title: A missense polymorphism in ATF6 gene is associated with susceptibility to hepatocellular carcinoma probably by altering ATF6 level.
abstract: 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.
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, People's Republic of China; School of Basic Medicine, Peking Union Medical College, Beijing, People's Republic of China.
authors.forename: Xiaopan
authors.initials: X
authors.lastname: Wu
authors.forename: Zhenhui
authors.initials: Z
authors.lastname: Xin
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Sujun
authors.initials: S
authors.lastname: Zheng
authors.forename: Jia
authors.initials: J
authors.lastname: Wu
authors.forename: Kangmei
authors.initials: K
authors.lastname: Chen
authors.forename: Huifen
authors.initials: H
authors.lastname: Wang
authors.forename: Xilin
authors.initials: X
authors.lastname: Zhu
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Li
authors.forename: Zhongping
authors.initials: Z
authors.lastname: Duan
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics*; D000328:Adult; D006528:Carcinoma, Hepatocellular / Q000150:complications / Q000235:genetics* / Q000473:pathology; D002681:China; D018450:Disease Progression; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D020022:Genetic Predisposition to Disease; D006515:Hepatitis B virus / Q000235:genetics / Q000472:pathogenicity; D019694:Hepatitis B, Chronic / Q000150:complications / Q000235:genetics / Q000821:virology; D006801:Humans; D008113:Liver Neoplasms / Q000150:complications / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human
keywords: ATF6; hepatocellular carcinoma; luciferase assay; real-time PCR; single nucleotide polymorphisms