Validation of association of the apolipoprotein e ε2 allele with neurodevelopmental dysfunction after cardiac surgery in neonates and infants

J. William Gaynor; Daniel Seung Kim; Cammon B. Arrington; Andrew M. Atz; David C. Bellinger; Amber A. Burt; Nancy S. Ghanayem; Jeffery P. Jacobs; Teresa M. Lee; Alan B. Lewis; William T. Mahle; Bradley S. Marino; Stephen G. Miller; Jane W. Newburger; Christian Pizarro; Chitra Ravishankar; Avni B. Santani; Nicole S. Wilder; Gail P. Jarvik; Seema Mital; Mark W. Russell

doi:10.1016/j.jtcvs.2014.07.052

Validation of association of the apolipoprotein e ε2 allele with neurodevelopmental dysfunction after cardiac surgery in neonates and infants

J. William Gaynor^*, Daniel Seung Kim, Cammon B. Arrington, Andrew M. Atz, David C. Bellinger, Amber A. Burt, Nancy S. Ghanayem, Jeffery P. Jacobs, Teresa M. Lee, Alan B. Lewis, William T. Mahle, Bradley S. Marino, Stephen G. Miller, Jane W. Newburger, Christian Pizarro, Chitra Ravishankar, Avni B. Santani, Nicole S. Wilder, Gail P. Jarvik, Seema MitalMark W. Russell

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

55 Scopus citations

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.

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.

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).

Original language	English (US)
Pages (from-to)	2560-2568
Number of pages	9
Journal	Journal of Thoracic and Cardiovascular Surgery
Volume	148
Issue number	6
DOIs	https://doi.org/10.1016/j.jtcvs.2014.07.052
State	Published - Dec 1 2014

Funding

The Infant Single Ventricle (ISV) trial was supported by the National Heart, Lung, and Blood Institute grants (NHLBI; HL068269 , HL068270 , HL068279 , HL068281 , HL068285 , HL068292 , HL068290 , HL068288 , and HL085057 ) and the Food and Drug Administration's Office of Orphan Products Development . The Single Ventricle Reconstruction (SVR) trial was supported by grants HL068269 , HL068270 , HL068279 , HL068281 , HL068285 , HL068288 , HL068290 , HL068292 , and HL085057 from the National Heart, Lung, and Blood Institute ; and with support from Harvard Catalyst / The Harvard Clinical and Translational Science Center (NIH Award UL1 RR 025758 and financial contributions from Harvard University and its affiliated academic health care centers). This study was supported by the Daniel M. Tabas Endowed Chair in Pediatric Cardiothoracic Surgery at The Children's Hospital of Philadelphia. D.S. Kim was funded by a grant from the National Institute of Mental Health ( 1F31MH101905-01 ).

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine
Pulmonary and Respiratory Medicine
Surgery

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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., ... Russell, M. W. (2014). Validation of association of the apolipoprotein e ε2 allele with neurodevelopmental dysfunction after cardiac surgery in neonates and infants. Journal of Thoracic and Cardiovascular Surgery, 148(6), 2560-2568. https://doi.org/10.1016/j.jtcvs.2014.07.052

@article{67ede53a0b834783acdfac9ed0f640eb,

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.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.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).",

author = "Gaynor, {J. William} and Kim, {Daniel Seung} and Arrington, {Cammon B.} and Atz, {Andrew M.} and Bellinger, {David C.} and Burt, {Amber A.} and Ghanayem, {Nancy S.} and Jacobs, {Jeffery P.} and Lee, {Teresa M.} and Lewis, {Alan B.} and Mahle, {William T.} and Marino, {Bradley S.} and Miller, {Stephen G.} and Newburger, {Jane W.} and Christian Pizarro and Chitra Ravishankar and Santani, {Avni B.} and Wilder, {Nicole S.} and Jarvik, {Gail P.} and Seema Mital and Russell, {Mark W.}",

