Abstract
Genome-wide association studies (GWAS) on colorectal cancer (CRC) have identified dozens of single nucleotide polymorphisms (SNPs) in more than 19 independent loci associated with CRC. Due to the heterogeneity of the studied subjects and the contrary results, it is challenging to verify the certainty of the association between these loci and CRC.We conducted a critical review of the published studies of SNPs associated with CRC. Five most frequently reported SNPs, which are rs6983267/8q24.21, rs4939827/18q21.1, rs10795668/10p14, rs4444235/14q22.2 and rs4779584/ 15q13.3, were selected for the current study from the qualified studies. Then meta-analyses based on larger sample sizes with average of 33,000 CRC cases and 34,000 controls were performed to assess the association between SNPs and CRC risk. Heterogeneity among studies and publication bias were assessed by the χ2-based Q statistic test Begg's funnel plot or Egger's test, respectively.Our meta-analysis confirmed significant associations of the five SNPs with CRC risk under different genetic models. Two risk variants at rs6983267 {Odds Ratio (OR) 1.388, 95% Confidence Interval (CI) 1.180-1.8633} and rs10795668 (OR 1.323, 95% CI 1.062-1.648) had the highest ORs in homogeneous model. While ORs of the other three variants at rs4939827 {OR 1.298, 95% CI 1.135-1.483}, rs4779584 (OR 1.261, 95% CI 1.146-1.386) and rs4444235 (OR 1.160, 95% CI 1.106-1.216) were also statistically significant. Sensitivity analyses and publication bias assessment indicated the robust stability and reliability of the results.
Highlights
Colorectal cancer (CRC) is a leading cause of cancer and cancer deaths in the Western countries [1]
Genome-wide association studies (GWAS) conducted in populations of European ancestry living in the United Kingdom (UK) and Canada have been published for the identification of 11 wellreplicated disease loci, of which most were not previously suspected to be related to colorectal cancer (CRC)
There were 149 individual single nucleotide polymorphisms (SNPs) reported to be associated with CRC risk. 19 of them were reported at least twice by different studies, 5 SNPs among which were most frequently reported: rs6983267, rs4939827, rs10795668, rs4444235 and rs4779584 (Table 1)
Summary
Colorectal cancer (CRC) is a leading cause of cancer and cancer deaths in the Western countries [1]. Linkage studies on multi-case families have identified a number of rare mutations in highly penetrant genes (e.g. FAP, HNPCC, DNA mismatch repair (MMR) gene). With the resources of human genome and high-throughput platforms, Genome-wide association studies (GWAS) provide a powerful new approach allowing the scanning of the entire genome for association with disease to identify common, low-penetrance susceptibility loci without prior knowledge of biological function. GWAS conducted in populations of European ancestry living in the United Kingdom (UK) and Canada have been published for the identification of 11 wellreplicated disease loci, of which most were not previously suspected to be related to CRC These variants map to 8q24.21 (rs6983267), 8q23.3 (rs16892766, EIF3H), 9q24 (rs719725), 10p14 (rs10795668), 11q23 (rs3802842), 14q22.2 (rs4444235, BMP4), 15q13.3 (rs4779584), 16q22.1 (rs9929218, CDH1), 18q21.1 (rs4939827, SMAD7), 19q13.1 (rs10411210, RHPN2) and 20p12.3 (rs961253) [15, 16]. We performed an up to date meta-analysis to more precisely characterize the association between these 5 SNPs and CRC on a larger sample sizes
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