Decoding AGT rs(699) variant and gene expression in relation to congenital heart defects

Abstract 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 rs (699) (M235T), likely influence susceptibility to CHDs. Aim: To investigate the association between the AGT rs (699) 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 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 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 indicates 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 rs (699) T allele and TT genotype are strongly associated with an increased risk of CHD. These findings suggest that AGT gene polymorphisms, potentially along with altered gene expression, may contribute to CHD pathogenesis. 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.