Decoding AGT Variant and Gene Expression in Relation to Congenital Heart Defects.

Background: Congenital Heart Defects (CHDs) are among the most common birth anomalies worldwide, with genetic and molecular factors contributing significantly to their development. The renin–angiotensin system (RAS) plays a key role in cardiovascular regulation, and polymorphisms in the angiotensinogen ( AGT ) gene, particularly rs699 (M235T), may influence susceptibility to CHDs. Aim: To investigate the association between the AGT (rs699) polymorphism and CHD risk in an Indian pediatric population. Methods: A case-control study was conducted involving 112 children with CHDs and 112 age- and sex-matched healthy controls. Genomic DNA was extracted and genotyped for the rs699 variant using PCR-RFLP. Genotype and allele frequencies were compared between groups to assess their association with CHD risk. Results: The TT genotype was significantly more frequent among CHD cases (44.6%) than controls (10.7%) ( P < 0.0001), indicating a strong association with disease risk. The CT genotype also showed a significant association ( P = 0.0090; OR = 2.3750, 95% CI: 1.2411–4.5450), while the CC genotype was more prevalent in controls. Under the dominant model (CT + TT), individuals carrying at least one T allele had a significantly higher risk of CHD ( P < 0.0001; OR = 4.2308, 95% CI: 2.3582–7.5903). Allele frequency analysis revealed a higher T allele frequency in cases (61.6%) than controls (28.6%) ( P < 0.0001; OR = 4.0116, 95% CI: 2.7008–5.9587). Additionally, gene expression analysis indicated a modest but significant upregulation of AGT in CHD cases, with a fold change of 1.773 ( P = 0.032676), suggesting that the T allele may influence both genetic susceptibility and gene activity. Conclusion: The AGT (rs699) T allele and TT genotype are strongly associated with an increased risk of CHD in this population. These findings suggest that AGT gene polymorphisms, potentially along with altered gene expression, may contribute to CHD pathogenesis. Additionally, AGT gene expression analysis revealed a modest but statistically significant upregulation in CHD cases compared to controls, with a fold change of 1.773 (p = 0.032676). Although the difference in expression was minimal, it may indicate a potential role of AGT gene activity in CHD pathogenesis. However, due to the limited number of samples, no significant clinical correlation could be established between gene expression levels and specific CHD subtypes. Further studies with larger cohorts are warranted to validate these findings and explore their clinical relevance.