Background:

Ventricular septal defects (VSDs), a congenital cardiac disease is the major abnormality of the heart that contributes to 40% of neonatal mortalities in the first month of childbirth. VSDs is a complex disease that is the result of interaction of various genetic determinants in regulators, transcription factors and enzymes including GATA4, SMAD7, VEGF, MTRR and ISL1.The understanding of genetic variations that contribute to VSDs is still underreported in the Pakistani population.
Methods:

Genotyping of seven polymorphisms was performed on 100 pediatric subjects (50 VSDs patients and 50 controls) by using Tetra ARMS-PCR and PCR–RFLP methodology. The single and polygenic variant analysis was conducted to identify the risk variants.
Results:

The results of the analysis showed that MAF of all selected variants was significantly associated with VSDs. The GATA4 rs4841587 [OR 0.40 (95% CI 0.15–1.01)], SMAD7 rs3736242 [OR 0.26 (95% CI 0.08–0.81)], SMAD7 rs16950113 [OR 0.48 (95% CI 0.26–0.88)], VEGF rs699947 [OR 0.89 (95% CI 0.51–1.55)] variants showed significant protective impact, whereas GATA4 rs104894073 [OR 1.19 (95% CI 0.67–2.12)], MTRR rs1532268 [OR 1.00 (95% CI 0.57–1.75)], ISL1 rs6867206 [OR 1.39 (95% CI 0.76–2.55)] variants showed association with increased risk of VSD. Genetic contrast analysis demonstrated that the GATA4 rs104894073, VEGF rs699947 and MTRR rs1532268 increased risk of VSDs in the dominant model and the heterozygous genotype in the co-dominant model. In contrast, polygenic risk score does not suggest conclusive results.
Conclusion:

Our findings especially for GATA4 rs104894073, VEGF rs699947 and MTRR rs1532268 variants need to be validated in future studies. Also, a more effective model of PRS should be developed that has more significant predictive power especially for the candidate SNP analysis.