Abstract
Atrial septal defect (ASD) is the third most frequent type of congenital heart anomaly, featuring shunting of blood between the two atria. Gene-environment interaction remains to be an acknowledged cause for ASD occurrence. A recent European genome-wide association study (GWAS) of congenital heart disease (CHD) identified 3 susceptibility SNPs at chromosome 4p16 associated with ASD: rs870142, rs16835979 and rs6824295. A Chinese-GWAS of CHD conducted in the corresponding period did not reveal the 3 susceptibility SNPs, but reported 2 different risk SNPs: rs2474937 and rs1531070. Therefore, we aimed to investigate the associations between the 3 European GWAS-identified susceptibility SNPs and ASD risk in the Han population in southwest China. Additionally, to increase the robustness of our current analysis, we conducted a meta-analysis combining published studies and our current case-control study. We performed association, linkage disequilibrium, and haplotype analysis among the 3 SNPs in 190 ASD cases and 225 age-, sex-, and ethnicity-matched healthy controls. Genotype and allele frequencies among the 3 SNPs showed statistically significant differences between the cases and controls. Our study found that individuals carrying the allele T of rs870142, the allele A of rs16835979, and the allele T of rs6824295 had a respective 50.1% (odds ratio (OR) = 1.501, 95% confidence interval (CI) = 1.122-2.009, PFDR-BH = 0.018), 48.5% (OR = 1.485, 95%CI = 1.109-1.987, PFDR-BH = 0.012), and 38.6% (OR = 1.386, 95%CI = 1.042-1.844, PFDR-BH = 0.025) increased risk to develop ASD than wild-type allele carriers in our study cohort. In the haplotype analysis, we identified a disease-risk haplotype (TAT) (OR = 1.540, 95%CI = 1.030-2.380, PFDR-BH = 0.016). Our meta-analysis also showed that the investigated SNP was associated with ASD risk (combined OR (95%CI) = 1.35 (1.24-1.46), P < 0.00001). Our study provides compelling evidence to motivate better understanding of the etiology of ASD.
Highlights
Congenital heart disease (CHD), characterized by cardiovascular structure and function abnormalities, is one of the most frequently occurring congenital malformations in infants and children
These include GATA4, a transcription factor essential for heart formation, and TBX5, a T-box protein required for cardiac conduction system, which have been reported as conferring predisposition to Atrial septal defect (ASD) occurrence [6,7]
For the rs16835979 polymorphism, we observed that the frequencies of the A-allele and AA-genotype were higher in the cases than in the controls, with the OR of an A allele carrier equaling 1.485 (95%CI = 1.109–1.987, PFDR-BH = 0.012) and the OR of an AA genotype carrier equaling 2.730 (95%CI = 1.425–5.228, PFDR-BH = 0.003)
Summary
Congenital heart disease (CHD), characterized by cardiovascular structure and function abnormalities, is one of the most frequently occurring congenital malformations in infants and children. Atrial septal defect (ASD), the third most common type of CHD, is mainly caused by the hypoplasia of atrial septum, resulting in abnormal flow of blood between the systemic and pulmonary circulations. Despite this defect, ASD patients lack specific symptoms in the early stages so that diagnosis can be difficult. Numerous genes encoding transcription factors and important heart proteins have been associated with ASD risk. These include GATA4, a transcription factor essential for heart formation, and TBX5, a T-box protein required for cardiac conduction system, which have been reported as conferring predisposition to ASD occurrence [6,7]. More genes that are known to play a role in normal heart function need to be investigated for mutations that may be associated with alterations in heart development
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