GWAS Identifies Novel Susceptibility Loci on 6p21.32 and 21q21.3 for Hepatocellu

StephenW

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

Shengping Li1#, Ji Qian2#, Yuan Yang3#, Wanting Zhao4, Juncheng Dai5, Jin-Xin Bei1, Jia Nee Foo6, Paul J. McLaren6, Zhiqiang Li7, Jingmin Yang2, Feng Shen3, Li Liu8, Jiamei Yang3, Shuhong Li1, Shandong Pan5, Yi Wang3, Wenjin Li7, Xiangjun Zhai9, Boping Zhou10, Lehua Shi3, Xinchun Chen10, Minjie Chu5, Yiqun Yan3, Jun Wang1, Shuqun Cheng3, Jiawei Shen7, Weihua Jia1, Jibin Liu8, Jiahe Yang3, Zujia Wen7, Aijun Li3, Ying Zhang1, Guoliang Zhang10, Xianrong Luo11, Hongbo Qin12, Minshan Chen1, Hua Wang9, Li Jin2, Dongxin Lin13, Hongbing Shen5, Lin He7,14,15, Paul I. W. de Bakker6, Hongyang Wang3, Yi-Xin Zeng1, Mengchao Wu3, Zhibin Hu5*, Yongyong Shi7*, Jianjun Liu4*, Weiping Zhou3*

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

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.

StephenW

全基因组关联研究（GWAS）最近已确定为B型肝炎病毒（HBV）的易感基因相关的肝细胞癌（HCC）KIF1B。为了进一步查明小说与HBV相关HCC的易感性相关的基因位点，复制先前报道的关联，我们在中国汉族人群中的一个大的三个阶段的GWAS。 523663常染色体显性遗传1538 HBV阳性肝癌患者和1465例慢性乙肝病毒携带者的SNPs进行基因分型的发现阶段。热门候选SNP基因型在2,112 HBV阳性肝癌和2,208例乙肝病毒携带者的初步验证样本，然后在1021和1491例乙肝病毒携带者的第二个验证样品。我们发现在rs9272105（HLA-DQA1/DRB1）6p21.32两个新的关联性（OR = 1.30，P = 1.13×10-19）和rs455804（GRIK1 21q21.3（OR = 0.84，P = 1.86×10） -8），其中在第四个独立样本1,298例和1026控制进一步复制（rs9272105：OR = 1.25，P = 1.71×10-4; rs455804：OR = 0.84，P = 6.92×10-3）。我们还透露协会的HLA-DRB1 * 0405和0901 * 0602，这可以部分解释为协会rs92​​72105。该协会在rs455804牵连为HBV相关HCC的一种新的易感基因GRIK1，表明HBV相关HCC的发展中，谷氨酸信号的参与。

作者综述
以往的研究强烈建议肝细胞癌（HCC）遗传易感性的重要性。然而，对HBV相关性肝癌的遗传病因研究是有限的。我们的全基因组关联研究包括523663在1538 HBV阳性的肝癌患者和分析，发现1465例慢性乙肝病毒携带者的自体SNPs。 2,112 HBV阳性肝癌和2,208例乙肝病毒携带者（初步验证），1021箱子和1491乙肝病毒携带者（第二次验证），然后分析进行验证。为复制1,298和1026例对照组的第四独立样本进行了分析。我们发现在6p21.32和rs455804（GRIK1）的两个新的协会上21q21.3在rs9272105（HLA-DQA1/DRB1）的。 HLA-DRB1基因的分子发挥重要的作用，在慢性乙肝病毒感染和进展为肝癌。该协会在rs455804牵连为HBV相关HCC的一种新的易感基因GRIK1，表明HBV相关HCC的发展中，谷氨酸信号的参与。

咬牙硬挺

感谢分享。这几天论坛上不了了。感谢动车

StephenW

回复 咬牙硬挺 的帖子

当这种情况发生
，我写信给官方中国报纸抱怨，并敦促政府调查和惩罚肇事者

Vitamins

回复 StephenW 的帖子

可否简单介绍一下这个对HBV的监控有何意义。是否能更好地定位哪些HBV更可能演变成HCC。

StephenW

回复 Vitamins 的帖子

我不是专家，所以我不能给你一个明确的答案.
维基百科:
应用前景GWAS为人们打开了一扇通往研究复杂疾病的大门，将在患者全基因组范围内检测出的SNP位点与对照组进行比较，找出所有的变异等位基因频率，从而避免了像候选基因策略一样需要预先假设致病基因。同时，GWAS研究让我们找到了许多从前未曾发现的基因以及染色体区域，为复杂疾病的发病机制提供了更多的线索。

