Identification of candidate susceptibility genes for colorectal cancer through eQTL analysis

Abstract

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.

Polymorphisms in CARS are associated with gastric cancer risk: a two-stage case–control study in the Chinese population

“…From statistical results, different SNPs could relate to different target genes. This situation could be explained by remote regulation among related genes, and is common in many other studies [32][33][34]. For example, Weinhold et al [32] conducted eQTL analysis and found that at 7p15.3 the strongest association with multiple myeloma risk was for rs4487645, residing within the DNAH11 gene, which was associated with allele-specific regulation of the CDCA7L gene (near the DNAH11 gene).…”

CDH1 rs9929218 variant at 16q22.1 contributes to colorectal cancer susceptibility

“…We identified significant regulation relations between rs9929218 variant and gene expression including CDH1, ZFP90, RP11-354M1.2 and MCOLN2 by both cis- effect and trans- effect. Recently, Closa et al analyzed the association between genotypes for 26 GWAS SNPs and the expression of genes within a 2 Mb region (cis-eQTLs) using Affymetrix Human Genome U219 expression arrays with 47 samples from healthy colonic mucosa and 97 samples from normal mucosa adjacent to colon cancer [26]. In all the samples, the cis-eQTL analysis showed significant association between rs9929218 variant and GFOD2 expression with P =3.90E-03 [26].…”

“…Recently, Closa et al analyzed the association between genotypes for 26 GWAS SNPs and the expression of genes within a 2 Mb region (cis-eQTLs) using Affymetrix Human Genome U219 expression arrays with 47 samples from healthy colonic mucosa and 97 samples from normal mucosa adjacent to colon cancer [26]. In all the samples, the cis-eQTL analysis showed significant association between rs9929218 variant and GFOD2 expression with P =3.90E-03 [26]. Closa et al further reported significant association of rs9929218 variant with expression of TSNAXIP1, HSF4 and NUTF2 in tumor tissue eQTL analysis with P =5.50E-03, P =6.70E-03 and P =1.70E-03, respectively, but not in normal tissue eQTL analysis with P =0.59, P =0.54 and P =0.27, respectively [26].…”

“…In all the samples, the cis-eQTL analysis showed significant association between rs9929218 variant and GFOD2 expression with P =3.90E-03 [26]. Closa et al further reported significant association of rs9929218 variant with expression of TSNAXIP1, HSF4 and NUTF2 in tumor tissue eQTL analysis with P =5.50E-03, P =6.70E-03 and P =1.70E-03, respectively, but not in normal tissue eQTL analysis with P =0.59, P =0.54 and P =0.27, respectively [26]. …”

“…However these studies reported consistent and inconsistent results. Evidence shows that rs9929218 variant may regulate different gene expressions in different human tissues, tumor tissues and normal tissues, and may have different regulatory mechanisms [26]. Here, we evaluated this association using large-scale samples from 16 studies (n=131768, 53656 CRC cases and 78112 controls) using meta-analysis method.…”