A colorectal cancer genome-wide association study in a Spanish cohort identifies two variants associated with colorectal cancer risk at 1p33 and 8p12

Abstract

BackgroundColorectal cancer (CRC) is a disease of complex aetiology, with much of the expected inherited risk being due to several common low risk variants. Genome-Wide Association Studies (GWAS) have identified 20 CRC risk variants. Nevertheless, these have only been able to explain part of the missing heritability. Moreover, these signals have only been inspected in populations of Northern European origin.ResultsThus, we followed the same approach in a Spanish cohort of 881 cases and 667 controls. Sixty-four variants at 24 loci were found to be associated with CRC at p-values <10-5. We therefore evaluated the 24 loci in another Spanish replication cohort (1481 cases and 1850 controls). Two of these SNPs, rs12080929 at 1p33 (Preplication=0.042; Ppooled=5.523x10-03; OR (CI95%)=0.866(0.782-0.959)) and rs11987193 at 8p12 (Preplication=0.039; Ppooled=6.985x10-5; OR (CI95%)=0.786(0.705-0.878)) were replicated in the second Phase, although they did not reach genome-wide statistical significance.ConclusionsWe have performed the first CRC GWAS in a Southern European population and by these means we were able to identify two new susceptibility variants at 1p33 and 8p12 loci. These two SNPs are located near the SLC5A9 and DUSP4 loci, respectively, which could be good functional candidates for the association signals. We therefore believe that these two markers constitute good candidates for CRC susceptibility loci and should be further evaluated in other larger datasets. Moreover, we highlight that were these two SNPs true susceptibility variants, they would constitute a decrease in the CRC missing heritability fraction.

Genetic susceptibility in the development of colorectal adenomas according to family history of colorectal cancer

“…Concerning the later, Fernandez-Rozadilla et al first reported the association of the rs8180040 variant and CRC in a GWAS performed in Spain. 19 According to the authors, the rs8180040 variant was inversely associated with CRC risk which is in agreement with the protective effect of the rs8180040 allele A against colorectal adenomas observed in our study.…”

“…Over the last two decades, numerous association studies have been conducted in order to assess the relevance of common gene polymorphisms on CRC risk . However, the influence of gene variants in the development of colorectal adenomas and the role of CRC family history in this association has been scarcely analyzed.…”

“…Over the last two decades, numerous association studies have been conducted in order to assess the relevance of common gene polymorphisms on CRC risk. [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] However, the influence of gene variants in the development of colorectal adenomas and the role of CRC family history in this association has been scarcely analyzed. In our study, seven SNPs located in the CASC8 (rs10505477 A>G, rs6983267G>T), ZFP90 (rs1728785C>A), ERCC2 (rs13181T>G), PTPN23 (rs8180040T>A), and CDH1 (rs9929218G>A, rs16260C>A) genes were significantly associated with reduced risk of colorectal adenomas, particularly in subjects with no family history of CRC.…”

“…5 In this context, a great progress in understanding the genetic factors involved in the susceptibility to CRC has been made in the last two decades. Numerous candidate gene analysis 6,7 and genome-wide association studies (GWAS) [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] have identified a number of genetic variants, mainly single nucleotide polymorphisms (SNPs), associated with CRC risk. The risk conferred by each of these variants is usually modest.…”

Distinct NF-κB and MAPK Activation Thresholds Uncouple Steady-State Microbe Sensing from Anti-pathogen Inflammatory Responses

“…Mice engineered with myeloid-cell specific genetic deletion of Tnf AREs succumb to spontaneous inflammatory disease (Kontoyiannis et al, 2002; Kontoyiannis et al, 1999), in accord with the idea that NF-κB signaling and transcription of Tnf occur in the steady state and that post-transcriptional regulation by MAPK provides a critical second barrier to initiation of aberrant inflammation. GWAS have linked genes for MAPK-regulating phosphatases in the dual-specificity phosphatases (DUSP) family with IBD and colorectal cancer (Fernandez-Rozadilla et al, 2013; Houlston et al, 2010; Jostins et al, 2012; Yang et al, 2014), which are also associated with aberrant TNF production (Croft et al, 2013). It is interesting to speculate that impaired MAPK de-phosphorylation by DUSPs, due to quantitative trait loci–related changes in protein expression, may shift the MAPK dose-response towards the type of higher sensitivity we see in RAW macrophages.…”