The allelic architecture whereas highpenetrance germline mutations account for cases. Common genetic variants at several loci involved in the transforming growth factor beta superfamily signaling pathway have been identified as low-penetrance variants that Alprostadil affect CRC development, when an unbiased approach is used, such as a genome-wide association analysis. TGF-beta is one of the most potent inhibitors of the proliferation of epithelial cells. Abnormalities in this signaling pathway are almost universal in cancer cells and are mediated through a variety of mechanisms. The TGF-beta receptor type I is a mediator of TGF-beta growth-inhibitory signals and has been targeted in several studies of cancer susceptibility and progression, with frequently discordant results. Recently, a phenomenon called ����allele-specific expression���� was described; ASE occurs in the germline at the TGFBR1 gene in 10%�C20% of CRC patients and generates an increased risk of CRC, althoughthe underlying geneticcause of this transcriptional variation remains unknown. More recently, contrary results were Simetryn reported, in that the ASE of TGFBR1 was observed as a rare event and no increased susceptibility to CRC could be detected. It is currently accepted that there is a direct association between a genetic susceptibility to cancer and the number of risk alleles carried by an individual. Evidence for this assumption comes from several studies in which the authors analyzed a combination of a small number of susceptibility alleles at different loci. The 2% of the population with the highest risk, who carried multiple low-risk alleles, had an increase in CRC of about fourfold compared with individuals with a median population risk. In the present study, we aimed to map the genetic susceptibility interactions for CRC at the TGFBR1 locus. Our results show that individuals carrying the combination of a specific haplotype and ASE have a substantially increased risk of CRC, although neither of these factors had a significant effect on CRC susceptibility when analyzed individually. According to our results, the combined analysis of multiple genetic factors associated with cancer susceptibility, with insubstantial individual weights, might reveal a more precise intralocus allelic architecture than can individual analyses, and define specific subgroups of individuals with important levels of risk for CRC. In the current work, we have presented evidence that individuals carrying the specific TGFBR1 H2 haplotype and TGFBR1 ASE have a high relative risk of CRC, whereas the individual risk associated with each of these factors is negligible.