A functional insertion/deletion polymorphism in the promoter of PDCD6IP is associated with the susceptibility of hepatocellular carcinoma in a Chinese population.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Apart from environmental factors such as hepatitis B virus (HBV) or hepatitis C virus, alcohol abuse, and exposure to dietary aflatoxin, genetic factors are also involved in the pathogenesis of HCC. By analyzing 390 HCC cases and 431 healthy controls in a Chinese population, we used a candidate gene approach to evaluate the association between a 15-bp insertion/deletion (indel) polymorphism (rs28381975) in the promoter region of the programmed cell death 6 interacting protein (PDCD6IP) gene and HCC susceptibility. Logistic regression analysis demonstrated that subjects carrying ins/del or ins/ins genotypes had significantly increased risk for HCC than individuals carrying del/del genotypes (adjusted odds ratio=1.39, 95% confidence interval=1.01-1.91, p=0.033]. Carrying the 15-bp insertion allele was associated with a 1.26-fold risk for HCC (95% CI=1.04-1.54, p=0.018). Moreover, significant differences were observed within HCC patients concerning genotypic frequencies of rs28381975 after stratifying by tumor stages and HBV infection. Computational modeling suggests that rs28381975 could disrupt the binding patterns of c-rel, a key subunit of nuclear factor-kappaB transcription factor. Further luciferase-based transient transfection assays revealed that rs28381975 can affect the promoter activity of PDCD6IP, indicating its possible functional significance. Taken together, our data suggest that common genetic variations in PDCD6IP may influence HCC risk, possibly through promoter activity-mediated regulation. Replication of our studies in other populations and further functional analysis will strengthen our understanding of this association.