Genomic variants link to hepatitis C racial disparities

Abstract

Chronic liver diseases are one of the major public health issues in United States, and there are substantial racial disparities in liver cancer-related mortality. We previously identified racially distinct alterations in the expression of transcripts and proteins of hepatitis C (HCV)-induced hepatocellular carcinoma (HCC) between Caucasian (CA) and African American (AA) subgroups. Here, we performed a comparative genome-wide analysis of normal vs. HCV+ (cirrhotic state), and normal adjacent tissues (HCCN) vs. HCV+HCC (tumor state) of CA at the gene and alternative splicing levels using Affymetrix Human Transcriptome Array (HTA2.0). Many genes and splice variants were abnormally expressed in HCV+ more than in HCV+HCC state compared with normal tissues. Known biological pathways related to cell cycle regulations were altered in HCV+HCC, whereas acute phase reactants were deregulated in HCV+ state. We confirmed by quantitative RT-PCR that SAA1, PCNAAS1, DAB2, and IFI30 are differentially deregulated, especially in AA compared with CA samples. Likewise, IHC staining analysis revealed altered expression patterns of SAA1 and HNF4a isoforms in HCV+ liver samples of AA compared with CA. These results demonstrate that several splice variants are primarily deregulated in normal vs. HCV+ stage, which is certainly in line with the recent observations showing that the premRNA splicing machinery may be profoundly remodeled during disease progression, and may, therefore, play a major role in HCV racial disparity. The confirmation that certain genes are deregulated in AA compared to CA tissues also suggests that there is a biological basis for the observed racial disparities.