Sex-Specific Genetic Susceptibility to Adverse Neurodevelopmental Outcome in Offspring of Pregnancies at Risk of Early Preterm Delivery

Author:

Varner Michael W.1,Costantine Maged M.2,Jablonski Kathleen A.3,Rouse Dwight J.4,Mercer Brian M.5,Leveno Kenneth J.6,Reddy Uma M.7,Buhimschi Catalin8,Wapner Ronald J.910,Sorokin Yoram11,Thorp John M.12,Ramin Susan M.13,Malone Fergal D.14,Carpenter Marshall15,O'sullivan Mary J.16,Peaceman Alan M.17,Dudley Donald J.18,Caritis Steve N.19,

Affiliation:

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

2. Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas

3. Department of Epidemiology and Biostatistics, George Washington University Biostatistics Center, Washington, Disctrict of Columbia

4. Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, Alabama

5. Department of Obstetrics and Gynecology, MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio

6. Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas

7. Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland

8. Department of Obstetrics and Gynecology, The Ohio State University, Columbus, Ohio

9. Department of Obstetrics and Gynecology, Thomas Jefferson University, Philadelphia, Pennsylvania

10. Department of Obstetrics and Gynecology, Drexel University, Philadelphia, Pennsylvania

11. Department of Obstetrics and Gynecology, Wayne State University, Detroit, Michigan

12. Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

13. Department of Obstetrics and Gynecology, University of Texas Health Science Center at Houston, Houston, Texas

14. Department of Obstetrics and Gynecology, Columbia University, New York, New York

15. Department of Obstetrics and Gynecology, Brown University, Providence, Rhode Island

16. Department of Obstetrics and Gynecology, University of Miami, Miami, Florida

17. Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois

18. Department of Obstetrics and Gynecology, University of Texas Health Science Center, San Antonio, Texas

19. Department of Obstetrics and Gynecology, University of Pittsburgh, Pittsburgh, Pennsylvania

Abstract

Objective To evaluate sex-specific genetic susceptibility to adverse neurodevelopmental outcome (ANO, defined as cerebral palsy [CP], mental, or psychomotor delay) at risk for early preterm birth (EPTB, < 32 weeks). Study Design Secondary case–control analysis of a trial of magnesium sulfate (MgSO4) before anticipated EPTB for CP prevention. Cases are infants who died by the age of 1 year or developed ANO. Controls, matched by maternal race and infant sex, were neurodevelopmentally normal survivors. Neonatal DNA was evaluated for 80 polymorphisms in inflammation, coagulation, vasoregulation, excitotoxicity, and oxidative stress pathways using Taqman assays. The primary outcome for this analysis was sex-specific ANO susceptibility. Conditional logistic regression estimated each polymorphism's odds ratio (OR) by sex stratum, adjusting for gestational age, maternal education, and MgSO4-corticosteroid exposures. Holm–Bonferroni corrections, adjusting for multiple comparisons (p < 7.3 × 10−4), accounted for linkage disequilibrium between markers. Results Analysis included 211 cases (134 males; 77 females) and 213 controls (130 males; 83 females). An interleukin-6 (IL6) polymorphism (rs2069840) was associated with ANO in females (OR: 2.6, 95% confidence interval [CI]: 1.5–4.7; p = 0.001), but not in males (OR: 0.8, 95% CI: 0.5–1.2; p = 0.33). The sex-specific effect difference was significant (p = 7.0 × 10−4) and was unaffected by MgSO4 exposure. No other gene–sex associations were significant. Conclusion An IL6 gene locus may confer susceptibility to ANO in females, but not males, after EPTB.

Funder

Eunice Kennedy Shriver National Institute of Child Health and Human Development

National Institute of Neurological Disorders and Stroke

Publisher

Georg Thieme Verlag KG

Subject

Obstetrics and Gynecology,Pediatrics, Perinatology and Child Health

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