Genetic epidemiological data in hepatocellular carcinoma (HCC) pedigrees indicate a pattern of X-linked recessive inheritance of HCC susceptibility genes. This study is designed to test the hypothesis that there are genes conferring susceptibility to HCC located on the X-chromosome.

An X-chromosomal association study was conducted among Chinese men recruited from an area with a high prevalence of HCC. The candidate gene was further investigated by quantitative reverse transcription–polymerase chain reaction (qRT–PCR).

By analyzing 5454 X-chromosome single nucleotide polymorphisms (SNPs) in 50 HCC patients and 50 controls, we found two promising regions in which the associated SNPs clustered, located at Xq22.1 and Xq26.2. We further selected 35 tag SNPs (tSNPs) from these two regions for additional genotyping analysis in another independent set of 290 cases and 242 controls. Notably, SNP rs5945919 at Xq22.1 exhibited a significant association with HBV-related HCC (odds ratio [OR]=2.22, 95% confidence interval [CI]=1.15–4.30, P=0.016). The expressions of the three genes near the rs5945919 locus, RAB40AL, BEX1, and NXF3, were analyzed by qRT–PCR between another 24 HCC tissues and paired peritumoral liver tissues. The results indicated that NXF3, rather than RAB40AL and BEX1, mRNA level was found to be more abundant in HCC tissue than in peritumoral liver tissue.

Our findings implicated Xq22.1 as a novel susceptibility locus for HCC and NXF3 as a candidate risk factor for relevant HCC.