Genetic Predisposition to Adverse Neurodevelopmental Outcome of Extremely Low Birth Weight Infants

Michael W. Varner; Elizabeth A. Thom; C. Michael Cotten; Susan R. Hintz; Grier P. Page; Dwight J. Rouse; Brian M. Mercer; Maged M. Costantine; Yoram Sorokin; John M. Thorp Jr.; Susan M. Ramin; Marshall W. Carpenter; Mary J. O'Sullivan; Alan M. Peaceman; George R. Saade; Donald J. Dudley; Steve N. Caritis; for the Eunice Kennedy Shriver National Institute of Child Health Human Development Maternal-Fetal Medicine Units Network Neonatal Research Network

doi:10.1055/s-0043-1774312

American Journal of Perinatology, Inhaltsverzeichnis

Am J Perinatol 2024; 41(S 01): e2710-e2716
DOI: 10.1055/s-0043-1774312

Original Article

Genetic Predisposition to Adverse Neurodevelopmental Outcome of Extremely Low Birth Weight Infants

Michael W. Varner

¹Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, Utah

,

Elizabeth A. Thom^*

²Biostatistics Coordinating Center, George Washington University, Washington, District of Columbia

,

C. Michael Cotten

³Department of Pediatrics, Duke University, Durham, North Carolina

,

Susan R. Hintz

⁴Department of Pediatrics, Stanford University School of Medicine and Lucile Packard Children's Hospital, Palo Alto, California

,

Grier P. Page

⁵Social, Statistical and Environmental Sciences Unit, RTI International, Atlanta, Georgia

,

Dwight J. Rouse

⁶Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, Alabama

,

Brian M. Mercer

⁷Case Western Reserve University-MetroHealth Medical Center, Cleveland, Ohio

⁸University of Tennessee, Memphis, Tennessee

,

Maged M. Costantine

⁹Department of Obstetrics and Gynecology, The Ohio State University, Columbus, Ohio

,

Yoram Sorokin

¹⁰Department of Obstetrics and Gynecology, Wayne State University, Detroit, Michigan

,

John M. Thorp Jr.

¹¹Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, North Carolina

,

Susan M. Ramin

¹²Department of Obstetrics and Gynecology, University of Texas Health Science Center at Houston-Children's Memorial Hermann Hospital, Houston, Texas

,

Marshall W. Carpenter

¹³Department of Obstetrics and Gynecology, Brown University, Providence, Rhode Island

,

Mary J. O'Sullivan

¹⁴Department of Obstetrics and Gynecology, University of Miami, Miami, Florida

,

Alan M. Peaceman

¹⁵Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois

,

George R. Saade

¹⁶Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas

,

Donald J. Dudley

¹⁷Department of Obstetrics and Gynecology, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas

,

Steve N. Caritis

¹⁸Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania

,

for the Eunice Kennedy Shriver National Institute of Child Health Human Development Maternal-Fetal Medicine Units Network Neonatal Research Network

› Institutsangaben

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.

Key Points

Early preterm and ELBW infants have dramatically increased risks of CP and developmental delay.
A genetic variant in SERPINE1 is associated with CP or death among ELBW infants.
The SERPINE1 gene encodes the serine protease inhibitor plasminogen activator inhibitor.

Keywords

candidate genes - extremely low birth weight - mental developmental delay - neurodevelopmental delay - preterm birth - polymorphisms - psychomotor delay - single-nucleotide polymorphisms

Volltext

Referenzen

References
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