Genome‐wide association study identifies a new SMAD7 risk variant associated with colorectal cancer risk in East Asians

Abstract

Genome-wide association studies (GWAS) of colorectal cancer (CRC) have been conducted primarily in European descendants. In a GWAS conducted in East Asians, we first analyzed approximately 1.7 million single-nucleotide polymorphisms (SNPs) in four studies with 1,773 CRC cases and 2,642 controls. We then selected 66 promising SNPs for replication and genotyped them in three independent studies with 3,612 cases and 3,523 controls. Five SNPs were further evaluated using data from four additional studies including up to 3,290 cases and 4,339 controls. SNP rs7229639 in the SMAD7 gene was found to be associated with CRC risk with an odds ratio (95% confidence interval) associated with the minor allele (A) of 1.22 (1.15-1.29) in the combined analysis of all 11 studies (P = 2.93×10−11). SNP rs7229639 is 2,487 bp upstream from rs4939827, a risk variant identified previously in a European-ancestry GWAS in relation to CRC risk. However, these two SNPs are not correlated in East Asians (r2 = 0.008) nor in Europeans (r2 = 0.146). The CRC association with rs7229639 remained statistically significant after adjusting for rs4939827 as well as three additional CRC risk variants (rs58920878, rs12953717, and rs4464148) reported previously in this region. SNPs rs7229639 and rs4939827 explained approximately 1% of the familial relative risk of CRC in East Asians. This study identifies a new CRC risk variant in the SMAD7 gene, further highlighting the significant role of this gene in the etiology of CRC.

Quantifying the Utility of Single Nucleotide Polymorphisms to Guide Colorectal Cancer Screening

“…Of these, four SNPs within 11q12.2 (rs174537, rs4246215, rs174550 and rs1535) were reported to be perfectly correlated and could be represented by a common haplotype [17] (named here as the 11q12.2 haplotype). Two SNPs within 19q13.2 (rs1800469 and rs2241714) were reported to be perfectly correlated and could be represented by a common haplotype [17] (named here as the 19q13.2 haplotype). One SNP is on the X chromosome (rs5934683) [18] and was not included in our simulation of colorectal cancer risk for males and females combined.…”

“…[32,34] 10p13 CUBN rs10904849 1.14 0.68 1.0037 0.46% [22] 10p14 GATA3 rs10795668 1.12 0.67 1.0028 0.35% [31] 10q22.3 ZMIZ1; AS1 rs704017 1.06 0.57 1.0008 0.10% [17] 10q24.2 SLC25A28; ENTPD7; COX15; CUTC; ABCC2 rs11190164 1.09 0.29 1.0015 0.19% [27] 10q25 VTI1A rs12241008 1.13 0.09 1.0012 0.15% [17] 11q12.2 FADS1; FEN1 11qhap ‡ 1.4 0.57 1.0281 3.41% [17] 11q13.4 POLD3 rs3824999 1.08 0.5 1.0015 0.18% [18] 11q23.1 COLCA2 rs3802842 1.11 0.29 1.0022 0.28% [35] 12p13.32 CCND2 rs3217810 1.2 0.16 1.0045 0.55% [23,24] 12p13.32 CCND2 rs3217901 1.1 0.41 1.0022 0.27% [23,24] 12p13.32 CCND2 rs10774214 1.09 0.38 1.0018 0.22% [30] 12q13.13 DIP2B; ATF1 rs11169552 1.09 0.72 1.0015 0.18% [25] 12q13.13 LARP4; DIP2B rs7136702 1.06 0.35 1.0008 0.10% [25] 12q24.12 SH2B3 rs3184504 1.09 0.53 1.0019 0.23% [27] 12q24.21 TBX3 rs59336 1.09 0.48 1.0019 0.23% [26] 12q24.22 NOS1 rs73208120 1.16 0.11 1.0021 0.26% [27] 14q22.2 BMP4 rs1957636 1.08 0.4 1.0014 0.18% [36] 14q22.2 BMP4 rs4444235 1.11 0.46 1.0027 0.33% [36,37] 15q13.3 SCG5; GREM1 rs11632715 1.12 0.47 1.0032 0.39% [36] 15q13.3 SCG5; GREM1 rs16969681 1.18 0.09 1.0022 0.28% [36] 16q22.1 CDH1 rs9929218 1.1 0.71 1.0019 0.23% [37] 16q24.1 FOXL1 rs16941835 1.15 0.21 1.0032 0.40% [22] 17q21 STAT3 rs744166 1.27 0.55 1.0142 1.74% [38] 18q21.1 SMAD7 rs4939827 1.18 0.52 1.0069 0.84% [35,39] 19q13.11 RHPN2 rs10411210 1.15 0.9 1.0018 0.22% [37] 19q13.2 TMEM91; TGFB1 19qhap ‡ 1.16 0.49 1.0055 0.68% [17] 20p12.3 FERMT1; BMP2 rs2423279, 1.14 0.3 1.0036 0.44% [24,30] 20p12.3 FERMT1; BMP2 rs4813802 1.09 0.36 1.0017 0.21% …”

“…† Gene/s closest to or likely regulatory target of SNP. ‡ Four SNPs within 11q12.2 (rs174537, rs4246215, rs174550, and rs1535) were reported to be perfectly correlated and could be represented by a common haplotype [17] (Figure 1). Compared with people in the middle quintile for the number of risk alleles, the odds ratio for colorectal cancer was 1.81 for people in the highest quintile of number of risk alleles, and 0.51 for people in the lowest quintile; this is equivalent to a 3.55-fold inter-quintile risk (highest vs lowest quintile).…”

“…† Gene/s closest to or likely regulatory target of SNP. ‡ Four SNPs within 11q12.2 (rs174537, rs4246215, rs174550, and rs1535) were reported to be perfectly correlated and could be represented by a common haplotype [17] …”

The genetic heterogeneity of colorectal cancer predisposition - guidelines for gene discovery

“…Since 2007, several genome-wide association studies (GWAS) have been conducted under the premise of the CDCV hypothesis for CRC [65–84]. These studies aimed to use unbiased genome-wide screens to identify non-random associations of alleles at nearby loci (linkage disequilibrium), which then served as proxies, or tagSNPs, for other nearby risk alleles [85].…”