Validation of association of the apolipoprotein E epsilon2 allele with neurodevelopmental dysfunction after cardiac surgery in neonates and infants

Gaynor, J. W.; Kim, D. S.; Arrington, C. B.; Atz, A. M.; Bellinger, D. C.; Burt, A. A.; Ghanayem, N. S.; Jacobs, J. P.; Lee, T. M.; Lewis, A. B.; Mahle, W. T.; Marino, B. S.; Miller, S. G.; Newburger, J. W.; Pizarro, C.; Ravishankar, C.; Santani, A. B.; Wilder, N. S.; Jarvik, G. P.; Mital, S.; Russell, M. W.

J Thorac Cardiovasc Surg. 2014 Oct 6; 148(6):2560-8

Abstract

OBJECTIVE: Apolipoprotein E (APOE) genotype is a determinant of neurologic recovery after brain ischemia and traumatic brain injury. The APOE epsilon2 allele has been associated with worse neurodevelopmental (ND) outcome after repair of congenital heart defects (CHD) in infancy. Replication of this finding in an independent cohort is essential to validate the observed genotype-phenotype association. METHODS: The association of APOE genotype with ND outcomes was assessed in a combined cohort of patients with single-ventricle CHD enrolled in the Single Ventricle Reconstruction and Infant Single Ventricle trials. ND outcome was assessed at 14 months using the Psychomotor Development Index (PDI) and Mental Development Index (MDI) of the Bayley Scales of Infant Development-II. Stepwise multivariable regression was performed to develop predictive models for PDI and MDI scores. RESULTS: Complete data were available for 298 of 435 patients. After adjustment for preoperative and postoperative covariates, the APOE epsilon2 allele was associated with a lower PDI score (P = .038). Patients with the epsilon2 allele had a PDI score approximately 6 points lower than those without the risk allele, explaining 1.04% of overall PDI variance, because the epsilon2 allele was present in only 11% of the patients. There was a marginal effect of the epsilon2 allele on MDI scores (P = .058). CONCLUSIONS: These data validate the association of the APOE epsilon2 allele with adverse early ND outcomes after cardiac surgery in infants, independent of patient and operative factors. Genetic variants that decrease neuroresilience and impair neuronal repair after brain injury are important risk factors for ND dysfunction after surgery for CHD.

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