPAR-γ may play a role in NAFLD (Cariou et al, 2012)
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