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

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. 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. 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. 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.