note = "Funding Information: The Infant Single Ventricle (ISV) trial was supported by the National Heart, Lung, and Blood Institute grants (NHLBI; HL068269 , HL068270 , HL068279 , HL068281 , HL068285 , HL068292 , HL068290 , HL068288 , and HL085057 ) and the Food and Drug Administration's Office of Orphan Products Development . Funding Information: The Single Ventricle Reconstruction (SVR) trial was supported by grants HL068269 , HL068270 , HL068279 , HL068281 , HL068285 , HL068288 , HL068290 , HL068292 , and HL085057 from the National Heart, Lung, and Blood Institute ; and with support from Harvard Catalyst / The Harvard Clinical and Translational Science Center (NIH Award UL1 RR 025758 and financial contributions from Harvard University and its affiliated academic health care centers). Funding Information: This study was supported by the Daniel M. Tabas Endowed Chair in Pediatric Cardiothoracic Surgery at The Children's Hospital of Philadelphia. D.S. Kim was funded by a grant from the National Institute of Mental Health ( 1F31MH101905-01 ). ",

year = "2014",

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doi = "10.1016/j.jtcvs.2014.07.052",

language = "English (US)",

volume = "148",

pages = "2560--2568",

journal = "Journal of Thoracic and Cardiovascular Surgery",

issn = "0022-5223",

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Gaynor, JW, Kim, DS, Arrington, CB, Atz, AM, Bellinger, DC, Burt, AA, Ghanayem, NS, Jacobs, JP, Lee, TM, Lewis, AB, Mahle, WT, Marino, BS, Miller, SG, Newburger, JW, Pizarro, C, Ravishankar, C, Santani, AB, Wilder, NS, Jarvik, GP, Mital, S & Russell, MW 2014, 'Validation of association of the apolipoprotein e ε2 allele with neurodevelopmental dysfunction after cardiac surgery in neonates and infants', Journal of Thoracic and Cardiovascular Surgery, vol. 148, no. 6, pp. 2560-2568. https://doi.org/10.1016/j.jtcvs.2014.07.052

Validation of association of the apolipoprotein e ε2 allele with neurodevelopmental dysfunction after cardiac surgery in neonates and infants. / Gaynor, J. William; Kim, Daniel Seung; Arrington, Cammon B. et al.
In: Journal of Thoracic and Cardiovascular Surgery, Vol. 148, No. 6, 01.12.2014, p. 2560-2568.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Validation of association of the apolipoprotein e ε2 allele with neurodevelopmental dysfunction after cardiac surgery in neonates and infants

AU - Gaynor, J. William

AU - Kim, Daniel Seung

AU - Arrington, Cammon B.

AU - Atz, Andrew M.

AU - Bellinger, David C.

AU - Burt, Amber A.

AU - Ghanayem, Nancy S.

AU - Jacobs, Jeffery P.

AU - Lee, Teresa M.

AU - Lewis, Alan B.

AU - Mahle, William T.

AU - Marino, Bradley S.

AU - Miller, Stephen G.

AU - Newburger, Jane W.

AU - Pizarro, Christian

AU - Ravishankar, Chitra

AU - Santani, Avni B.

AU - Wilder, Nicole S.

AU - Jarvik, Gail P.

AU - Mital, Seema

AU - Russell, Mark W.

N1 - Funding Information: The Infant Single Ventricle (ISV) trial was supported by the National Heart, Lung, and Blood Institute grants (NHLBI; HL068269 , HL068270 , HL068279 , HL068281 , HL068285 , HL068292 , HL068290 , HL068288 , and HL085057 ) and the Food and Drug Administration's Office of Orphan Products Development . Funding Information: The Single Ventricle Reconstruction (SVR) trial was supported by grants HL068269 , HL068270 , HL068279 , HL068281 , HL068285 , HL068288 , HL068290 , HL068292 , and HL085057 from the National Heart, Lung, and Blood Institute ; and with support from Harvard Catalyst / The Harvard Clinical and Translational Science Center (NIH Award UL1 RR 025758 and financial contributions from Harvard University and its affiliated academic health care centers). Funding Information: This study was supported by the Daniel M. Tabas Endowed Chair in Pediatric Cardiothoracic Surgery at The Children's Hospital of Philadelphia. D.S. Kim was funded by a grant from the National Institute of Mental Health ( 1F31MH101905-01 ).

PY - 2014/12/1

Y1 - 2014/12/1

N2 - 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.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.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).

AB - 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.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.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).

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DO - 10.1016/j.jtcvs.2014.07.052

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AN - SCOPUS:84920024512

SN - 0022-5223

VL - 148

SP - 2560

EP - 2568

JO - Journal of Thoracic and Cardiovascular Surgery

JF - Journal of Thoracic and Cardiovascular Surgery

IS - 6

ER -

Validation of association of the apolipoprotein e ε2 allele with neurodevelopmental dysfunction after cardiac surgery in neonates and infants

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