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The Association of Genetic Variants with Hepatic Steatosis in Patients with Genotype 1 Chronic Hepatitis C Infection

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An Erratum to this article was published on 12 July 2012

Abstract

Background

Single-nucleotide polymorphisms (SNPs) in the IL28B and PNPLA3 gene regions have been associated with hepatic steatosis in genotype 1 (G1) chronic HCV infection but their clinical impacts remain to be determined.

Aim

We sought to validate these associations and to explore their impact on treatment response to peginterferon and ribavirin therapy.

Methods

A total of 972 G1 HCV-infected Caucasian patients were genotyped for the SNPs rs12979860 (IL28B) and rs2896019 (PNPLA3). Multivariable analysis tested IL28B and PNPLA3 for association with the presence of any steatosis (>0 %); clinically significant steatosis (>5 %); steatosis severity (grade 0–3/4); and the interacting associations of the SNPs and hepatic steatosis to sustained viral response (SVR).

Results

IL28B and PNPLA3 polymorphisms were associated with the presence of any steatosis (rs12979860, p = 1.87 × 10−7; rs2896019, p = 7.56 × 10−4); clinically significant steatosis (rs12979860, p = 1.82 × 10−3; rs2896019, p = 1.27 × 10−4); and steatosis severity (rs12979860, p = 2.05 × 10−8; rs2896019, p = 2.62 × 10−6). Obesity, hypertriglyceridemia, hyperglycemia, liver fibrosis, and liver inflammation were all independently associated with worse steatosis. Hepatic steatosis was associated with lower SVR, and this effect was attenuated by IL28B. PNPLA3 had no independent association with SVR.

Conclusions

IL28B and PNPLA3 are associated with hepatic steatosis prevalence and severity in Caucasians with G1 HCV, suggesting differing potential genetic risk pathways to steatosis. IL28B attenuates the association between steatosis and SVR. Remediable metabolic risk factors remain important, independently of these polymorphisms, and remain key therapeutic goals to achieve better outcomes for patients with HCV-associated hepatic steatosis.

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Abbreviations

HCV:

Hepatitis C virus

SNP:

Single-nucleotide polymorphism

IL28B :

Interleukin 28B

PNPLA3 :

Patatin-like phospholipase domain-containing 3

G1:

Genotype 1

MVA:

Multivariable analysis

SVR:

Sustained viral response

NAFLD:

Non-alcoholic fatty liver disease

References

  1. Hourigan LF, Macdonald GA, Purdie D, et al. Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis. Hepatology. 1999;29:1215–1219.

    Article  PubMed  CAS  Google Scholar 

  2. Poynard T, Ratziu V, McHutchison J, et al. Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with hepatitis C. Hepatology. 2003;38:75–85.

    Article  PubMed  CAS  Google Scholar 

  3. Patton HM, Patel K, Behling C, et al. The impact of steatosis on disease progression and early and sustained treatment response in chronic hepatitis C patients. J Hepatol. 2004;40:484–490.

    Article  PubMed  Google Scholar 

  4. Hui JM, Kench J, Farrell GC, et al. Genotype-specific mechanisms for hepatic steatosis in chronic hepatitis C infection. J Gastroenterol Hepatol. 2002;17:873–881.

    Article  PubMed  Google Scholar 

  5. Fartoux L, Poujol-Robert A, Guéchot J, Wendum D, Poupon R, Serfaty L. Insulin resistance is a cause of steatosis and fibrosis progression in chronic hepatitis C. Gut. 2005;54:1003–1008.

    Article  PubMed  CAS  Google Scholar 

  6. Hu K-Q, Kyulo NL, Esrailian E, et al. Overweight and obesity, hepatic steatosis, and progression of chronic hepatitis C: a retrospective study on a large cohort of patients in the United States. J Hepatol. 2004;40:147–154.

    Article  PubMed  CAS  Google Scholar 

  7. Walls HL, Magliano DJ, Stevenson CE, et al. Projected progression of the prevalence of obesity in Australia. Obesity. 2012;20:872–878.

    Article  PubMed  Google Scholar 

  8. Wang Y, Beydoun MA. The obesity epidemic in the United States—gender, age, socioeconomic, racial/ethnic, and geographic characteristics: a systematic review and meta-regression analysis. Epidemiol Rev. 2007;29:6–28.

    Article  PubMed  CAS  Google Scholar 

  9. Thein HH, Walter SR, Gidding HF, et al. Trends in incidence of hepatocellular carcinoma after diagnosis of hepatitis B or C infection: a population-based cohort study, 1992–2007. J Viral Hepatitis. 2011;18:e232–e241.

    Article  CAS  Google Scholar 

  10. Sievert W, Altraif I, Razavi HA, et al. A systematic review of hepatitis C virus epidemiology in Asia, Australia and Egypt. Liver Int. 2011;31:61–80.

