Association of the IL28B genotype with insulin resistance in patients with chronic hepatitis C

Background & Aims: Insulin resistance, fibrosis and steatosis are established predictors of response to peg-interferon/ribavirin therapy in chronic hepatitis C (CHC). Several host genetic polymorphisms (IL28B, PNPLA3) modify treatment-outcome, the degree of steatosis or fibrosis. The aim of our study was to evaluate the role of these polymorphisms on insulin resistance (IR) in treatment-naive patients with chronic hepatitis C. Methods: Two hundred and two non-diabetic CHC patients (GT1: 181, GT4: 21; m = 126, f = 76) undergoing liver biopsy in two tertiary academic centers were studied. The SNPs rs12979860 (IL28B) and rs738409 (PNPLA3) were investigated by RT-PCR. HOMA-IR, BMI, stage of fibrosis, extent of steatosis, and genetic data were analyzed. Results: Insulin resistance (HOMA-IR >= 3.0) was associated with rs12979860 genotype, presence of advanced fibrosis, and higher BMI. HOMA-IR in CC and in TC/TT was 2.08 +/- 1.61 (mean +/- SD) and 2.94 +/- 2.89 (p = 0.041), respectively. HOMA-IR was higher in advanced than in mild fibrosis (F3-4: 3.92 +/- 3.15; F0-2: 2.38 +/- 2.38; p = 0.004). The percentage of steatotic hepatocytes was higher in patients with advanced fibrosis (21.3 +/- 21.5 vs. 9.1 +/- 14.2; p <0.001), HOMA-IR >= 3.0 (17.7 +/- 17.8 vs. 8.8 +/- 15.4%; p <0.001), and BMI >25.0 kg/m(2) (14.7 +/- 17.0 vs. 9.1 +/- 16.1; p < 0.001). The rs738409 GG genotype was associated with advanced fibrosis and steatosis, but not with HOMA-IR. Multivariable logistic regression identified advanced fibrosis (OR: 2.820, 95% CI: 1.344-5.917; p = 0.006) and the IL28B genotype non-CC (OR: 3.000, 1.348-6.676; p = 0.007) as independent risk factors for insulin resistance. Conclusions: Insulin resistance is more common in carriers of the T allele of SNP rs12979860 than in CC homozygotes and may partly explain the poor outcome of peginterferon/ribavirin therapy in these patients. (C) 2012 European Association for the Study of the Liver. Published by Elsevier B. V. All rights reserved.