Clinical applications

One of the challenges for a successful GWA study in the future will be to apply the findings in a way that accelerates drug and diagnostics development, including better integration of genetic studies into the drug-development process and a focus on the role of genetic variation in maintaining health as a blueprint for designing new drugs and diagnostics.[29] Several studies have looked into the use of risk-SNP markers as a means of directly improving the accuracy of prognosis. Some have found that the accuracy of prognosis improves,[30] while others report only minor benefits from this use.[31] Generally, a problem with this direct approach is the small magnitudes of the effects observed. A small effect ultimately translates into a poor separation of cases and controls and thus only a small improvement of prognosis accuracy. An alternative application is therefore the potential for GWA studies to elucidate pathophysiology.[32]
临床应用

在未来的成功GWA研究的挑战之一将是适用于一种方式，加快药物和诊断发展的结果，包括遗传研究到药物开发过程中更好地整合，重点是遗传变异的作用保持健康的蓝图，为设计新的药物和诊断。[29]一些研究看着风险SNP标记作为改善预后的准确性直接的手段使用。一些已经发现，预后的准确性提高，[30]，而其他报告使用从这个只有轻微的好处。[31]一般来说，这种直接的方法中存在的问题是小幅度的观察效果。小的影响，最终转换成的病例组和对照组差分离，因此只有一个小的改善预后的准确性。因此，另一种应用是GWA研究的潜力，阐明病理生理学。[32]

One of such successes is related to identifying the genetic variant associating with response to anti-hepatitis C virus treatment. For genotype 1 hepatitis C treated with Pegylated interferon-alpha-2a or Pegylated interferon-alpha-2b combined with ribavirin, a GWA study[33] has shown that SNPs near the human IL28B gene, encoding interferon lambda 3, are associated with significant differences in response to the treatment. A later report demonstrated that the same genetic variants are also associated with the natural clearance of the genotype 1 hepatitis C virus.[34]
这样的成就是确定基因变异与响应关联的抗丙型肝炎病毒治疗有关。基因型1丙型肝炎的治疗与利巴韦林联合聚乙二醇干扰素α-2a或聚乙二醇干扰素α-2b干扰素一项GWA研究表明，有显著差异相关的单核苷酸多态性附近的人IL28B基因编码干扰素兰布达3，[33]在反应的治疗。 [34]以后的一份报告表明，在相同的遗传变异也与基因型1丙型肝炎病毒的自然间隙。
The goal of elucidating pathophysiology has also led to increased interest in the association between risk-SNPs and the gene expression of nearby genes, the so-called eQTL studies.[35] The reason is that GWAS studies identifies risk-SNPs, but not risk-genes, and specification of genes is one step closer towards actionable drug targets. As a result, major GWA studies of 2011 typically included extensive eQTL analysis.[36][37][37][38] One of the strongests eQTL effects observed for a GWA-identified risk SNP is the SORT1 locus.[24] Functional follow up studies of this locus using small interfering RNA and gene knock-out mice have shed light on the metabolism of low-density lipoprotein, which have important clinical implications for cardiovascular disease.[24][39][40]
阐发的病理生理的目标也导致了风险SNP和附近的基因，所谓的eQTL研究的基因表达之间的关联的兴趣增加。[35]原因是GWAS研究确定风险的SNPs，但没有风险基因和基因的规范，是朝着可操作的药物靶标接近一步。因此，2011年主要的GWA研究通常包括广泛的eQTL分析。[36] [37] [37] [38]观察一项GWA确定风险的SNP的strongests eQTL效应之一是SORT1的轨迹。[24]功能跟进该位点的研究，利用小分子干扰RNA和基因敲除小鼠光棚上的低密度脂蛋白的代谢，心血管疾病有重要的临床意义。[24] [39] [40]