Identification of potential functional variants and genes at 18q21.1 associated with the carcinogenesis of colorectal cancer.
Identification of potential functional variants and genes at 18q21.1 associated with the carcinogenesis of colorectal cancer.
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鉴定与结直肠癌发生相关的 18q21.1 潜在功能变异和基因
DOI：
10.1371/journal.pgen.1010050
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发表时间：
2022-03
期刊：
影响因子：
4.5
通讯作者：
Zhang D
中科院分区：
文献类型：
--
作者：
Cheng X;Zhang F;Gong J;Li Y;Zhou D;Wang J;Vong EG;Yuan Y;Lai M;Zhang D
全基因组关联研究（GWAS）已经确定了160多个结直肠癌（CRC）的易感基因座。然而，这些变异的影响，特别是它们的机制仍不清楚。本研究首先对CRC相关的GWAS信号进行了全面的功能注释，以确定潜在的致病变体。我们发现18q21.1处SMAD 7内含子3中的SNP rs7229639可能是CRC中推定的功能变体。SNP rs7229639位于具有调控潜力证据的区域。双荧光素酶报告基因分析显示，与rs7229639处于强连锁不平衡（LD）的其他三个SNP（rs77544449、rs60385309和rs72917785）表现出等位基因特异性增强子活性，其中一个靶基因可能是LIPG，如eQTL关联数据和Hi-C数据所示。我们还证实了LIPG在体外促进CRC细胞的恶性化，支持的临床数据表明LIPG上调并与CRC的不良预后相关。最后，观察到匹伐他汀表现出抗CRC活性和对LIPG mRNA水平的适度抑制。总的来说，我们的数据表明，在18q21.1的这些功能变异参与CRC的发病机制，通过调节增强子的活性，并可能LIPG的表达，从而表明一个有前途的治疗CRC的目标。本研究的功能注释结果也可作为结直肠癌易感性SNPs的清单，并为GWAS后的下游功能研究提供指导。在最新的统计数据中，结直肠癌（CRC）的发病率和死亡率居高不下。全基因组关联研究（GWAS）已成为鉴定赋予疾病显著风险的遗传易感性位点的有力工具，并已鉴定出160多个与CRC相关的风险位点。然而，已经证明很难识别这些GWAS信号背后涉及的调控变体和靶基因。在这里，我们利用多组学数据和多种生物学实验来揭示影响CRC易感性的新生物学途径。我们发现，一个特定的遗传变异，rs7229639，和其他三个高度连锁的功能变异（rs77544449，rs60385309和rs72917785）在18q21.1可能调节LIPG的表达，一个基因，显示出致癌功能，通过我们的体外实验和临床数据分析。我们建立的大肠癌基因变异、基因表达与大肠癌表型之间的联系可为后续的基础和临床研究提供参考。
Genome-wide association studies (GWAS) have identified more than 160 susceptibility loci for colorectal cancer (CRC). The effects of these variants, particularly their mechanisms, however, remain unclear. In this study, a comprehensive functional annotation of CRC-related GWAS signals was firstly conducted to identify the potential causal variants. We found that the SNP rs7229639 in intron 3 of SMAD7 at 18q21.1 might serve as a putative functional variant in CRC. The SNP rs7229639 is located in a region with evidence of regulatory potential. Dual-luciferase reporter assays revealed that three other SNPs (rs77544449, rs60385309 and rs72917785), in strong linkage disequilibrium (LD) with rs7229639, exhibited allele-specific enhancer activity, of which one of the target genes may conceivably be LIPG, as suggested by eQTL association data and Hi-C data. We also verified that LIPG promoted malignancy of CRC cells in vitro, with supporting clinical data indicating that LIPG is upregulated and correlated with a poor prognosis in CRC. Finally, pitavastatin was observed to exhibit an anti-CRC activity and modest inhibition of LIPG mRNA levels. Collectively, our data suggest that these functional variants at 18q21.1 are involved in the pathogenesis of CRC by modulating enhancer activity, and possibly LIPG expression, thus indicating a promising therapeutic target for CRC. The results of functional annotation in our investigation could also serve as an inventory for CRC susceptibility SNPs and offer guides for post-GWAS downstream functional studies. In the latest statistics, the incidence and mortality rate of colorectal cancer (CRC) remains high. Genome-wide association studies (GWAS) have become a powerful tool for identifying genetic susceptibility loci that confer significant risk on disease, and have identified more than 160 risk loci associated with CRC. However, it has proven quite difficult to identify the regulatory variants and target genes involved behind these GWAS signals. Here, we take advantage of multi-omics data and multiple biological experiments to reveal new biological pathways affecting susceptibility to CRC. We show that a specific genetic variant, rs7229639, and three other high linked functional variants (rs77544449, rs60385309 and rs72917785) at 18q21.1 might regulate the expression of LIPG, a gene that was shown to exhibit an oncogenic function by our in-vitro experiments and clinical data analysis. The link between genetic variants, gene expression and CRC phenotype established by us could provide references for follow-up basic and clinical studies.
