Background Recently, several studies have demonstrated that two long non-coding RNAs (lncRNAs), HULC and MALAT1, may participate in hepatocellular carcinoma (HCC) development and progression. However, genetic variations in the two lncRNAs and their associations with HCC susceptibility have not been reported. In this study, we hypothesized that single nucleotide polymorphisms (SNPs) in HULC and MALAT1 may contribute to HCC risk. Methods We conducted a case-control study and genotyped two SNPs, rs7763881 in HULC and rs619586 in MALAT1, in 1300 HBV positive HCC patients, 1344 HBV persistent carriers and 1344 subjects with HBV natural clearance to test the associations between the two SNPs and susceptibility to HCC and HBV chronic infection. Results The variant genotypes of rs7763881 were significantly associated with decreased HCC risk in a dominant genetic model [AC/CC vs. AA: adjusted odds ration (OR) = 0.81, 95% confidence intervals (CIs) = 0.68–0.97, P = 0.022]. Furthermore, the variant genotypes of rs619586 was associated with decreased HCC risk with a borderline significance (AG/GG vs. AA: adjusted OR = 0.81, 95% CIs = 0.65–1.01, P = 0.057). However, no significant association was found between the two SNPs and HBV clearance. Conclusions The variant genotypes of rs7763881 in HULC may contribute to decreased susceptibility to HCC in HBV persistent carriers.
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