    Article  PubMed  Google Scholar 

  11. Cai T, Dufour JF, Muellhaupt B, et al. Viral genotype-specific role of PNPLA3, PPARG, MTTP, and IL28B in hepatitis C virus-associated steatosis. J Hepatol. 2011;55:529–535.

    Article  PubMed  CAS  Google Scholar 

  12. Tillmann HL, Patel K, Muir AJ, et al. Beneficial IL28B genotype associated with lower frequency of hepatic steatosis in patients with chronic hepatitis C. J Hepatol. 2011;55:1195–1200.

    Article  PubMed  CAS  Google Scholar 

  13. Romeo S, Kozlitina J, Xing C, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2008;40:1461–1465.

    Article  PubMed  CAS  Google Scholar 

  14. Sookoian S, Castano GO, Burgueno AL, Gianotti TF, Rosselli MS, Pirola CJ. A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity. J Lipid Res. 2009;50:2111–2116.

    Article  PubMed  CAS  Google Scholar 

  15. Speliotes EK, Butler JL, Palmer CD, Voight BF, Hirschhorn JN. PNPLA3 variants specifically confer increased risk for histologic nonalcoholic fatty liver disease but not metabolic disease. Hepatology. 2010;52:904–912.

    Article  PubMed  CAS  Google Scholar 

  16. Valenti L, Rumi M, Galmozzi E, et al. Patatin-Like phospholipase domain-containing 3 I148 M polymorphism, steatosis, and liver damage in chronic hepatitis C. Hepatology. 2011;53:791–799.

    Article  PubMed  CAS  Google Scholar 

  17. Trepo E, Pradat P, Potthoff A, et al. Impact of patatin-like phospholipase-3 (rs738409 C > G) polymorphism on fibrosis progression and steatosis in chronic hepatitis C. Hepatology. 2011;54:60–69.

    Article  PubMed  CAS  Google Scholar 

  18. McHutchison JG, Lawitz EJ, Shiffman ML, et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580–593.

    Article  PubMed  CAS  Google Scholar 

  19. Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. 2009;461:399–401.

    Article  PubMed  CAS  Google Scholar 

  20. Fellay J, Thompson AJ, Ge D, et al. ITPA gene variants protect against anaemia in patients treated for chronic hepatitis C. Nature. 2010;464:405–408.

    Article  PubMed  CAS  Google Scholar 

  21. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D. Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet. 2006;38:904–909.

    Article  PubMed  CAS  Google Scholar 

  22. Johnson AD, Handsaker RE, Pulit SL, Nizzari MM, O’Donnell CJ, de Bakker PIW. SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics. 2008;24:2938–2939.

    Article  PubMed  CAS  Google Scholar 

  23. The 1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature. 2010;467:1061–1073.

    Google Scholar 

  24. Purcell S, Neale B, Todd-Brown K, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–575.

    Article  PubMed  CAS  Google Scholar 

  25. Hickman IJ, Clouston AD, Macdonald GA, et al. Effect of weight reduction on liver histology and biochemistry in patients with chronic hepatitis C. Gut. 2002;51:89–94.

    Article  PubMed  CAS  Google Scholar 

  26. Appel LJ, Clark JM, Yeh H-C, et al. Comparative effectiveness of weight-loss interventions in clinical practice. N Engl J Med. 2011;365:1959–1968.

    Article  PubMed  CAS  Google Scholar 

  27. Monto A, Patel K, Bostrom A, et al. Risks of a range of alcohol intake on hepatitis C-related fibrosis. Hepatology. 2004;39:826–834.

    Article  PubMed  Google Scholar 

  28. Stickel F, Buch S, Lau K, et al. Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in Caucasians. Hepatology. 2011;53:86–95.

    Article  PubMed  CAS  Google Scholar 

  29. Trepo E, Gustot T, Degré D, et al. Common polymorphism in the PNPLA3/adiponutrin gene confers higher risk of cirrhosis and liver damage in alcoholic liver disease. J Hepatol. 2011;55:906–912.

    Article  PubMed  CAS  Google Scholar 

  30. Stickel F, Trepo E, Moreno C, Hampe J. Modulation of the effect of PNPLA3 I148M mutation on steatosis and liver damage by alcohol intake in patients with chronic hepatitis C. J Hepatol. 2011;55:1471–1472.

    Article  Google Scholar 

  31. Valenti L, Colombo M, Fargion S. Modulation of the effect of PNPLA3 I148M mutation on steatosis and liver damage by alcohol intake in patients with chronic hepatitis C. J Hepatol. 2011;55:1470–1471.

    Article  PubMed  Google Scholar 

  32. Younossi ZM, Afendy A, Stepanova M, et al. Gene expression profile associated with superimposed non-alcoholic fatty liver disease and hepatic fibrosis in patients with chronic hepatitis C. Liver Int. 2009;29:1403–1412.

