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000143418 0247_ $$2doi$$a10.1053/j.gastro.2018.11.066
000143418 0247_ $$2pmid$$apmid:30529582
000143418 0247_ $$2pmc$$apmc:PMC6441622
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000143418 0247_ $$2ISSN$$a1528-0012
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000143418 037__ $$aDKFZ-2019-01006
000143418 041__ $$aeng
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000143418 1001_ $$aLu, Yingchang$$b0
000143418 245__ $$aLarge-Scale Genome-Wide Association Study of East Asians Identifies Loci Associated With Risk for Colorectal Cancer.
000143418 260__ $$aPhiladelphia, Pa. [u.a.]$$bSaunders$$c2019
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000143418 520__ $$aGenome-wide association studies (GWASs) have associated approximately 50 loci with risk of colorectal cancer (CRC)-nearly one third of these loci were initially associated with CRC in studies conducted in East Asian populations. We conducted a GWAS of East Asians to identify CRC risk loci and evaluate the generalizability of findings from GWASs of European populations to Asian populations.We analyzed genetic data from 22,775 patients with CRC (cases) and 47,731 individuals without cancer (controls) from 14 studies in the Asia Colorectal Cancer Consortium. First, we performed a meta-analysis of 7 GWASs (10,625 cases and 34,595 controls) and identified 46,554 promising risk variants for replication by adding them to the Multi-Ethnic Global Array (MEGA) for genotype analysis in 6445 cases and 7175 controls. These data were analyzed, along with data from an additional 5705 cases and 5961 controls genotyped using the OncoArray. We also obtained data from 57,976 cases and 67,242 controls of European descent. Variants at identified risk loci were functionally annotated and evaluated in correlation with gene expression levels.A meta-analyses of all samples from people of Asian descent identified 13 loci and 1 new variant at a known locus (10q24.2) associated with risk of CRC at the genome-wide significance level of P < 5 × 10-8. We did not perform experiments to replicate these associations in additional individuals of Asian ancestry. However, the lead risk variant in 6 of these loci was also significantly associated with risk of CRC in European descendants. A strong association (44%-75% increase in risk per allele) was found for 2 low-frequency variants: rs201395236 at 1q44 (minor allele frequency, 1.34%) and rs77969132 at 12p11.21 (minor allele frequency, 1.53%). For 8 of the 13 associated loci, the variants with the highest levels of significant association were located inside or near the protein-coding genes L1TD1, EFCAB2, PPP1R21, SLCO2A1, HLA-G, NOTCH4, DENND5B, and GNAS. For other intergenic loci, we provided evidence for the possible involvement of the genes ALDH7A1, PRICKLE1, KLF5, WWOX, and GLP2R. We replicated findings for 41 of 52 previously reported risk loci.We showed that most of the risk loci previously associated with CRC risk in individuals of European descent were also associated with CRC risk in East Asians. Furthermore, we identified 13 loci significantly associated with risk for CRC in Asians. Many of these loci contained genes that regulate the immune response, Wnt signaling to β-catenin, prostaglandin E2 catabolism, and cell pluripotency and proliferation. Further analyses of these genes and their variants is warranted, particularly for the 8 loci for which the lead CRC risk variants were not replicated in persons of European descent.
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000143418 7001_ $$aKweon, Sun-Seog$$b1
000143418 7001_ $$aTanikawa, Chizu$$b2
000143418 7001_ $$aJia, Wei-Hua$$b3
000143418 7001_ $$aXiang, Yong-Bing$$b4
000143418 7001_ $$aCai, Qiuyin$$b5
000143418 7001_ $$aZeng, Chenjie$$b6
000143418 7001_ $$aSchmit, Stephanie L$$b7
000143418 7001_ $$aShin, Aesun$$b8
000143418 7001_ $$aMatsuo, Keitaro$$b9
000143418 7001_ $$aJee, Sun Ha$$b10
000143418 7001_ $$aKim, Dong-Hyun$$b11
000143418 7001_ $$aKim, Jeongseon$$b12
000143418 7001_ $$aWen, Wanqing$$b13
000143418 7001_ $$aShi, Jiajun$$b14
000143418 7001_ $$aGuo, Xingyi$$b15
000143418 7001_ $$aLi, Bingshan$$b16
000143418 7001_ $$aWang, Nan$$b17
000143418 7001_ $$aZhang, Ben$$b18
000143418 7001_ $$aLi, Xinxiang$$b19
000143418 7001_ $$aShin, Min-Ho$$b20
000143418 7001_ $$aLi, Hong-Lan$$b21
000143418 7001_ $$aRen, Zefang$$b22
000143418 7001_ $$aOh, Jae Hwan$$b23
000143418 7001_ $$aOze, Isao$$b24
000143418 7001_ $$aAhn, Yoon-Ok$$b25
000143418 7001_ $$aJung, Keum Ji$$b26
000143418 7001_ $$aConti, David V$$b27
000143418 7001_ $$aSchumacher, Fredrick R$$b28
000143418 7001_ $$aRennert, Gad$$b29
000143418 7001_ $$aJenkins, Mark A$$b30
000143418 7001_ $$aCampbell, Peter T$$b31
000143418 7001_ $$0P:(DE-He78)6c5d058b7552d071a7fa4c5e943fff0f$$aHoffmeister, Michael$$b32$$udkfz
000143418 7001_ $$aCasey, Graham$$b33
000143418 7001_ $$aGruber, Stephen B$$b34
000143418 7001_ $$aGao, Jing$$b35
000143418 7001_ $$aGao, Yu-Tang$$b36
000143418 7001_ $$aPan, Zhi-Zhong$$b37
000143418 7001_ $$aKamatani, Yoichiro$$b38
000143418 7001_ $$aZeng, Yi-Xin$$b39
000143418 7001_ $$aShu, Xiao-Ou$$b40
000143418 7001_ $$aLong, Jirong$$b41
000143418 7001_ $$aMatsuda, Koichi$$b42
000143418 7001_ $$aZheng, Wei$$b43
000143418 773__ $$0PERI:(DE-600)1478699-0$$a10.1053/j.gastro.2018.11.066$$gVol. 156, no. 5, p. 1455 - 1466$$n5$$p1455 - 1466$$tGastroenterology$$v156$$x0016-5085$$y2019
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