Genetic Variations in Heme Oxygenase-1 and Chronic Hepatitis
Authors: Herbert L. Bonkovsky, Richard W. Lambrecht, Deepa Naishadham
Journal: Hepatology (2010)

We read with interest the recent article by Lehmann et al. in Hepatology,1 showing that biliverdin decreased expression of hepatitis C virus (HCV) genes in cell lines expressing HCV replicons. Heme oxygenase-1 (HMOX1), which catalyzes the rate-controlling step of heme catabolism, with formation of equimolar amounts of biliverdin, carbon monoxide, and iron, is recognized to be a key cytoprotective and antioxidant enzyme.2, 3 Although the HMOX1 gene is up-regulated by many stressful stimuli, including increased oxidative stress,2, 3 its activity has been reported to be low in livers of subjects with chronic hepatitis C,4 even though this is a condition characterized by increased hepatic oxidative stress.5 Genetic variations in the promoter region of the HMOX1 genes, including the A/T polymorphism at position −413 and the length of (GT)n repeats closer to the transcription starting point, have been reported to influence HMOX1 gene expression. Specifically, variants associated with higher activities of HMOX1 (the −413 A allele and shorter lengths of (GT)n repeats [n ≤ 27]) correlate with less severe chronic inflammatory diseases, including chronic obstructive pulmonary disease, coronary artery disease, diabetes mellitus, and arthritis.3 We hypothesized that carriage of genetic variants associated with higher HMOX1 gene expression would be associated with slower progression and/or better outcomes of advanced chronic hepatitis C. To test this hypothesis, we performed genetic analyses on DNA obtained from 1106 subjects (849 non-Hispanic Caucasians; 166 African-Americans; 91 Hispanic Caucasians) in the HALT-C (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis) Trial.6, 7 Assays for the −413 A/T genetic variation and for lengths of GT repeats were performed as described.8, 9 Results were correlated with demographic and clinical features and clinical outcomes, by using SAS software, version 9.1 (SAS Inc., Cary, NC). Genetic results are summarized in Table 1. The frequency distributions of the genetic variations among Caucasians studied did not differ significantly from those previously described in European Caucasian cohorts.8, 9 The distributions adhered to Hardy-Weinberg equilibrium. It is noteworthy that Caucasians, who respond better to interferon and ribavirin than do African Americans, had significantly higher frequencies of −413 A/A and of short-short (SS) or short-long (SL) GT repeats, both of which are associated with higher activities of HMOX1.8, 9 After controlling for race/ethnicity or therapy, there were no significant correlates of the genetic variations on responses to lead-in therapy or to the likelihood of developing outcomes. The odds ratios for relative likelihood of sustained virological response for SS (versus long-long [LL]) was 0.77 (95% confidence interval [CI] = 0.43-1.34) and for likelihood of experiencing a primary outcome was 1.49 (95% CI = 0.88-2.52). The odds ratio for −413 AA versus TT and for combinations of AA + SS or AT + SS also were nonsignificant (1.76-2.30 with CI ranges = 0.5-6.16 and 0.71-8.38). Thus, in the United States, among Caucasian or African-American subjects with advanced chronic hepatitis C, genetic variations in the HMOX1 gene promoter are not predictive of responsiveness to antiviral therapy or risks of outcomes of HCV infection. Whether up-regulation of HMOX1 activity or excess biliverdin may be useful as adjunct therapy of HCV infection is an unresolved issue. Herbert L. Bonkovsky*, Richard W. Lambrecht , Deepa Naishadham , * Carolinas Medical Center, Charlotte, NC, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, New England Research Institutes, Watertown, MA.