Interleukin 28B polymorphisms are the only common genetic variants associated with low‐density lipoprotein cholesterol (LDL‐C) in genotype‐1 chronic hepatitis C and determine the association between LDL‐C and treatment response

<jats:p><jats:bold>Summary. </jats:bold> Low‐density lipoprotein cholesterol (LDL‐C) levels and interleukin 28B (<jats:italic>IL28B</jats:italic>) polymorphism are associated with sustained viral response (SVR) to peginterferon/ribavirin (pegIFN/RBV) for chronic hepatitis C (CHC) infection. <jats:italic>IL28B</jats:italic> has been linked with LDL‐C levels using a candidate gene approach, but it is not known whether other genetic variants are associated with LDL‐C, nor how these factors definitively affect SVR. We assessed genetic predictors of serum lipid and triglyceride levels in 1604 patients with genotype 1 (G1) chronic hepatitis C virus (HCV) infection by genome‐wide association study and developed multivariable predictive models of SVR. <jats:italic>IL28B</jats:italic> polymorphisms were the only common genetic variants associated with pretreatment LDL‐C level in Caucasians (rs12980275, <jats:italic>P</jats:italic> = 4.7 × 10<jats:sup>−17</jats:sup>, poor response <jats:italic>IL28B</jats:italic> variants associated with lower LDL‐C). The association was dependent on HCV infection, <jats:italic>IL28B</jats:italic> genotype was no longer associated with LDL‐C in SVR patients after treatment, while the association remained significant in non‐SVR patients (<jats:italic>P</jats:italic> < 0.001). LDL‐C was significantly associated with SVR for heterozygous <jats:italic>IL28B</jats:italic> genotype patients (<jats:italic>P</jats:italic> < 0.001) but not for homozygous genotypes. SVR modelling suggested that <jats:italic>IL28B</jats:italic> heterozygotes with LDL‐C > 130 mg/dL and HCV RNA ≤600 000 IU/mL may anticipate cure rates >80%, while the absence of these two criteria was associated with an SVR rate of <35%. <jats:italic>IL28B</jats:italic> polymorphisms are the only common genetic variants associated with pretreatment LDL‐C in G1‐HCV. LDL‐C remains significantly associated with SVR for heterozygous <jats:italic>IL28B</jats:italic> genotype patients, where LDL‐C and HCV RNA burden may identify those patients with high or low likelihood of cure with pegIFN/RBV therapy.</jats:p>