However, response in patients with NASH is variable, and improvement in liver histology is not always observed. The aim of this study was to identify genetic polymorphisms that contribute to variability Selleck BAY 80-6946 in treatment response. Methods: A total of 55 patients with NASH and prediabetes/ type 2 diabetes mellitus (T2DM) (age: 53 ± 9 years; gender: 41 males and 14 females; weight: 99 ± 17 kg; prevalence of T2DM: 60%) were treated for 18 months with pioglitazone 45 mg/day; 32 patients from

the initial randomized placebo-controlled trial and 23 patients, originally randomized to placebo, that were treated as part of the open-label phase from 18 to 36 months (NCT00994682). Patients were genotyped for 63 single nucleotide polymorphisms, which were selected based on previous association with the pathophysiology of

NAFLD or with pioglitazone response in patients with T2DM. Selected genes include: MLN0128 RETN (resistin, a hormone believed to link obesity with T2DM), PLIN1 (perilipin, a key protein that coats and protects lipid storage droplets in adipocytes), ADORA1 (ade-nosine receptor present in adipose tissue that inhibits lipoly-sis), and PPARG (PPAR-γ, pioglitazone target) among others. Results: After 18 months of pioglitazone treatment, resolution of NASH was more likely in patients with ADORA1 rs903361 G allele (OR=3.60, p=0.02). Specifically, improvement in steatosis was associated with the presence of the PPARG rs4135247 G allele

(OR=9.74, p=0.04) while improvement in necroinflammation was more frequent with RETN rs4804765 T allele (OR=3.76, p=0.03) and ADORA1 rs903361 G allele (OR=7.96, p=0.03). Improvement was defined as reduction of at least 2 grades in the histology. Overall, polymorphisms associated with change in the NAFLD activity score were: RETN rs4804765 (better reduction by 0.85 points for each T allele, p=0.003), ADORA1 rs903361 (better reduction by 0.85 points for each G allele, p=0.006), and PLIN1 rs894160 (worse reduction by 0.76 points for each T allele, p=0.01). Of note, this last variant was associated with worse response in inflammation (β=0.38, p=0.0004) and fibrosis (β=0.34, p=0.003). PNPLA3 rs738409 and rs2281135 polymorphisms were not associated with response to pioglitazone therapy. Conclusions: Genetic polymorphisms likely have significant impact medchemexpress on response to pioglitazone treatment in patients with NASH and may potentially help to identify responders and individualize therapy (i.e., RETN rs4804765, ADORA1 rs903361, PLIN1 rs894160, and PPARG rs4135247). Future studies in larger populations are warranted. Disclosures: Kenneth Cusi – Consulting: Merck, Daichi-Sankyo, Roche, Janssen; Grant/ Research Support: Takeda, Novartis, Mannkind The following people have nothing to disclose: Marina Kawaguchi-Suzuki, Fernando Bril, Taimour Langaee, Yan Gong, Reginald Frye More than 400 human genes encode proteases.