Identification of candidate susceptibility genes for colorectal cancer through eQTL analysis
Identification of candidate susceptibility genes for colorectal cancer through eQTL analysis
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DOI：
10.1093/carcin/bgu092
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发表时间：
2014-09-01
期刊：
影响因子：
4.7
通讯作者：
Moreno, Victor
中科院分区：
文献类型：
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作者：
Closa, Adria;Cordero, David;Moreno, Victor
在这项研究中，我们的目标是确定在全基因组关联研究（GWAS）中发现的位点背后负责结直肠癌风险的基因。这些基因可能是开发新的预防或治疗策略的候选靶点。我们分析了26个GWAS单核苷酸多态性（snp）的基因型与2 Mb区域内基因表达的关系（顺式-等距qtl）。采用Affymetrix Human Genome U219表达阵列检测两组样本的基因表达，一组是健康结肠黏膜（n = 47），另一组是结肠癌旁正常粘膜（n = 97，共144）。配对肿瘤组织（n = 97）也进行了分析，但没有提供额外的发现。偏Pearson相关(r)，根据样本类型调整，用于分析。我们在三个位点上发现了bonferroni显著的cis- eqtl: 11q23.1中的rs3802842位点与C11orf53、COLCA1 （C11orf92）和COLCA2 （C11orf93; r = 0.60）相关；12q13.12中的rs7136702与DIP2B相关（r = 0.63）， Xp22.3中的rss5934683与SHROOM2和GPR143相关（r = 0.47）。对于11号和12号染色体上的位点，我们已经发现了其他与鉴定基因表达相关性更强的连锁不平衡snp，并且是更好的功能候选者：11q23.1的rs7130173 （r = 0.66）和12q13.12的rs61927768 （r = 0.86）。这些snp位于可能含有增强子或转录因子结合位点的DNA区域。反式eqtl的分析已经在这些位点上发现了其他基因，这些基因可能具有共同的调节机制，如蛋白质-蛋白质相互作用网络的分析所示。
In this study, we aim to identify the genes responsible for colorectal cancer risk behind the loci identified in genome-wide association studies (GWAS). These genes may be candidate targets for developing new strategies for prevention or therapy. We analyzed the association of genotypes for 26 GWAS single nucleotide polymorphisms (SNPs) with the expression of genes within a 2 Mb region (cis-eQTLs). Affymetrix Human Genome U219 expression arrays were used to assess gene expression in two series of samples, one of healthy colonic mucosa (n = 47) and other of normal mucosa adjacent to colon cancer (n = 97, total 144). Paired tumor tissues (n = 97) were also analyzed but did not provide additional findings. Partial Pearson correlation (r), adjusted for sample type, was used for the analysis. We have found Bonferroni-significant cis-eQTLs in three loci: rs3802842 in 11q23.1 associated to C11orf53, COLCA1 (C11orf92) and COLCA2 (C11orf93; r = 0.60); rs7136702 in 12q13.12 associated to DIP2B (r = 0.63) and rs5934683 in Xp22.3 associated to SHROOM2 and GPR143 (r = 0.47). For loci in chromosomes 11 and 12, we have found other SNPs in linkage disequilibrium that are more strongly associated with the expression of the identified genes and are better functional candidates: rs7130173 for 11q23.1 (r = 0.66) and rs61927768 for 12q13.12 (r = 0.86). These SNPs are located in DNA regions that may harbor enhancers or transcription factor binding sites. The analysis of trans-eQTLs has identified additional genes in these loci that may have common regulatory mechanisms as shown by the analysis of protein-protein interaction networks.