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影响因子：
7.7
作者：
Lo PK;Yao Y;Lee JS;Zhang Y;Huang W;Kane MA;Zhou Q
通讯作者：
Zhou Q
影响因子：
64.8
作者：
Frazer, Kelly A.;Ballinger, Dennis G.;Cox, David R.;Hinds, David A.;Stuve, Laura L.;Gibbs, Richard A.;Belmont, John W.;Boudreau, Andrew;Hardenbol, Paul;Leal, Suzanne M.;Pasternak, Shiran;Wheeler, David A.;Willis, Thomas D.;Yu, Fuli;Yang, Huanming;Zeng, Changqing;Gao, Yang;Hu, Haoran;Hu, Weitao;Li, Chaohua;Lin, Wei;Liu, Siqi;Pan, Hao;Tang, Xiaoli;Wang, Jian;Wang, Wei;Yu, Jun;Zhang, Bo;Zhang, Qingrun;Zhao, Hongbin;Zhao, Hui;Zhou, Jun;Gabriel, Stacey B.;Barry, Rachel;Blumenstiel, Brendan;Camargo, Amy;Defelice, Matthew;Faggart, Maura;Goyette, Mary;Gupta, Supriya;Moore, Jamie;Nguyen, Huy;Onofrio, Robert C.;Parkin, Melissa;Roy, Jessica;Stahl, Erich;Winchester, Ellen;Ziaugra, Liuda;Altshuler, David;Shen, Yan;Yao, Zhijian;Huang, Wei;Chu, Xun;He, Yungang;Jin, Li;Liu, Yangfan;Shen, Yayun;Sun, Weiwei;Wang, Haifeng;Wang, Yi;Wang, Ying;Xiong, Xiaoyan;Xu, Liang;Waye, Mary M. Y.;Tsui, Stephen K. W.;Wong, J. Tze-Fei;Galver, Luana M.;Fan, Jian-Bing;Gunderson, Kevin;Murray, Sarah S.;Oliphant, Arnold R.;Chee, Mark S.;Montpetit, Alexandre;Chagnon, Fanny;Ferretti, Vincent;Leboeuf, Martin;Olivier, Jean-Franccois;Phillips, Michael S.;Roumy, Stephanie;Sallee, Clementine;Verner, Andrei;Hudson, Thomas J.;Kwok, Pui-Yan;Cai, Dongmei;Koboldt, Daniel C.;Miller, Raymond D.;Pawlikowska, Ludmila;Taillon-Miller, Patricia;Xiao, Ming;Tsui, Lap-Chee;Mak, William;Song, You Qiang;Tam, Paul K. H.;Nakamura, Yusuke;Kawaguchi, Takahisa;Kitamoto, Takuya;Morizono, Takashi;Nagashima, Atsushi;Ohnishi, Yozo;Sekine, Akihiro;Tanaka, Toshihiro;Tsunoda, Tatsuhiko;Deloukas, Panos;Bird, Christine P.;Delgado, Marcos;Dermitzakis, Emmanouil T.;Gwilliam, Rhian;Hunt, Sarah;Morrison, Jonathan;Powell, Don;Stranger, Barbara E.;Whittaker, Pamela;Bentley, David R.;Daly, Mark J.;de Bakker, Paul I. W.;Barrett, Jeff;Chretien, Yves R.;Maller, Julian;McCarroll, Steve;Patterson, Nick;Pe'er, Itsik;Price, Alkes;Purcell, Shaun;Richter, Daniel J.;Sabeti, Pardis;Saxena, Richa;Schaffner, Stephen F.;Sham, Pak C.;Varilly, Patrick;Altshuler, David;Stein, Lincoln D.;Krishnan, Lalitha;Smith, Albert Vernon;Tello-Ruiz, Marcela K.;Thorisson, Gudmundur A.;Chakravarti, Aravinda;Chen, Peter E.;Cutler, David J.;Kashuk, Carl S.;Lin, Shin;Abecasis, Goncalo R.;Guan, Weihua;Li, Yun;Munro, Heather M.;Qin, Zhaohui Steve;Thomas, Daryl J.;McVean, Gilean;Auton, Adam;Bottolo, Leonardo;Cardin, Niall;Eyheramendy, Susana;Freeman, Colin;Marchini, Jonathan;Myers, Simon;Spencer, Chris;Stephens, Matthew;Donnelly, Peter;Cardon, Lon R.;Clarke, Geraldine;Evans, David M.;Morris, Andrew P.;Weir, Bruce S.;Tsunoda, Tatsuhiko;Johnson, Todd A.;Mullikin, James C.;Sherry, Stephen T.;Feolo, Michael;Skol, Andrew
通讯作者：
Skol, Andrew
遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
30.8
作者：
Huyghe, Jeroen R.;Bien, Stephanie A.;Peters, Ulrike
通讯作者：
Peters, Ulrike
影响因子：
4.4
作者：
Inoue F;Ahituv N
通讯作者：
Ahituv N