Angiotensin-converting enzyme insertion/deletion polymorphism as a potential risk factor of congenital heart disease: insights from a tertiary pediatric cardiac care centre from North India

Background: Our study aims to elucidate the genetic influence of angiotensin-converting enzyme insertion/deletion (ACE I/D) polymorphism on congenital heart disease (CHD) in a north Indian cohort. Methods: 667 CHD cases, including 433 individuals with parental data and 104 controls were enrolled and genotyped by polymerase chain reaction. Case-control association, parental transmission test, and association of patients' and parents' clinical parameters with ACE I/D were explored. Results: Our findings highlight significant associations, notably the increased CHD risk conferred by the DD genotype in females (p=0.036; OR=1.68), its correlation with abnormal hemoglobin levels (p=0.049; OR=1.68), and its impact on primigravida (p=0.05). Conversely, the II genotype was found to significantly elevate the risk of CHD in offspring of tobacco-consuming fathers by 2.5-fold (p=0.029). Notably, cyanotic cases exhibited a heightened prevalence of ACE I/D mutations (p=0.059), with tetralogy of Fallot (TOF) showing the strongest association (p=0.024). Additionally, the DD genotype's involvement in conditions such as stenosis (p=0.026) and pulmonary artery hypertension (PAH) (p=0.05) underscores its clinical relevance. The parent of origin test showed maternal transmission of the D allele in combined (p=0.037) and acyanotic cases (p=0.039) and paternal transmission in ventricular septal defect (p=0.021). Conclusions: This is the first study from India and possibly the only study globally that reports a significant association between ACE I/D and CHD, highlighting the importance of genetic factors in CHD susceptibility.