Birth defects, the ventricular septal defect (VSD) in particular, have major public health significance. There is evidence that genetic factors play a role in VSD risk. We report here our findings on the relationship between VSD and microRNA (miRNA)-3691-3p target sequence single-nucleotide polymorphisms (SNPs) in the 3' untranslated region of the NOTCH1 gene. Functional SNPs in NOTCH1 target sequence were screened from the SNP database. A case-control study in a large Chinese Han population sample of 350 children with VSD and 430 healthy controls examined the association between rs6563 SNPs and VSD. NOTCH1 wild and mutant recombinant expression vectors were constructed by the luciferase reporter gene system. The effects of miRNA on gene regulatory effects were also analyzed. The allelic distributions at the locus rs6563 showed statistically significant susceptibility to VSD (odds ratio [OR] = 1.502, 95% confidence interval [CI] = 1.209-1.866, p < 0.001). Compared with the subjects with G/G genotype, individuals with G/A genotype or A/A genotype showed ORs 1.414 (95% CI = 1.047-1.908, p = 0.020) and 2.366 (95% CI = 1.430-3.914, p < 0.001), respectively. The miRNA-3691-3p reduced luciferase activity of the A allele. The rs6563G > A genetic variation appears to be associated with congenital VSD through gene regulatory effects of miR-3691-3p on the NOTCH1 gene. Further studies in other population samples are called for diagnostics and public health innovation in relation to birth defects.
Keywords: gene; birth defects; gene regulation; genetic polymorphism; microRNA; ventricular septal defect.