Systematical analyses of variants in DNase I hypersensitive sites to identify hepatocellular carcinoma susceptibility loci in a Chinese population.

BACKGROUND AND AIM: Although several variants located at coding and non-coding regions were evaluated by previous studies, the evidence for associations between variants located in DNase I-hypersensitive sites (DHSs) and hepatocellular carcinoma (HCC) risk was still limited. Recent advances using ENCODE data indicated that genetic variants in DHSs played an important role in carcinogenesis. Therefore, systematically investigating the associations between regulatory variants in DHSs and HCC risk should be put on the agenda.

METHODS: We conducted a case-control design (1538 HCC cases vs 1465 normal controls) to evaluate the effects on HCC for the variants located at the uniform DNase I hypersensitive sites sequencing peaks in a Chinese population.

RESULTS: We found two novel single nucleotide polymorphisms rs12309362 (odds ratio = 0.64, P = 5.61 × 10-6 ) and rs9970827 (odds ratio = 0.73, P = 7.23 × 10-6 ) significantly associated with decreased risk of HCC. Conditional analysis proved that both of them independently contributed to the susceptibility of HCC. Expression quantitative trait loci analysis found that A allele of rs12309362 was significantly associated with an elevated expression of phosphatase phosphoglycerate mutase 5 in liver tissues. In addition, gene-based analysis indicated that CEBPB (P = 1 × 10-4 ) was associated with the risk of HCC, and the expression of CEBPB was significantly lower in 50 The Cancer Genome Atlas HCC tumor tissues compared with matched normal tissues.

CONCLUSIONS: Our results indicated that rs12309362 (G > A), rs9970827 (A > G) in DHSs, and elevated expression of CEBPB were associated with a decreased risk of HCC. These results may contribute us to understand the function of regulatory DNA sequences in HCC development.