Advertisement

PNPLA3 Gene Polymorphisms in HCV/HIV-Coinfected Individuals

  • Kenneth E. Sherman
  • Susan D. Rouster
  • Minhee Kang
  • Triin Umbleja
  • Richard Sterling
  • Adeel A. Butt
  • For the ACTG 5294 BIRTH Study Team
Original Article

Abstract

Background and Aims

The patatin-like phospholipase domain-containing 3 (PNPLA3) gene has been associated with the development of alcoholic and nonalcoholic steatohepatitis. Using a newly developed and validated assay for PNPLA3, we explored the prevalence of gene polymorphisms in a cohort of HCV/HIV-coinfected individuals to determine whether there was an association with insulin resistance or hepatic fibrosis.

Methods

A high-resolution melting point (HRM) assay was developed and validated. The assay was used to evaluate samples obtained in the context of a clinical trial performed at ACTG sites across the USA in HIV-infected patients. Clinical features and treatment outcomes were assessed in relation to the PNPLA3 genotype.

Results

The HRM methodology demonstrated 100% concordance with results obtained by Sanger sequencing. Among 241 participants tested, 66.0% had the wild-type allele (CC) and the remainder had the aberrant PNPLA3 gene polymorphism in the homozygotic (GG) or heterozygotic (CG) form. Race and ethnicity were associated with PNPLA3 genotype but fibrosis stage, Homeostatic Model Assessment of Insulin Resistance, and HCV treatment outcome were not.

Conclusion

The HRM method is an effective, rapid technique for characterizing PNPLA3 genotype. In those with HCV/HIV infection, nearly 40% carry gene polymorphisms associated with the development of NASH or ASH. Prospective studies should focus on this group to determine whether they represent a subset of HIV-infected persons at increased risk of fibrotic progression.

Keywords

Patatin-like Human immunodeficiency AIDS Fibrosis Steatosis 

Notes

Acknowledgments

ACTG 5294 Supplement Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number UM1 AI068634, UM1 AI068636, and UM1 AI106701.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Sherman KE, Rockstroh J, Thomas D. Human immunodeficiency virus and liver disease: an update. Hepatology. 2015;62:1871–1882.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Valenti L, Al-Serri A, Daly AK, et al. Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatology. 2010;51:1209–1217.CrossRefPubMedGoogle Scholar
  3. 3.
    Seth D, Daly AK, Haber PS, Day CP. Patatin-like phospholipase domain containing 3: a case in point linking genetic susceptibility for alcoholic and nonalcoholic liver disease. Hepatology. 2010;51:1463–1465.CrossRefPubMedGoogle Scholar
  4. 4.
    Romeo S, Huang-Doran I, Baroni MG, Kotronen A. Unravelling the pathogenesis of fatty liver disease: patatin-like phospholipase domain-containing 3 protein. Curr Opin Lipidol. 2010;21:247–252.CrossRefPubMedGoogle Scholar
  5. 5.
    Santoro N, Kursawe R, D’Adamo E, et al. A common variant in the patatin-like phospholipase 3 gene (PNPLA3) is associated with fatty liver disease in obese children and adolescents. Hepatology. 2010;52:1281–1290.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Price JC, Seaberg EC, Latanich R, et al. Risk factors for fatty liver in the multicenter AIDS cohort study. Am J Gastroenterol. 2014;109:695–704.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Enache EL, Sin A, Bancu L, et al. Duplex high-resolution melting assay for the simultaneous genotyping of IL28B rs12979860 and PNPLA3 rs738409 polymorphisms in chronic hepatitis C patients. Int J Mol Sci. 2015;16:22223–22242.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Sherman KE, Kang M, Sterling R, et al. Phase 3 trial of first generation protease inhibitor therapy for hepatitis C virus/human immunodeficiency virus coinfection. World J Hepatol. 2017;9:217–223.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43:1317–1325.CrossRefPubMedGoogle Scholar
  10. 10.
    Speliotes EK, Yerges-Armstrong LM, Wu J, et al. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet. 2011;7:e1001324.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    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.CrossRefPubMedGoogle Scholar
  12. 12.
    Dold L, Luda C, Schwarze-Zander C, et al. Genetic polymorphisms associated with fatty liver disease and fibrosis in HIV positive patients receiving combined antiretroviral therapy (cART). PLoS ONE. 2017;12:e0178685.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Jimenez-Sousa MA, Berenguer J, Garcia-Alvarez M, et al. Impact of patatin-like phospholipase domain-containing 3 gene polymorphism (rs738409) on severity of liver disease in HIV/hepatitis C virus-coinfected patients. Aids. 2016;30:465–470.CrossRefPubMedGoogle Scholar
  14. 14.
    Fan JH, Xiang MQ, Li QL, Shi HT, Guo JJ. PNPLA3 rs738409 polymorphism associated with hepatic steatosis and advanced fibrosis in patients with chronic hepatitis C virus: a meta-analysis. Gut Liver. 2016;10:456–463.CrossRefPubMedGoogle Scholar
  15. 15.
    Chitturi S, Abeygunasekera S, Farrell GC, et al. NASH and insulin resistance: Insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology. 2002;35:373–379.CrossRefPubMedGoogle Scholar
  16. 16.
    Nunez-Torres R, Macias J, Mancebo M, et al. The PNPLA3 genetic variant rs738409 influences the progression to cirrhosis in HIV/hepatitis C virus coinfected patients. PLoS ONE. 2016;11:e0168265.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Scheiner B, Mandorfer M, Schwabl P, et al. The impact of PNPLA3 rs738409 SNP on liver fibrosis progression, portal hypertension and hepatic steatosis in HIV/HCV coinfection. PLoS ONE. 2015;10:e0143429.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Chen L, Du S, Lu L, et al. The additive effects of the TM6SF2 E167K and PNPLA3 I148M polymorphisms on lipid metabolism. Oncotarget. 2017;8:74209–74216.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Kenneth E. Sherman
    • 1
  • Susan D. Rouster
    • 1
  • Minhee Kang
    • 2
  • Triin Umbleja
    • 2
  • Richard Sterling
    • 4
    • 5
  • Adeel A. Butt
    • 3
  • For the ACTG 5294 BIRTH Study Team
  1. 1.Division of Digestive DiseasesUniversity of Cincinnati College of MedicineCincinnatiUSA
  2. 2.Harvard TH Chan School of Public HealthBostonUSA
  3. 3.Virginia Commonwealth UniversityRichmondUSA
  4. 4.Weill Cornell Medical CollegeNew YorkUSA
  5. 5.DohaQatar

Personalised recommendations