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

Paul J. Clark, A. J. Thompson, M. Zhu, D. M. Vock, Q. Zhu, D. Ge, K. Patel, S. A. Harrison, T. J. Urban, S. Naggie, J. Fellay, H. L. Tillmann, K. Shianna, S. Noviello, L. D. Pedicone, R. Esteban, P. Kwo, M. S. Sulkowski, N. Afdhal, J. K. Albrecht & 3 others D. B. Goldstein, J. G. McHutchison, A. J. Muir

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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.

Original languageEnglish
Pages (from-to)332-340
Number of pages9
JournalJournal of Viral Hepatitis
Volume19
Issue number5
DOIs
StatePublished - May 2012

Fingerprint

Interleukins
Chronic Hepatitis C
LDL Cholesterol
Genotype
Hepacivirus
Therapeutics
Ribavirin
Virus Diseases
RNA
Genome-Wide Association Study
Triglycerides
Lipids

Keywords

  • Cholesterol
  • Hepatitis C virus
  • Interleukin 28B
  • Lipids
  • Sustained viral response

ASJC Scopus subject areas

  • Hepatology
  • Infectious Diseases
  • Virology

Cite this

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. / Clark, Paul J.; Thompson, A. J.; Zhu, M.; Vock, D. M.; Zhu, Q.; Ge, D.; Patel, K.; Harrison, S. A.; Urban, T. J.; Naggie, S.; Fellay, J.; Tillmann, H. L.; Shianna, K.; Noviello, S.; Pedicone, L. D.; Esteban, R.; Kwo, P.; Sulkowski, M. S.; Afdhal, N.; Albrecht, J. K.; Goldstein, D. B.; McHutchison, J. G.; Muir, A. J.

In: Journal of Viral Hepatitis, Vol. 19, No. 5, 05.2012, p. 332-340.

Research output: Contribution to journalArticle

Clark, PJ, Thompson, AJ, Zhu, M, Vock, DM, Zhu, Q, Ge, D, Patel, K, Harrison, SA, Urban, TJ, Naggie, S, Fellay, J, Tillmann, HL, Shianna, K, Noviello, S, Pedicone, LD, Esteban, R, Kwo, P, Sulkowski, MS, Afdhal, N, Albrecht, JK, Goldstein, DB, McHutchison, JG & Muir, AJ 2012, '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', Journal of Viral Hepatitis, vol. 19, no. 5, pp. 332-340. https://doi.org/10.1111/j.1365-2893.2011.01553.x
Clark, Paul J. ; Thompson, A. J. ; Zhu, M. ; Vock, D. M. ; Zhu, Q. ; Ge, D. ; Patel, K. ; Harrison, S. A. ; Urban, T. J. ; Naggie, S. ; Fellay, J. ; Tillmann, H. L. ; Shianna, K. ; Noviello, S. ; Pedicone, L. D. ; Esteban, R. ; Kwo, P. ; Sulkowski, M. S. ; Afdhal, N. ; Albrecht, J. K. ; Goldstein, D. B. ; McHutchison, J. G. ; Muir, A. J. / 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. In: Journal of Viral Hepatitis. 2012 ; Vol. 19, No. 5. pp. 332-340.
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T1 - 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

AU - Clark, Paul J.

AU - Thompson, A. J.

AU - Zhu, M.

AU - Vock, D. M.

AU - Zhu, Q.

AU - Ge, D.

AU - Patel, K.

AU - Harrison, S. A.

AU - Urban, T. J.

AU - Naggie, S.

AU - Fellay, J.

AU - Tillmann, H. L.

AU - Shianna, K.

AU - Noviello, S.

AU - Pedicone, L. D.

AU - Esteban, R.

AU - Kwo, P.

AU - Sulkowski, M. S.

AU - Afdhal, N.

AU - Albrecht, J. K.

AU - Goldstein, D. B.

AU - McHutchison, J. G.

AU - Muir, A. J.

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N2 - 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.

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KW - Cholesterol

KW - Hepatitis C virus

KW - Interleukin 28B

KW - Lipids

KW - Sustained viral response

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