Digestive Diseases and Sciences

, Volume 57, Issue 8, pp 2213–2221

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

  • Paul J. Clark
  • Alexander J. Thompson
  • Qianqian Zhu
  • David M. Vock
  • Mingfu Zhu
  • Keyur Patel
  • Stephen A. Harrison
  • Susanna Naggie
  • Dongliang Ge
  • Hans L. Tillmann
  • Thomas J. Urban
  • Kevin Shianna
  • Jacques Fellay
  • Zachary Goodman
  • Stephanie Noviello
  • Lisa D. Pedicone
  • Nezam Afdhal
  • Mark Sulkowski
  • Janice K. Albrecht
  • David B. Goldstein
  • John G. McHutchison
  • Andrew J. Muir
Original Article

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.

Keywords

Polymorphism, single-nucleotide, SNP IL28B protein, human PNPLA3 protein, human Adiponutrin, human Fatty liver Abdominal obesity metabolic syndrome 

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

Supplementary material

10620_2012_2171_MOESM1_ESM.doc (89 kb)
Supplementary material 1 (DOC 89 kb)

References

  1. 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.PubMedCrossRefGoogle Scholar
  2. 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.PubMedCrossRefGoogle Scholar
  3. 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.PubMedCrossRefGoogle Scholar
  4. 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.PubMedCrossRefGoogle Scholar
  5. 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.PubMedCrossRefGoogle Scholar
  6. 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.PubMedCrossRefGoogle Scholar
  7. 7.
    Walls HL, Magliano DJ, Stevenson CE, et al. Projected progression of the prevalence of obesity in Australia. Obesity. 2012;20:872–878.PubMedCrossRefGoogle Scholar
  8. 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.PubMedCrossRefGoogle Scholar
  9. 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.CrossRefGoogle Scholar
  10. 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.PubMedCrossRefGoogle Scholar
  11. 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.PubMedCrossRefGoogle Scholar
  12. 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.PubMedCrossRefGoogle Scholar
  13. 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.PubMedCrossRefGoogle Scholar
  14. 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.PubMedCrossRefGoogle Scholar
  15. 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.PubMedCrossRefGoogle Scholar
  16. 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.PubMedCrossRefGoogle Scholar
  17. 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.PubMedCrossRefGoogle Scholar
  18. 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.PubMedCrossRefGoogle Scholar
  19. 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.PubMedCrossRefGoogle Scholar
  20. 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.PubMedCrossRefGoogle Scholar
  21. 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.PubMedCrossRefGoogle Scholar
  22. 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.PubMedCrossRefGoogle Scholar
  23. 23.
    The 1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature. 2010;467:1061–1073.Google Scholar
  24. 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.PubMedCrossRefGoogle Scholar
  25. 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.PubMedCrossRefGoogle Scholar
  26. 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.PubMedCrossRefGoogle Scholar
  27. 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.PubMedCrossRefGoogle Scholar
  28. 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.PubMedCrossRefGoogle Scholar
  29. 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.PubMedCrossRefGoogle Scholar
  30. 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.CrossRefGoogle Scholar
  31. 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.PubMedCrossRefGoogle Scholar
  32. 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.PubMedCrossRefGoogle Scholar
  33. 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.PubMedCrossRefGoogle Scholar
  34. 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.PubMedCrossRefGoogle Scholar
  35. 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.CrossRefGoogle Scholar
  36. 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.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Paul J. Clark
    • 1
    • 8
  • Alexander J. Thompson
    • 1
  • Qianqian Zhu
    • 2
  • David M. Vock
    • 1
  • Mingfu Zhu
    • 2
  • Keyur Patel
    • 1
  • Stephen A. Harrison
    • 3
  • Susanna Naggie
    • 1
  • Dongliang Ge
    • 2
  • Hans L. Tillmann
    • 1
  • Thomas J. Urban
    • 2
  • Kevin Shianna
    • 2
  • Jacques Fellay
    • 2
  • Zachary Goodman
    • 4
  • Stephanie Noviello
    • 5
  • Lisa D. Pedicone
    • 5
  • Nezam Afdhal
    • 6
  • Mark Sulkowski
    • 7
  • Janice K. Albrecht
    • 5
  • David B. Goldstein
    • 2
  • John G. McHutchison
    • 1
  • Andrew J. Muir
    • 1
  1. 1.Duke Clinical Research InstituteDuke UniversityDurhamUSA
  2. 2.Center for Human Genome VariationDuke UniversityDurhamUSA
  3. 3.Brooke Army Medical CenterFort Sam HoustonUSA
  4. 4.Armed Forces Institute of PathologyWashingtonUSA
  5. 5.Schering-Plough Corporation (now Merck & Co., Inc.)Whitehouse StationUSA
  6. 6.Beth Israel Deaconess Medical CenterBostonUSA
  7. 7.Johns Hopkins University School of MedicineBaltimoreUSA
  8. 8.Kirby Institute for Infection and Immunity in SocietyUniversity of New South WalesKensingtonAustralia

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