A low-frequency variant in SMAD7 modulates TGF-β signaling and confers risk for colorectal cancer in Chinese population

The TGF-beta pathway plays an essential role in regulating cell proliferation and differentiation. GWASs and candidate approaches have identified a battery of genetic variants in the TGF-beta pathway contributingto colorectal cancer (CRC). However, most of the significant variants are commonvariants and their functions remain ambiguous. To identify causal variants with low-frequency in the TGF-beta pathway contributing to CRC susceptibility in Chinese population, we performed targeted sequencing of 12 key genes in TGF-beta signaling in CRC patients followed by a two-stage case-control study with a total of 5109 cases and 5169 controls. Bioinformatic annotations and biochemical experimentswere applied to reveal the potential functions of significant variants. Seven low-frequency genetic variants were captured through targeted sequencing. The two stage association studies showed that missense variant rs3764482 (c. 83C> T; p. S28F) in the gene SMAD7 was consistently and significantly associated with CRC risk. Compared with the wild type, the ORs for variant allele were 1.37 (95% CI: 1.10-1.70, P = 0.005), 1.55 (95% CI: 1.30-1.86, P= 1.15x10(6)), and 1.48 (1.29-1.70, P= 2.44x10; 8) in stage 1, stage 2, and the combined analyses, respectively. Functional annotations revealed that the minor allele T of rs3764482 was more effective than themajor allele C in blocking the TGF-beta signaling and inhibiting the phosphorylation of receptor-regulated SMADs (R-SMADs). In conclusion, low frequency coding variant rs3764482inSMAD7 is associated with CR Crisk in Chinese population. The rs3764482 variant may block the TGF-beta signaling via impeding the activation of downstream genes, leading to cancer cell proliferation, thus contributing to CRC pathogenesis.