Survival after cardiac surgery in infancy requires adaptive responses from oxidative stress management and vascular regulation pathways. We tested the hypothesis that genetic variation in these pathways influences postoperative survival in nonsyndromic congenital heart disease children.Methods
This is an analysis of a cohort of nonsyndromic congenital heart disease patients who underwent cardiac surgery with cardiopulmonary bypass before 6 months of age (n = 422). Six single nucleotide polymorphisms (SNPs) in six genes involved in oxidative stress and vascular response pathways, identified through a priori literature search, were tested for effects on transplant-free survival. Survival curves, adjusting for confounding covariates, were calculated using the Cox proportional hazard models.Results
Long-term survival was strongly associated with vascular endothelial growth factor A gene SNP rs833069 (p = 7.03×10−4) and superoxide dismutase 2 gene SNP rs2758331 (p = 0.019). To test for joint effects of the two SNPs on transplant-free survival, the genotypes were grouped to form a risk score reflecting the cumulative number of risk alleles (0 to 4 alleles per patient). A higher risk score based on the VEGFA and SOD2 SNP genotypes was associated with worse transplant-free survival (p = 3.02×10−4) after confounder adjustment. The total burden of risk alleles was additive; subjects with the highest risk score of 4 (n = 59 subjects, 14.2% of the cohort) had a total covariate-adjusted hazard ratio of 15.64 for worse transplant-free survival.Conclusions
After cardiac surgery, infants who are homozygous for the high-risk alleles for both the VEGFA and SOD2 SNPs have an approximately 16-fold increased risk of death or heart transplant, suggesting that genetic variants are important modifiers of survival after surgery for congenital heart disease.