SNPs in the promoter region of the osteopontin gene as a possible host factor for sex difference in hepatocellular carcinoma development in patients with HCV.

Abstract

Four single nucleotide polymorphisms (SNPs) exist in the promoter region of the osteopontin (OPN) gene, namely, the SNPs at nucleotide (nt) -155, -616, and -1748 showing linkage disequilibrium to each other, and an independent SNP at nt -443. The significance of these SNPs in the risk of hepatocellular carcinoma (HCC) development was examined in patients with hepatitis C virus (HCV). The SNPs at nt -155 and nt -443 were analyzed in 120 patients with HCC. The promoter activity was measured in HepG2 cells by the dual-luciferase reporter assay. The electrophoretic mobility shift assay was performed using nuclear extracts from the cells. Peripheral platelet counts at the time of HCC detection were greater in women with homozygous deletion at nt -155 and C/C or C/T at nt -443 than in those showing other allelic combinations, while no such difference was observed in men. The promoter activity was greater in oligonucleotides with deletions at nt -155 and C at nt -443 than in those with other haplotypes. The mobility shift assay showed double and single complexes with oligonucleotides around nt -155 and nt -443, respectively. Binding activities were greater in deletion than in G in the case of the retarded complex in the former assay and in T than in C in the latter assay. The other complex in the former assay included SRY, showing an equivalent binding activity to oligonucleotides with both alleles. OPN promoter SNPs may play a role in the sexual difference in the risk of HCC development through the regulation of OPN expression in patients with HCV.