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Accumulated evidences indicate that single nucleotide polymorphisms (SNP) are associated with risk of hepatocellular carcinoma (HCC). Activating transcription factor 6 (ATF6) is an important modulator of the unfolded protein response (UPR), which is regarded to be involved in carcinogenesis. So we speculate that SNPs in ATF6 may be associated with susceptibility to HCC. We carried out a two-stage association study in three independent case–control groups in a total of 1,082 chronic hepatitis B (CHB) patients and 816 hepatitis B virus (HBV) related HCC patients in Han Chinese. Four SNPs which can represent all potential functional SNPs with MAF > 0.1 recorded in HapMap database in ATF6 gene were genotyped using TaqMan methods. Functional analyses were conducted to verify the biological significances of the associated SNP. We identified a missense SNP (rs2070150) was significantly associated with susceptibility to HCC (p = 0.008, 0.001 and 0.007 in Beijing_302, Beijing_You'an and Guangxi samples, respectively). This SNP was further validated in four independent groups of major HBV outcomes, indicating it may associate exclusively to HCC. ATF6 mRNA expression was significantly decreased as the disease progressed (p <0.001). Functional analyses show that the protective allele of rs2070150 could significantly increase the expression levels of ATF6 mRNA, as well as ATF6 regulated genes such as GRP78, XBP1 and CHOP. These findings indicate that a common missense SNP in ATF6 may contribute to susceptibility of HCC functionally.Hepatocellular carcinoma (HCC) is caused by a complex interplay between genetic and environmental factors. Hepatitis B virus (HBV) infection is a frequent cause of HCC, and there is accumulating evidence that single nucleotide polymorphisms (SNPs) are also associated with risk of HCC. Because ATF6 is an important modulator of the unfolded protein response (UPR), which is involved in carcinogenesis, here the authors speculated that SNPs in ATF6 may be associated with susceptibility to HCC. Using a 2-stage association study, they found a missense polymorphism that was strongly associated with HBV-related HCC and may contribute to susceptibility by altering ATF6 expression.