44
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

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

      research-article
      1 , 2 , 3 , 4 , 5 , 1 , 6 , 6 , 7 , 2 , 3 , 8 , 3 , 1 , 5 , 3 , 7 , 9 , 10 , 3 , 10 , 5 , 3 , 1 , 3 , 7 , 1 , 8 , 3 , 7 , 3 , 1 , 10 , 11 , 12 , 1 , 9 , 2 , 13 , 5 , 7 , 14 , 15 , 6 , 3 , 1 , 3 , 5 , * , 7 , * , 4 , * , 3 , *
      PLoS Genetics
      Public Library of Science

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          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.

          Related collections

          Most cited references26

          • Record: found
          • Abstract: found
          • Article: not found

          A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC.

          The proteins encoded by the classical HLA class I and class II genes in the major histocompatibility complex (MHC) are highly polymorphic and are essential in self versus non-self immune recognition. HLA variation is a crucial determinant of transplant rejection and susceptibility to a large number of infectious and autoimmune diseases. Yet identification of causal variants is problematic owing to linkage disequilibrium that extends across multiple HLA and non-HLA genes in the MHC. We therefore set out to characterize the linkage disequilibrium patterns between the highly polymorphic HLA genes and background variation by typing the classical HLA genes and >7,500 common SNPs and deletion-insertion polymorphisms across four population samples. The analysis provides informative tag SNPs that capture much of the common variation in the MHC region and that could be used in disease association studies, and it provides new insight into the evolutionary dynamics and ancestral origins of the HLA loci and their haplotypes.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma.

            To identify the genetic susceptibility factor(s) for hepatitis C virus-induced hepatocellular carcinoma (HCV-induced HCC), we conducted a genome-wide association study using 432,703 autosomal SNPs in 721 individuals with HCV-induced HCC (cases) and 2,890 HCV-negative controls of Japanese origin. Eight SNPs that showed possible association (P < 1 × 10(-5)) in the genome-wide association study were further genotyped in 673 cases and 2,596 controls. We found a previously unidentified locus in the 5' flanking region of MICA on 6p21.33 (rs2596542, P(combined) = 4.21 × 10(-13), odds ratio = 1.39) to be strongly associated with HCV-induced HCC. Subsequent analyses using individuals with chronic hepatitis C (CHC) indicated that this SNP is not associated with CHC susceptibility (P = 0.61) but is significantly associated with progression from CHC to HCC (P = 3.13 × 10(-8)). We also found that the risk allele of rs2596542 was associated with lower soluble MICA protein levels in individuals with HCV-induced HCC (P = 1.38 × 10(-13)).
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Glutamate and the biology of gliomas.

              Several important and previously unrecognized roles for the neurotransmitter glutamate in the biology of primary brain tumors have recently been elucidated. Glutamate is produced and released from glioma cells via the system x(c) (-) cystine glutamate transporter as a byproduct of glutathione synthesis. Glutamate appears to play a central role in the malignant phenotype of glioma via multiple mechanisms. By binding to peritumoral neuronal glutamate receptors, glutamate is responsible for seizure induction and similarly causes excitotoxicity, which aids the expansion of tumor cells into the space vacated by destroyed tissue. Glutamate also activates ionotropic and metabotropic glutamate receptors on glioma cells in a paracrine and autocrine manner. α-Amino-3-hydroxy-5-methyl-4-isoaxazolepropionate acid (AMPA) glutamate receptors lack the GluR2 subunit rendering them Ca(2+) permeable and capable of activating the AKT and MAPK pathways. Furthermore, these receptors are critical in aiding the invasion of glioma cells into normal brain. AMPA-Rs accumulate at focal adhesion sites where they may indirectly mediate interactions between the extracellular matrix and integrins. Glutamate receptor stimulation results in activation of focal adhesion kinase, which is critical to the regulation of growth factor and integrin-stimulated cell motility and invasion. The multitude of effects of glutamate on glioma biology supports the rationale for pharmacological targeting of glutamate receptors and transporters. Several ongoing and recently completed clinical trials are exploring the therapeutic potential of interrupting glutamate-mediated brain tumor growth. Copyright © 2010 Wiley-Liss, Inc.
                Bookmark

