Sex-Specific Genetic Susceptibility to Adverse Neurodevelopmental Outcome in Offspring of Pregnancies at Risk of Early Preterm DeliveryFunding The project described was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke (HD27869, HD34208, HD34116, HD40544, HD27915, HD34136, HD21414, HD27917, HD27860, HD40560, HD40545, HD40485, HD40500, HD27905, HD27861, HD34122, HD40512, HD53907, HD34210, HD21410, HD36801, HD19897, and MO1-RR-000080). Comments and views of the authors do not necessarily represent the views of the NIH.
04 November 2018
27 December 2018
07 February 2019 (online)
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.
Keywordsgenetic - interleukin-6 - neurodevelopmental delay - preterm birth - polymorphisms - sex - single-nucleotide polymorphisms
This study was presented at the 33th Annual Meeting of the Society for Maternal–Fetal Medicine, San Francisco, CA, February 11–16, 2013.
All authors have made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; drafting and revising the article critically for important intellectual content; and approving of the final version of the article submitted.
* The other members of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units Network are listed in Appendix A.
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