Apolipoprotein E genotype and outcome in infants with hypoxic-ischemic encephalopathy

Abstract

Background: Adults with the apolipoprotein E (APOE) gene alleles e4 and e2 are at high risk of poor neurological outcome after brain injury. The e4 allele has been associated with cerebral palsy (CP), and the e2 allele has been associated with worse neurological outcome with congenital heart disease. This study was done to test the hypothesis that the APOE genotype is associated with outcome among neonates who survive after hypoxic-ischemic encephalopathy (HIE).

Methods: We conducted a cohort study of infants who survived HIE and had 18-22 mo standardized neurodevelopmental evaluations to assess associations between disability and the APOE genotypes e3/e3, e4/-, and e2/-.

Results: A total of 139 survivors were genotyped. Of these, 86 (62%) were of the e3/e3, 41 (29%) were of the e4/-, and 14 (10%) were of the e2/- genotypes. One hundred and twenty-nine infants had genotype and follow-up data; 26% had moderate or severe disabilities. Disability prevalence was 30 and 19% among those with and without the e3/e3 genotype, 25 and 26% among those with and without the e2 allele, and 18 and 29% among those with and without the e4 allele, respectively. None of the differences were statistically significant. CP prevalence was also similar among genotype groups.

Conclusion: Disability was not associated with the APOE genotype in this cohort of HIE survivors.

Figure 1. Number of infants enrolled in the APOE candidate gene study from each of the two primary Network studies

Follow up is defined as non-missing primary outcome (moderate or severe disability) among survivors. ^a One infant was lost but was assigned primary outcome through adjudication; data are missing for other follow up outcomes. ^b Among aEEG infants, 47 infants were followed but we were only able to assign primary outcome to 46 of them (one had the Bayley exam but was missing CP and hearing data). Ten infants did not have adequate information to allow determination of the primary outcome.

Figure 2. Prevalence of moderate/severe disability for infants of different genotypes

For each genotype, white bars denote the percent of those with the genotype surviving with moderate to severe disability and black bars denote the percent without the genotype surviving with moderate to severe disability. Among 81 infants with APOE e3/e3 genotype and follow-up, prevalence of the primary outcome was 30%, and among the 48 infants not homozygous for e3/e3, prevalence was 19% (p = 0.21). Among 12 infants with the APOE e2 allele the prevalence of primary outcome was 25%, compared with 26% among the 117 infants without the e2 allele (p = 1.00). Among those with the APOE e4 allele (n = 38) the prevalence of the primary outcome was 18%, compared with 29% among the 91 without the e4 allele (p = 0.27).

Figure 3. Prevalence of MDI < 70 among infants of different genotypes

For each genotype, white bars denote the percent of those with the genotype surviving with MDI < 70, and black bars denote the percent without the genotype surviving with MDI < 70. Among 79 infants with APOE e3/e3 genotype and follow-up, prevalence of MDI < 70 was 28%, and among the 49 infants not homozygous for e3, prevalence was 16% (p = 0.20). Among 13 infants with the APOE e2 allele the prevalence of primary outcome was 15%, compared with 24% among the 115 infants without the e2 allele (p = 0.73). Among those with the APOE e4 allele (n = 38) the prevalence of the primary outcome was 16%, compared with 27% among the 90 without the e4 allele (p = 0.25).

Figure 4. Prevalence of moderate to severe cerebral palsy among infants of different genotypes

For each genotype, white bars denote the percent of those with the genotype surviving with moderate to severe cerebral palsy, and black bars denote the percent without the genotype surviving with moderate to severe cerebral palsy. Among 80 infants with APOE e3/e3 genotype and follow-up, prevalence of moderate to severe cerebral palsy was 14%, and among the 48 infants not homozygous for APOE e3, prevalence was 13% (p = 1.00). Among 12 infants with the APOE e2 allele the prevalence of moderate to severe cerebral palsy was 17%, compared with 13% among the 116 infants without the e2 allele (p = 0.66). Among those with the APOE e4 allele (n = 38) the prevalence of moderate to severe cerebral palsy was 11%, compared with 14% among the 90 without the e4 allele (p = 0.78).