                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                July 2012
                July 2012
                12 July 2012
                : 8
                : 7
                : e1002791
                Affiliations
                [1 ]Department of Hepatobiliary Oncology, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
                [2 ]State Key Laboratory of Genetic Engineering, Center for Fudan–VARI Genetic Epidemiology and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
                [3 ]Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
                [4 ]Human Genetics, Genome Institute of Singapore, A*STAR, Singapore, Singapore
                [5 ]MOE Key Laboratory of Modern Toxicology, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention, and Treatment, and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
                [6 ]Division of Genetics, Brigham and Women's Hospital, Harvard Medical School Boston and Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America
                [7 ]Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China
                [8 ]Department of Hepatobiliary Surgery, Nantong Tumor Hospital, Nantong, China
                [9 ]Department of Infection Diseases, Jiangsu Province Center for Disease Prevention and Control, Nanjing, China
                [10 ]The Third People's Municipal Hospital of Shenzhen, Shenzhen, China
                [11 ]No. 458 Hospital of Chinese People's Liberation Army, Guangzhou, China
                [12 ]The Eighth Municipal People's Hospital of Guangzhou, Guangzhou, China
                [13 ]State Key Laboratory of Molecular Oncology and Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
                [14 ]Institutes for Nutritional Sciences, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, Shanghai, China
                [15 ]Institutes of Biomedical Sciences, Fudan University, Shanghai, China
                Imperial College London, United Kingdom
                Author notes

                Study concept and design: Weiping Zhou, Shengping Li, Jianjun Liu, Zhibin Hu, Yongyong Shi, Ji Qian, Yuan Yang. Subject recruitment and sample preparation: Weiping Zhou, Yuan Yang, Ji Qian, Jingmin Yang, Feng Shen, Jiamei Yang, Yi Wang, Lehua Shi, Yiqun Yan, Shuqun Cheng, Jiahe Yang, Aijun Li, Li Jin (Shanghai samples); Shengping Li, Shuhong Li, Jun Wang, Boping Zhou, Weihua Jia, Ying Zhang, Xinchun Chen, Guoliang Zhang, Xianrong Luo, Hongbo Qin, Minshan Chen (Guangzhou samples); Zhibin Hu, Li Liu, Shandong Pan, Minjie Chu, Xiangjun Zhai, Jibin Liu, Hua Wang (Jiangsu samples). GWAS data processing: Zhiqiang Li, Jiawei Shen, Lehua Shi. Sample genotyping: Wenjin Li, Zujia Wen (GWAS Scan); Li Liu, Shandong Pan, Minjie Chu (Validation stages). Analysis and interpretation of data: Weiping Zhou, Shengping Li, Jianjun Liu, Zhibin Hu, Yongyong Shi, Ji Qian, Yuan Yang, Juncheng Dai, Wanting Zhao. Drafting of the manuscript: Jianjun Liu, Zhibin Hu. Critical revision of the manuscript for important intellectual content: Weiping Zhou, Shengping Li, Jianjun Liu, Zhibin Hu, Yongyong Shi, Jin-Xin Bei, Dongxin Lin, Hongbing Shen, Lin He, Hongyang Wang, Yi-Xin Zeng, Mengchao Wu. Statistical analysis: Jungheng Dai, Wanting Zhao, Jia Nee Foo, Paul J McLaren, Paul IW de Bakker, Zhibin Hu, Jianjun Liu. Obtained funding: Weiping Zhou, Shengping Li, Jianjun Liu, Zhibin Hu, Yongyong Shi, Ji Qian. Administrative, technical, or material support: Hongbing Shen, Lin He, Hongyang Wang, Yi-Xin Zeng, Mengchao Wu. Study supervision: Weiping Zhou, Shengping Li, Jianjun Liu, Zhibin Hu, Yongyong Shi, Ji Qian.

                Article
                PGENETICS-D-11-02735
                10.1371/journal.pgen.1002791
                3395595
                22807686
                c731ae2f-7d4a-4ac6-80f3-6709f8ff1d91
                Li et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 16 December 2011
                : 13 May 2012
                Page count
                Pages: 8
                Categories
                Research Article
                Biology
                Genetics
                Cancer Genetics
                Genome-Wide Association Studies

                Genetics
                Genetics

                Comments

                Comment on this article