Abstract
Objective This study aimed to evaluate whether there are genetic variants associated with adverse neurodevelopmental outcomes in extremely low birth weight (ELBW) infants. Study Design We conducted a candidate gene association study in two well-defined cohorts of ELBW infants (<1,000 g). One cohort was for discovery and the other for replication. The discovery case-control analysis utilized anonymized DNA samples and evaluated 1,614 single-nucleotide polymorphisms (SNPs) in 145 genes concentrated in inflammation, angiogenesis, brain development, and oxidation pathways. Cases were children who died by age one or who were diagnosed with cerebral palsy (CP) or neurodevelopmental delay (Bayley II mental developmental index [MDI] or psychomotor developmental index [PDI] < 70) by 18 to 22 months. Controls were survivors with normal neurodevelopment. We assessed significant epidemiological variables and SNPs associated with the combined outcome of CP or death, CP, mental delay (MDI < 70) and motor delay (PDI < 70). Multivariable analyses adjusted for gestational age at birth, small for gestational age, sex, antenatal corticosteroids, multiple gestation, racial admixture, and multiple comparisons. SNPs associated with adverse neurodevelopmental outcomes with p < 0.01 were selected for validation in the replication cohort. Successful replication was defined as p < 0.05 in the replication cohort. Results Of 1,013 infants analyzed (452 cases, 561 controls) in the discovery cohort, 917 were successfully genotyped for >90% of SNPs and passed quality metrics. After adjusting for covariates, 26 SNPs with p < 0.01 for one or more outcomes were selected for replication cohort validation, which included 362 infants (170 cases and 192 controls). A variant in SERPINE1, which encodes plasminogen activator inhibitor (PAI1), was associated with the combined outcome of CP or death in the discovery analysis (p = 4.1 × 10 -4) and was significantly associated with CP or death in the replication cohort (adjusted odd ratio: 0.4; 95% confidence interval: 0.2-1.0; p = 0.039). Conclusion A genetic variant in SERPINE1, involved in inflammation and coagulation, is associated with CP or death among ELBW infants.
| Original language | English (US) |
|---|---|
| Pages (from-to) | E2710-E2716 |
| Journal | American journal of perinatology |
| Volume | 41 |
| DOIs | |
| State | Published - Jun 4 2024 |
Funding
This study is supported by U10 grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD; HD36790, HD21364, HD21373, HD21385, HD21397, HD21415, HD27851, HD27853, HD27856, HD27871, HD27880, HD27881, HD27904, HD34216, HD40461, HD40492, HD40498, HD40689, HD27869, HD34208, HD34116, HD40544, HD27915, HD34136, HD21414, HD27917, HD27860, HD40560, HD40545, HD40485, HD40500, HD27905, HD27861, HD34122, HD40512, HD53907, HD34210, HD21410, U01 HD36801, HD19897), MO1-RR-000080, and by the National Institute of Neurological Disorders and Stroke (NINDS). The National Center for Research Resources provided grant support for the Neonatal Research Network's Glutamine trial, which included the Genomic Study through cooperative agreements (General Clinical Research Center M01 grants RR30, RR32, RR39, RR70, RR80, RR633, RR750, RR997, RR6022, RR7122, RR8084, RR16587). Comments and views of the authors do not necessarily represent views of the NICHD, the National Institutes of Health, the Department of Health and Human Services, or the U.S. Government.
Keywords
- candidate genes
- extremely low birth weight
- mental developmental delay
- neurodevelopmental delay
- polymorphisms
- preterm birth
- psychomotor delay
- single-nucleotide polymorphisms
ASJC Scopus subject areas
- Pediatrics, Perinatology, and Child Health
- Obstetrics and Gynecology