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

Article-In-Press published online 5-28-12 on the Journal of Hepatology website.  Interesting study that finds higher insulin resistance in non-diabetic HCV-subjects that have the T/T and T/C-allele than their CC allele counterparts. IR, along with fibrosis and steatosis, have been established predictors of response to PEG + Ribavirin therapy - Insulin resistance could be one factor that explains the the difficulty in treating HCV patients with IL28B TT and TC genotypes. 

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

Albert Friedrich Stättermayer, Karoline Rutter, Sandra Beinhardt, Thomas-Matthias Scherzer, Andreas Stadlmayr, Harald Hofer, Fritz Wrba, Petra Steindl-Munda, Michael Krebs, Christian Datz, Michael Trauner, Peter Ferenci

Received 29 December 2011; received in revised form 20 March 2012; accepted 5 April 2012. published online 28 May 2012.
Accepted Manuscript

Abstract
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 in treatment-naïve patients with chronic hepatitis C.

Methods
202 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-IR3.0) was associated with the 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=.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=.004). The percentage of steatotic hepatocytes was greater in patients with advanced fibrosis (21.3±21.5 vs. 9.1±14.2; P<.001), HOMA-IR3.0 (17.7±17.8 vs. 8.8±15.4%; P<.001) and BMI>25.0kg/m2 (14.7±17.0 vs. 9.1±16.1; P<.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=.006) and the IL28B genotype non-CC (OR: 3.000, 1.348-6.676; P=.007) as independent risk factors for insulin resistance.

Conclusion
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.

Abbreviations: CHC, chronic hepatitis C, HCV, hepatitis C virus, HOMA, homeostasis model of assessment, IR, insulin resistance, IL28B, interleukin 28 B, PNPLA3, patatin like phospholipase domain-containing 3, SVR, sustained virologic response, SNP, single nucleotide polymorphism, T2DM, type 2 diabetes mellitus