Genetic variations in death receptor domain 4 gene and the susceptibility to hepatitis C related hepatocellular carcinoma.

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide, particularly in Egypt. The role of apoptosis in tumorigenesis has been well-documented and resistance to apoptosis is a hallmark of cancer. Several studies discussed the association between death receptor 4 (DR4) genetic variants and HCC risk. To study the possible link between DR4 gene polymorphisms and the susceptibility to HCC. Genotyping of DR4-C626G, -A683C, and DR4-A1322G single nucleotide polymorphisms (SNP) was determined by polymerase chain reaction assay for 100 de novo HCV-related HCC patients, 100 chronic hepatitis C-related liver cirrhosis patients, and 150 healthy controls. DR4-A1322G polymorphic genotypes (AG and GG) were significantly higher in HCC and cirrhotic patients than controls. The AG genotype conferred two-fold increased risk of HCC (odds ratio [OR],2.34; 95% confidence interval [CI], 1.56-3.51) and the risk increased to three-fold for the GG genotype (OR,3.51; 95%CI, 2.33-5.28). The frequency of DR4-C626G and -A683C SNPs in HCC and cirrhotic patients were not significantly different from the controls. Combined genotype analysis showed that coinheritance of the polymorphic genotypes of DR4-C626G and -A1322G conferred nine-fold increased risk of HCC (OR,9.34; 95%CI, 3.76-23.12). The risk increased to be 12-fold when DR4-A683C and -A1322G variants were coinherited (OR,11.9; 95%CI,4.82-29.39). Coexistence of the variant genotypes of the three SNPs conferred almost 10-foldincreased risk of HCC (OR,9.75; 95%CI, 1.86-51.19). The G allele of DR4 -A1322G could be considered as a novel independent molecular predictor for HCV-related HCC in the Egyptian population.