Abstract
SMAD7 is a general antagonist of TGF-β signaling and has been found to be involved in cardiogenesis in mouse models, but its role in human congenital heart disease (CHD) has yet to be investigated. To examine if SMAD7 is associated with CHD, we conducted a case-control study in the Han Chinese population. Exon1 and exon4 of SMAD7, which encode the functional MH1 and MH2 domains, were directly sequenced in 1,201 sporadic CHD patients and 1,116 control individuals. A total of 18 sequence variations were identified. Two common variants rs3809922 and rs3809923 are located at exon4 of SMAD7, and were found in strong linkage disequilibrium with each other (r 2 = 0.93). We analyzed the association of these two loci with CHD in 3 independent subgroup case-control studies, and found that in some subgroups, rs3809922 and rs3809923 were significantly associated with CHD through genetic model analysis. In the combined data set, TT genotype in rs3809922 significantly increased the risk of CHD compared with CC and CT, while GG genotype in rs3809923 significantly increased the risk of CHD compared with CC and CG, particularly in the recessive model. In addition, haplotype analyses showed that haplotype TG significantly increased the risk of CHD (P = 6.9×10−6); this finding supports the results from the analyses based on single locus. According to data from the 1000 Genomes Project, the frequencies of the two risk alleles varied greatly between populations worldwide, which indicate the identified associations might have a population difference. To our knowledge, this is the first report that genetic variants in SMAD7 influence susceptibility to CHD risk.
Highlights
Cardiac morphogenesis involves acute spatial and temporal regulation of numerous factors and signal pathways
The other variations in the coding region were rare mutations (MAF,0.005), including five synonymous mutations and one non-synonymous mutation only found in the Congenital heart disease (CHD) population, three synonymous and five non-synonymous mutations only found in the control population and one synonymous mutation found in both case and control populations
Statistical result Here, we focused on analysis of the two common variants, rs3809922 and rs3809923. They were located in exon4 of SMAD7, which encodes the MH2 functional domain. These two loci were in strong linkage disequilibrium (LD) with each other according to the sequencing result (r2 = 0.93) and were both in Hardy-Weinberg Equilibrium in the control population (Table S3)
Summary
Cardiac morphogenesis involves acute spatial and temporal regulation of numerous factors and signal pathways. Any disturbance to this finely regulated, complex process may lead to the occurrence of heart defects [1]. Congenital heart disease (CHD) is one of the most common birth defects worldwide and is the leading cause of mortality and morbidity in newborns. CHD occurs in approximately 1–8% of live births and is responsible for approximately 10% of infant deaths [1,2,3]. It is generally accepted that CHD has a genetic component and that environmental factors contribute to disease etiology [4,5]; the underlying mechanisms remain largely obscure
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
