Study of variants associated with ventricular septal defects (VSDs) highlights the unique genetic structure of the Pakistani population

Abstract

Background Ventricular septal defects (VSDs) are one of the leading causes of death due to cardiac anomalies during the first months of life. The prevalence of VSD in neonates is reported up to 4%. Despite the remarkable progress in medication, treatment and surgical procedure for VSDs, the genetic etiology of VSDs is still in infancy because of the complex genetic and environmental interactions. Methods Three hundred fifty subjects (200 VSD children and 150 healthy controls) were recruited from different pediatric cardiac units. Pediatric clinical and demographic data were collected. A total of six variants, rs1017 (ISL1), rs7240256 (NFATc1), rs36208048 (VEGF), variant of HEY2, rs11067075 (TBX5) and rs1801133 (MTHFR) genes were genotyped by tetra-ARMS PCR and PCR–RFLP methods. Results The results showed that in cases, the rs1017 (g.16138A > T) variant in the ISL1 gene has an allele frequency of 0.42 and 0.58 respectively for the T and A alleles, and 0.75 and 0.25 respectively in the controls. The frequencies of the AA, TA and TT genotypes were, 52%, 11% and 37% in cases versus 21%, 8% and 71% respectively in the controls. For the NFATc1 variant rs7240256, minor allele frequency (MAF) was 0.43 in cases while 0.23 in controls. For the variant in the VEGF gene, genotype frequencies were 0% (A), 32% (CA) and 68% (CC) in cases and 0.0%, 33% and 67% respectively in controls. The allele frequency of C and A were 0.84 and 0.16 in cases and 0.83 and 0.17 respectively in controls. The TBX5 polymorphism rs11067075 (g.51682G > T) had an allelic frequency of 0.44 and 0.56 respectively for T and G alleles in cases, versus 0.26 and 0.74 in the controls. We did not detect the presence of the HEY2 gene variant (g.126117350A > C) in our pediatric cohort. For the rs1801133 (g.14783C > T) variant in the MTHFR gene, the genotype frequencies were 25% (CC), 62% (CT) and 13% (TT) in cases, versus 88%, 10% and 2% in controls. The ISL1, NFATc1, TBX5 and MTHFR variants were found to be in association with VSD in the Pakistani pediatric cohort whilst the VEGF and HEY2 variants were completely absent in our cohort. Conclusion We propose that a wider programme of genetic screening of the Pakistani population for genetic markers in heart development genes would be helpful in reducing the risk of VSDs.

Genetic Polymorphisms of Vascular Endothelial Growth Factor in Neonatal Pathologies: A Systematic Search and Narrative Synthesis of the Literature

“…The first study analyzed the rs699947 (c.-2578C > A) variant of the VEGF gene and found a significant statistical difference in the frequencies of the A and C alleles in children with isolated VSD and controls, suggesting that the presence of the A allele can increase the rate for heart development issues (allelic odds ratio for A versus C was 2.03, with a confidence interval (CI) of 1.41–2.92 and a p -value of 0.0001) [ 59 ]. However, the second study selected the rs36208048 SNP of VEGF and did not find a statistical difference in allele frequencies between cases with VSD and non-VSD children [ 60 ].…”

Genetic studies in the Pakistani population reveal novel associations with ventricular septal defects (VSDs)

“…Size, number and exact location of the defect as well as magnitude of shunt were identified by two dimensional and Doppler echocardiography. The samples having VSD with other cardiac or extra-cardiac symptoms (syndromic VSD) and any seropositive sample (for HBV/HCV/HIV) in both cases and controls were excluded from the study as described previously [ 6 , 15 , 16 ].…”