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

Michael W. Varner, Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, Utah.
Elizabeth A. Thom, Biostatistics Coordinating Center, George Washington University, Washington, District of Columbia.
C Michael Cotten, Department of Pediatrics, Duke University, Durham, North Carolina.
Susan R. Hintz, Department of Pediatrics, Stanford University School of Medicine and Lucile Packard Children's Hospital, Palo Alto, California.
Grier P. Page, Social, Statistical and Environmental Sciences Unit, RTI International, Atlanta, Georgia.
Dwight J. Rouse, Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, Alabama.
Brian M. Mercer, Case Western Reserve University-MetroHealth Medical Center, Cleveland, Ohio.
Maged M. Costantine, Department of Obstetrics and Gynecology, The Ohio State University, Columbus, Ohio.
Yoram Sorokin, Department of Obstetrics and Gynecology, Wayne State University, Detroit, Michigan.
John M. Thorp, Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, North Carolina.
Susan M. Ramin, Department of Obstetrics and Gynecology, University of Texas Health Science Center at Houston-Children's Memorial Hermann Hospital, Houston, Texas.
Marshall W. Carpenter, Department of Obstetrics and Gynecology, Brown University, Providence, Rhode Island.
Mary J. O'Sullivan, Department of Obstetrics and Gynecology, University of Miami, Miami, Florida.
Alan M. Peaceman, Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois.
George R. Saade, Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas.
Donald J. Dudley, Department of Obstetrics and Gynecology, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas.
Steve N. Caritis, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania.

Document Type

Journal Article

Publication Date

9-19-2023

Journal

American journal of perinatology

DOI

10.1055/s-0043-1774312

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  < 0.01 were selected for validation in the replication cohort. Successful replication was defined as  < 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  < 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 ( = 4.1 × 10) and was significantly associated with CP or death in the replication cohort (adjusted odd ratio: 0.4; 95% confidence interval: 0.2-1.0;  = 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..

Department

Biostatistics and Bioinformatics

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