These processes are finely regulated, and abnormal expression of SMAD7 has been proved to affect a variety of human diseases, such as various tumorigenesis, tissue fibrosis, and intestinal inflammation. SMAD7 contains two functional mad homology AbMole Gemifloxacin mesylate domains linked by a non-conserved linker region. The MH1 domain is located at the N-terminus and the MH2 domain is located at the C-terminus. Truncated SMAD7 lacking the C-terminal MH2 domain is unable to promote myogenic AbMole Benzyl alcohol differentiation. Studies of mice deficient in Smad7 demonstrated the critical roles this protein played in heart homeostasis. Chen et al. reported that most Smad7 homozygous mutant mice lacking the MH2 domain died in utero due to severe defects in cardiovascular development, such as ventricular septal defects and outflow tract malformation; however, deletion of exon1 did not manifest a different heart phenotype. Over-expression of Smad7 also results in congenital cardiovascular defects. Therefore, SMAD7 is essential for cardiac development. It is assumed that SMAD7, especially the MH2 domain, is associated with an increased risk of human CHD, but no research has been conducted to explore this hypothesis as yet. Ongoing researches demonstrate that variations in genes contribute to the occurrence of CHD to a large degree. Thus, we carried out a case-control study in a large Han Chinese population to examine if SMAD7 was associated with CHD. We found that two highly linked SNPs, rs3809922 and rs3809923, were associated with an increased risk of CHD, especially with septation defects, the main CHD subtype. These results established common genetic variations of SMAD7 as susceptibility loci for CHD for the first time and further analysis indicated that the association might be population specific. Our study provided new insight into the development of congenital heart defects. In the recessive model, individuals that were homozygous for risk alleles were coded as 1, while other genotypes were coded as 0. In the dominant model, individuals carrying at least one risk allele were coded as 1, and those who were homozygous for two non-risk alleles were coded as 0. In the multiplicative model, the total number of risk and nonrisk alleles was compared between cases and controls, regardless of the genotypes of the individuals carrying the alleles. TGF-b signaling mediated by SMADs is critical for a great many cellular and developmental processes and plays a key role in embryogenesis and tissue homeostasis. Recent studies have shown that TGF-b signaling is essential for the function of the cardiovascular system and in particular, SMAD6 has been reported to be associated with human congenital cardiovascular malformation. Smad7 is critical for heart development in mouse models. Therefore, it was hypothesized that SMAD7 might be associated with the risk of congenital heart defects in humans. Here, we provide evidence supporting this assumption. We performed a large case-control study to test the hypothesis that variants in SMAD7 are associated with CHD, and initially identified that alleles in two genetic variants of SMAD7 were significantly associated with susceptibility for CHD in the Han Chinese population. Both allele T in rs3809922 and allele G in rs3809923 were risk factors, especially when analyzed with a recessive model. The association was more significant when the septation defects subtype was considered. Further analysis of the haplotypes showed that the haplotype TG was significantly enriched in CHD cases. This result was essentially consistent with the analysis based on each single locus.