Genetic variation in the mitochondrial enzyme carbamyl-phosphate synthetase I predisposes children to increased pulmonary artery pressure following surgical repair of congenital heart defects: A validated genetic association study

Abstract

Increased pulmonary artery pressure (PAP) can complicate the postoperative care of children undergoing surgical repair of congenital heart defects. Endogenous NO regulates PAP and is derived from arginine supplied by the urea cycle. The rate-limiting step in the urea cycle is catalyzed by a mitochondrial enzyme, carbamoyl-phosphate synthetase I (CPSI). A well-characterized polymorphism in the gene encoding CPSI (T1405N) has previously been implicated in neonatal pulmonary hypertension. A consecutive modeling cohort of children (N=131) with congenital heart defects requiring surgery was prospectively evaluated to determine key factors associated with increased postoperative PAP, defined as a mean PAP > 20mmHg for at least one hour during the 48 hours following surgery measured by an indwelling pulmonary artery catheter. Multiple Dimensionality Reduction (MDR) was used to both internally validate observations and develop optimal two-variable through five-variable models that were tested prospectively in a validation cohort (N= 41). Unconditional logistic regression analysis of the modeling cohort revealed that age (OR= 0.92, p=0.01), CPSI T1405N genotype (AC vs. AA: OR=4.08, p=0.04, CC vs. AA: OR=5.96, p=0.01), and Down syndrome (OR=5.25, p=0.04) were independent predictors of this complex phenotype. MDR predicted that the best two-variable model consisted of age and CPSI T1405N genotype (p<0.001). This two-variable model correctly predicted 73% of the outcomes from the validation cohort. A five-variable model that added race, gender and Down's syndrome was not significantly better than the two-variable model. In conclusion, the CPSI T1405N genotype appears to be an important new factor in predicting susceptibility to increased PAP following surgical repair of congenital cardiac defects in children.

Association between the p.Thr1406Asn polymorphism of the carbamoyl-phosphate synthetase 1 gene and necrotizing enterocolitis: A prospective multicenter study

“…In accordance with our results, it has been reported a protective role of the A-allele toward persistent pulmonary hypertension of the newborn15, pulmonary hypertension following surgical repair of congenital heart defects26, and hepatic veno-occlusive disease after bone marrow transplantation23. Moreover, the haplotype formed by the SNPs of CPS1 rs715 and rs1047891 (p.Thr1406Asn) yield a protective association with decreased risk of coronary artery disease in women35.…”

“…It has been suggested that the A-allele may confer an advantage in terms of NO production, especially under conditions of environmental stress15. Previous studies demonstrated the association of the CPS1 p.Thr1406Asn genotype with clinical situations where endogenous NO production is critically important, such as persistent pulmonary hypertension of the newborn15, pulmonary hypertension following surgical repair of congenital heart defects26, and hepatic veno-occlusive disease after bone marrow transplantation23.…”

Carbamoyl Phosphate Synthetase 1 deficiency in Italy: Clinical and genetic findings in a heterogeneous cohort

“…In subjects who are homozygous for the A allele the nitric oxide metabolite concentration was lower than in those who are homozygote for C allele or heterozygous (Summar et al, 1995). The p.Thr1406Asn amino acid substitution results in a significant change of CPS1 enzymatic function (Canter et al, 2007) with a reported 30-40% difference in enzyme activity (Summar et al, 1995). The polymorphism is located at a variable position in the MSA, and asparagine at 1406 is found in homolog sequences.…”

Population screening in a Druze community: the challenge and the reward

“…In the CPS1 group, for example, we are alert to the possibility of increased incidence of pulmonary hypertension or a pathologic condition involving compromised NO production. 32 In the CTX group, the development of accelerated atherosclerosis, abnormal lipid profiles, and the dietary affect of cholestanol 33 are matters for future follow up.…”