GWAS Identifies Novel Susceptibility Loci on 6p21.32 and 21q21.3 for Hepatocellular Carcinoma in Chronic Hepatitis B Virus Carriers

Shengping Li, Ji Qian, Yuan Yang, Wanting Zhao, Juncheng Dai, Jin-Xin Bei, Jia Nee Foo, Paul J McLaren, Zhiqiang Li, Jingmin Yang, Feng Shen, Li Liu, Jiamei Yang, Shuhong Li, Shandong Pan, Yi Wang, Wenjin Li, Xiangjun Zhai, Boping Zhou, Lehua Shi, Xinchun Chen, Minjie Chu, Yiqun Yan, Jun Wang, Shuqun Cheng, Jiawei Shen, Weihua Jia, Jibin Liu, Jiahe Yang, Zujia Wen, Aijun Li, Ying Zhang, Guoliang Zhang, Xianrong Luo, Hongbo Qin, Minshan Chen, Hua Wang, Li Jin, Dongxin Lin, Hongbing Shen, Lin He, Paul I W de Bakker, Hongyang Wang, Yi-Xin Zeng, Mengchao Wu, Zhibin Hu, Yongyong Shi, Jianjun Liu and Weiping Zhou

PLOS Genetics, 2012, vol. 8, issue 7, 1-8

Abstract: Genome-wide association studies (GWAS) have recently identified KIF1B as susceptibility locus for hepatitis B virus (HBV)–related hepatocellular carcinoma (HCC). To further identify novel susceptibility loci associated with HBV–related HCC and replicate the previously reported association, we performed a large three-stage GWAS in the Han Chinese population. 523,663 autosomal SNPs in 1,538 HBV–positive HCC patients and 1,465 chronic HBV carriers were genotyped for the discovery stage. Top candidate SNPs were genotyped in the initial validation samples of 2,112 HBV–positive HCC cases and 2,208 HBV carriers and then in the second validation samples of 1,021 cases and 1,491 HBV carriers. We discovered two novel associations at rs9272105 (HLA-DQA1/DRB1) on 6p21.32 (OR = 1.30, P = 1.13×10−19) and rs455804 (GRIK1) on 21q21.3 (OR = 0.84, P = 1.86×10−8), which were further replicated in the fourth independent sample of 1,298 cases and 1,026 controls (rs9272105: OR = 1.25, P = 1.71×10−4; rs455804: OR = 0.84, P = 6.92×10−3). We also revealed the associations of HLA-DRB1*0405 and 0901*0602, which could partially account for the association at rs9272105. The association at rs455804 implicates GRIK1 as a novel susceptibility gene for HBV–related HCC, suggesting the involvement of glutamate signaling in the development of HBV–related HCC. Author Summary: Previous studies strongly suggest the importance of genetic susceptibility for hepatocellular carcinoma (HCC). However, the studies about genetic etiology on HBV–related HCC were limited. Our genome-wide association study included 523,663 autosomal SNPs in 1,538 HBV–positive HCC patients and 1,465 chronic HBV carriers for the discovery analysis. 2,112 HBV–positive HCC cases and 2,208 HBV carriers (the initial validation), and 1,021 cases and 1,491 HBV carriers (the second validation), were then analyzed for validation. The fourth independent samples of 1,298 cases and 1,026 controls were analyzed as replication. We discovered two novel associations at rs9272105 (HLA-DQA1/DRB1) on 6p21.32 and rs455804 (GRIK1) on 21q21.3. HLA-DRB1 molecules play an important role in chronic HBV infection and progression to HCC. The association at rs455804 implicates GRIK1 as a novel susceptibility gene for HBV–related HCC, suggesting the involvement of glutamate signaling in the development of HBV–related HCC.

Date: 2012
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pgen00:1002791

DOI: 10.1371/journal.pgen.1002791

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