    Article  PubMed  CAS  Google Scholar 

  33. Honda M, Sakai A, Yamashita T, et al. Hepatic ISG expression is associated with genetic variation in interleukin 28B and the outcome of IFN therapy for chronic hepatitis C. Gastroenterology. 2010;139:499–509.

    Article  PubMed  CAS  Google Scholar 

  34. Urban TJ, Thompson AJ, Bradrick SS, et al. IL28B genotype is associated with differential expression of intrahepatic interferon-stimulated genes in patients with chronic hepatitis C. Hepatology. 2010;52:1888–1896.

    Article  PubMed  CAS  Google Scholar 

  35. Dill MT, Duong FHT, Vogt JE, et al. Interferon-induced gene expression is a stronger predictor of treatment response than IL28B genotype in patients with hepatitis C. Gastroenterology. 2011;140:1021e1010–1031e1010.

    Article  Google Scholar 

  36. Valenti L, Aghemo A, Stattermayer AF. Interaction between IL28B and PNPLA3 genotypes in the pathogenesis of steatosis in chronic hepatitis C non genotype-3 patients. J Hepatol. 2012;56:1209–1210.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors would like to thank the patients in the IDEAL trial as well as the principal investigators, study coordinators, and nurses involved. The authors thank Megan Koehler, DCRI for her statistical review. The study was funded by Schering-Plough Research Institute, Kenilworth, NJ (now Merck and Co.). Drs. Clark and Thompson received funding support from the Duke Clinical Research Institute, the Richard Boebel Family Fund, the National Health and Medical Research Council of Australia (PJC: APP1017139), the Gastroenterological Society of Australia. Dr Thompson received funding from the Royal Australian College of Physicians. Dr. Clark received funding from the National Centre in HIV Epidemiology and Clinical Research (now The Kirby Institute for Infection and Immunity in Society), University of New South Wales, Australia, and the AASLD/LIFER Clinical and Translational Research Fellowship in Liver Diseases Award.

Conflict of interest

The authors disclose the following: Drs. Thompson, Harrison, Sulkowski, Afdhal, McHutchison and Muir report having received research and grant support from Schering-Plough (now Merck); Drs Afdhal, Harrison, McHutchison, Goldstein and Muir have received consulting fees or acted in an advisory capacity for Schering-Plough or Merck. Dr Harrison has received grant and research support from Genentech, Merck, and Rottapharm, worked in an advisory capacity for Three Rivers Pharmaceuticals and Amylin and for speaker’s bureau for Bristol Myers Squibb and Merck. Drs Albrecht and Pedicone are employees of Schering-Plough (now Merck & Co.) and are stockholders in this entity. Dr McHutchison is now employed by Gilead Sciences. Dr Noviello is a former employee of Schering-Plough and is now a consultant to Merck & Co. Drs. Thompson, Ge, Urban, McHutchison and Goldstein are co-inventors of a patent application based on the IL28B finding.

Author information

Authors and Affiliations

  1. Duke Clinical Research Institute, Duke University, PO Box 17969, Durham, NC, 27715, USA

    Paul J. Clark, Alexander J. Thompson, David M. Vock, Keyur Patel, Susanna Naggie, Hans L. Tillmann, John G. McHutchison & Andrew J. Muir

  2. Center for Human Genome Variation, Duke University, Durham, NC, USA

    Qianqian Zhu, Mingfu Zhu, Dongliang Ge, Thomas J. Urban, Kevin Shianna, Jacques Fellay & David B. Goldstein

  3. Brooke Army Medical Center, Fort Sam Houston, TX, USA

    Stephen A. Harrison

  4. Armed Forces Institute of Pathology, Washington, DC, USA

    Zachary Goodman

  5. Schering-Plough Corporation (now Merck & Co., Inc.), Whitehouse Station, NJ, USA

    Stephanie Noviello, Lisa D. Pedicone & Janice K. Albrecht

  6. Beth Israel Deaconess Medical Center, Boston, MA, USA

    Nezam Afdhal

  7. Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Mark Sulkowski

  8. Kirby Institute for Infection and Immunity in Society, University of New South Wales, Kensington, Australia

    Paul J. Clark

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  1. Paul J. Clark
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  2. Alexander J. Thompson
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Corresponding author

Correspondence to Paul J. Clark.

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Clark, P.J., Thompson, A.J., Zhu, Q. et al. The Association of Genetic Variants with Hepatic Steatosis in Patients with Genotype 1 Chronic Hepatitis C Infection. Dig Dis Sci 57, 2213–2221 (2012). https://doi.org/10.1007/s10620-012-2171-y

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  • DOI: https://doi.org/10.1007/s10620-012-2171-y

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