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

Background 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. Aim To study the possible link between DR4 gene polymorphisms and the susceptibility to HCC. Methods 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. Results 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‐fold increased risk of HCC (OR, 9.75; 95%CI, 1.86‐51.19). Conclusions The G allele of DR4 ‐A1322G could be considered as a novel independent molecular predictor for HCV‐related HCC in the Egyptian population.