title: Validation of association of the apolipoprotein E ε2 allele with neurodevelopmental dysfunction after cardiac surgery in neonates and infants.
abstract: OBJECTIVE
  Apolipoprotein E (APOE) genotype is a determinant of neurologic recovery after brain ischemia and traumatic brain injury. The APOE ε2 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 ε2 allele was associated with a lower PDI score (P = .038). Patients with the ε2 allele had a PDI score approximately 6 points lower than those without the risk allele, explaining 1.04% of overall PDI variance, because the ε2 allele was present in only 11% of the patients. There was a marginal effect of the ε2 allele on MDI scores (P = .058).
  
  
  CONCLUSIONS
  These data validate the association of the APOE ε2 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.
authors.affiliation: Division of Cardiothoracic Surgery, The Children's Hospital of Philadelphia, Philadelphia, Pa. Electronic address: gaynor@email.chop.edu.
authors.forename: J William
authors.initials: JW
authors.lastname: Gaynor
authors.affiliation: Departments of Medicine (Division of Medical Genetics) and Genome Sciences, University of Washington School of Medicine, Seattle, Wash.
authors.forename: Daniel Seung
authors.initials: DS
authors.lastname: Kim
authors.affiliation: Primary Children's Medical Center, Salt Lake City, Utah.
authors.forename: Cammon B
authors.initials: CB
authors.lastname: Arrington
authors.affiliation: Division of Pediatric Cardiology, Medical University of South Carolina, Charleston, SC.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Atz
authors.affiliation: Department of Neurology, Boston Children's Hospital, Boston, Mass, and Department of Neurology, Harvard Medical School, Boston, Mass.
authors.forename: David C
authors.initials: DC
authors.lastname: Bellinger
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, Wash.
authors.forename: Amber A
authors.initials: AA
authors.lastname: Burt
authors.affiliation: Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wis.
authors.forename: Nancy S
authors.initials: NS
authors.lastname: Ghanayem
authors.affiliation: Johns Hopkins Children's Heart Institute, All Children's Hospital and Florida Hospital for Children, St Petersburg, Fla.
authors.forename: Jeffery P
authors.initials: JP
authors.lastname: Jacobs
authors.affiliation: Department of Pediatrics, Columbia University Medical Center, New York, NY.
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Lee
authors.affiliation: Children's Hospital Los Angeles, Los Angeles, Calif.
authors.forename: Alan B
authors.initials: AB
authors.lastname: Lewis
authors.affiliation: Children's Healthcare of Atlanta, Atlanta, Ga.
authors.forename: William T
authors.initials: WT
authors.lastname: Mahle
authors.affiliation: Ann and Robert F. Lurie Children's Hospital of Chicago, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Marino
authors.affiliation: Division of Pediatric Oncology, Duke University Medical Center, Durham, NC.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Miller
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Boston, Mass.
authors.forename: Jane W
authors.initials: JW
authors.lastname: Newburger
authors.affiliation: Nemours Cardiac Center, Alfred I. Dupont Hospital for Children, Wilmington, Del.
authors.forename: Christian
authors.initials: C
authors.lastname: Pizarro
authors.affiliation: Division of Pediatric Cardiology, The Children's Hospital of Philadelphia, Philadelphia, Pa.
authors.forename: Chitra
authors.initials: C
authors.lastname: Ravishankar
authors.affiliation: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pa.
authors.forename: Avni B
authors.initials: AB
authors.lastname: Santani
authors.affiliation: Department of Anesthesia, University of Michigan Medical School, Ann Arbor, Mich.
authors.forename: Nicole S
authors.initials: NS
authors.lastname: Wilder
authors.affiliation: Departments of Medicine (Division of Medical Genetics) and Genome Sciences, University of Washington School of Medicine, Seattle, Wash.
authors.forename: Gail P
authors.initials: GP
authors.lastname: Jarvik
authors.affiliation: Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Seema
authors.initials: S
authors.lastname: Mital
authors.affiliation: Department of Pediatrics and Communicable Diseases (Division of Pediatric Cardiology), University of Michigan Medical School, Ann Arbor, Mich.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Russell
mesh_terms: D000367:Age Factors; D053329:Apolipoprotein E2 / Q000235:genetics*; D006348:Cardiac Surgical Procedures / Q000009:adverse effects*; D002657:Child Development; D002658:Developmental Disabilities / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology; D005260:Female; D020022:Genetic Predisposition to Disease; D006330:Heart Defects, Congenital / Q000601:surgery*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D015999:Multivariate Analysis; D009420:Nervous System / Q000254:growth & development*; D009483:Neuropsychological Tests; D010641:Phenotype; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D012307:Risk Factors
chemical_list: D053329:Apolipoprotein E2