Identification of Novel Loci and New Risk Variant in Known Loci for Colorectal Cancer Risk in East Asians.
Identification of Novel Loci and New Risk Variant in Known Loci for Colorectal Cancer Risk in East Asians.
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DOI：
10.1158/1055-9965.epi-19-0755
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发表时间：
2020-03
期刊：
影响因子：
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通讯作者：
Zheng W
中科院分区：
文献类型：
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作者：
Lu Y;Kweon SS;Cai Q;Tanikawa C;Shu XO;Jia WH;Xiang YB;Huyghe JR;Harrison TA;Kim J;Shin A;Kim DH;Matsuo K;Jee SH;Guo X;Wen W;Shi J;Li B;Wang N;Shin MH;Li HL;Ren Z;Oh JH;Oze I;Ahn YO;Jung KJ;Gao J;Gao YT;Pan ZZ;Kamatani Y;Chan AT;Gsur A;Hampe J;Le Marchand L;Li L;Lindblom A;Moreno V;Newcomb PA;Offit K;Pharoah PDP;van Duijnhoven FJB;Van Guelpen B;Vodicka P;Weinstein SJ;Wolk A;Wu AH;Hsu L;Zeng YX;Long J;Peters U;Matsuda K;Zheng W
到目前为止发现的结直肠癌风险变异只解释了这种癌症的一小部分家族风险，特别是在亚洲人中。我们对东亚人的结直肠癌进行了全基因组关联研究，包括23,572例结直肠癌病例和48,700名对照。为了确定新的风险位点，我们选择了60个有希望的风险变量进行复制，使用了58,131例结直肠癌病例和67,347名欧洲血统对照的数据。为了确定已知结直肠癌基因座的其他风险变量，我们对东亚人进行了条件分析。位于1p13.3的插入变异rs67052019在亚洲人中被发现与结直肠癌的风险相关，P=3.9x10−8(每等位基因缺失的OR=1.13，95%可信区间=1.08-1.18)。这种关联在使用与rs67052019完全连锁不平衡的变异(Rs2938616)的欧洲后代中复制(P=7.7x10−3)。在剩下的59个变异中，12个在欧洲血统研究中显示出与P<；0.05的关联，包括P<；5×10−8的rs11108175和rs9634162，以及在亚洲和欧洲血统数据的联合分析中接近全基因组显著水平的两个变异(rs60911071，P=5.8x10−8；rs62558833，P=7.5x10−8)。此外，利用东亚人的数据，我们在以前的GWA11个基因座上发现了13个新的风险变异。在这个大型的GWA中，我们确定了三个新的风险基因和两个高度提示结直肠癌风险的基因，并为多基因和通路在结直肠癌病因学中的潜在作用提供了证据。此外，我们还发现在先前确定的许多结直肠癌风险基因中存在额外的风险变量。我们的研究为提高对结直肠癌风险的遗传基础的理解提供了新的数据。
Risk variants identified so far for colorectal cancer explain only a small proportion of familial risk of this cancer, particularly in Asians. We performed a genome-wide association study (GWAS) of colorectal cancer in East Asians, including 23,572 colorectal cancer cases and 48,700 controls. To identify novel risk loci, we selected 60 promising risk variants for replication using data from 58,131 colorectal cancer cases and 67,347 controls of European descent. To identify additional risk variants in known colorectal cancer loci, we performed conditional analyses in East Asians. An indel variant, rs67052019 at 1p13.3, was found to be associated with colorectal cancer risk at P = 3.9 × 10−8 in Asians (OR per allele deletion = 1.13, 95% confidence interval = 1.08–1.18). This association was replicated in European descendants using a variant (rs2938616) in complete linkage disequilibrium with rs67052019 (P = 7.7 × 10−3). Of the remaining 59 variants, 12 showed an association at P < 0.05 in the European-ancestry study, including rs11108175 and rs9634162 at P < 5 × 10−8 and two variants with an association near the genome-wide significance level (rs60911071, P = 5.8 × 10−8; rs62558833, P = 7.5 × 10−8)in the combined analyses of Asian- and European-ancestry data. In addition, using data from East Asians, we identified 13 new risk variants at 11 loci reported from previous GWAS. In this large GWAS, we identified three novel risk loci and two highly suggestive loci for colorectal cancer risk and provided evidence for potential roles of multiple genes and pathways in the etiology of colorectal cancer. In addition, we showed that additional risk variants exist in many colorectal cancer risk loci identified previously. Our study provides novel data to improve the understanding of the genetic basis for colorectal cancer risk.