title: 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.
abstract: Low-density lipoprotein cholesterol (LDL-C) levels and interleukin 28B (IL28B) polymorphism are associated with sustained viral response (SVR) to peginterferon/ribavirin (pegIFN/RBV) for chronic hepatitis C (CHC) infection. IL28B 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. IL28B polymorphisms were the only common genetic variants associated with pretreatment LDL-C level in Caucasians (rs12980275, P = 4.7 × 10(-17), poor response IL28B variants associated with lower LDL-C). The association was dependent on HCV infection, IL28B genotype was no longer associated with LDL-C in SVR patients after treatment, while the association remained significant in non-SVR patients (P < 0.001). LDL-C was significantly associated with SVR for heterozygous IL28B genotype patients (P < 0.001) but not for homozygous genotypes. SVR modelling suggested that IL28B 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%. IL28B polymorphisms are the only common genetic variants associated with pretreatment LDL-C in G1-HCV. LDL-C remains significantly associated with SVR for heterozygous IL28B genotype patients, where LDL-C and HCV RNA burden may identify those patients with high or low likelihood of cure with pegIFN/RBV therapy.
authors.affiliation: Duke Clinical Research Institute, Duke University, Durham, NC 27715, USA. paul.clark@dm.duke.edu
authors.forename: P J
authors.initials: PJ
authors.lastname: Clark
authors.forename: A J
authors.initials: AJ
authors.lastname: Thompson
authors.forename: M
authors.initials: M
authors.lastname: Zhu
authors.forename: D M
authors.initials: DM
authors.lastname: Vock
authors.forename: Q
authors.initials: Q
authors.lastname: Zhu
authors.forename: D
authors.initials: D
authors.lastname: Ge
authors.forename: K
authors.initials: K
authors.lastname: Patel
authors.forename: S A
authors.initials: SA
authors.lastname: Harrison
authors.forename: T J
authors.initials: TJ
authors.lastname: Urban
authors.forename: S
authors.initials: S
authors.lastname: Naggie
authors.forename: J
authors.initials: J
authors.lastname: Fellay
authors.forename: H L
authors.initials: HL
authors.lastname: Tillmann
authors.forename: K
authors.initials: K
authors.lastname: Shianna
authors.forename: S
authors.initials: S
authors.lastname: Noviello
authors.forename: L D
authors.initials: LD
authors.lastname: Pedicone
authors.forename: R
authors.initials: R
authors.lastname: Esteban
authors.forename: P
authors.initials: P
authors.lastname: Kwo
authors.forename: M S
authors.initials: MS
authors.lastname: Sulkowski
authors.forename: N
authors.initials: N
authors.lastname: Afdhal
authors.forename: J K
authors.initials: JK
authors.lastname: Albrecht
authors.forename: D B
authors.initials: DB
authors.lastname: Goldstein
authors.forename: J G
authors.initials: JG
authors.lastname: McHutchison
authors.forename: A J
authors.initials: AJ
authors.lastname: Muir
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage*; D008078:Cholesterol, LDL / Q000097:blood*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D016174:Hepacivirus / Q000145:classification* / Q000235:genetics / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007372:Interferons / Q000008:administration & dosage*; D007378:Interleukins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012254:Ribavirin / Q000008:administration & dosage; D016896:Treatment Outcome; D019562:Viral Load; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D008078:Cholesterol, LDL; D007372:Interferons; D007378:Interleukins; D012254:Ribavirin; C000624353:interferon-lambda, human; D000095022:Interferon Lambda