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

Michael W. Varner; Maged M. Costantine; Kathleen A. Jablonski; Dwight J. Rouse; Brian M. Mercer; Kenneth J. Leveno; Uma M. Reddy; Catalin Buhimschi; Ronald J. Wapner; Yoram Sorokin; John M. Thorp; Susan M. Ramin; Fergal D. Malone; Marshall Carpenter; Mary J. O'Sullivan; Alan M. Peaceman; Donald J. Dudley; Steve N. Caritis

doi:10.1055/s-0039-1678535

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

Michael W. Varner, Maged M. Costantine, Kathleen A. Jablonski, Dwight J. Rouse, Brian M. Mercer, Kenneth J. Leveno, Uma M. Reddy, Catalin Buhimschi, Ronald J. Wapner, Yoram Sorokin, John M. Thorp, Susan M. Ramin, Fergal D. Malone, Marshall Carpenter, Mary J. O'Sullivan, Alan M. Peaceman, Donald J. Dudley, Steve N. Caritis

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3 Scopus citations

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 (MgSO ₄) 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 MgSO ₄ -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 MgSO ₄ 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.

Original language	English (US)
Pages (from-to)	281-290
Number of pages	10
Journal	American Journal of Perinatology
Volume	37
Issue number	3
DOIs	https://doi.org/10.1055/s-0039-1678535
State	Published - Feb 1 2020

Keywords

genetic
interleukin-6
neurodevelopmental delay
polymorphisms
preterm birth
sex
single-nucleotide polymorphisms

ASJC Scopus subject areas

Pediatrics, Perinatology, and Child Health
Obstetrics and Gynecology

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10.1055/s-0039-1678535

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Varner, M. W., Costantine, M. M., Jablonski, K. A., Rouse, D. J., Mercer, B. M., Leveno, K. J., Reddy, U. M., Buhimschi, C., Wapner, R. J., Sorokin, Y., Thorp, J. M., Ramin, S. M., Malone, F. D., Carpenter, M., O'Sullivan, M. J., Peaceman, A. M., Dudley, D. J., & Caritis, S. N. (2020). Sex-Specific Genetic Susceptibility to Adverse Neurodevelopmental Outcome in Offspring of Pregnancies at Risk of Early Preterm Delivery. American Journal of Perinatology, 37(3), 281-290. https://doi.org/10.1055/s-0039-1678535

Varner, MW, Costantine, MM, Jablonski, KA, Rouse, DJ, Mercer, BM, Leveno, KJ, Reddy, UM, Buhimschi, C, Wapner, RJ, Sorokin, Y, Thorp, JM, Ramin, SM, Malone, FD, Carpenter, M, O'Sullivan, MJ, Peaceman, AM, Dudley, DJ & Caritis, SN 2020, 'Sex-Specific Genetic Susceptibility to Adverse Neurodevelopmental Outcome in Offspring of Pregnancies at Risk of Early Preterm Delivery', American Journal of Perinatology, vol. 37, no. 3, pp. 281-290. https://doi.org/10.1055/s-0039-1678535

@article{25d0acaa46ad421bb8b987dfde2508e5,

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

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 (MgSO 4) 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 MgSO 4 -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 MgSO 4 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.",

keywords = "genetic, interleukin-6, neurodevelopmental delay, polymorphisms, preterm birth, sex, single-nucleotide polymorphisms",

author = "Varner, {Michael W.} and Costantine, {Maged M.} and Jablonski, {Kathleen A.} and Rouse, {Dwight J.} and Mercer, {Brian M.} and Leveno, {Kenneth J.} and Reddy, {Uma M.} and Catalin Buhimschi and Wapner, {Ronald J.} and Yoram Sorokin and Thorp, {John M.} and Ramin, {Susan M.} and Malone, {Fergal D.} and Marshall Carpenter and O'Sullivan, {Mary J.} and Peaceman, {Alan M.} and Dudley, {Donald J.} and Caritis, {Steve N.}",

year = "2020",

month = feb,

day = "1",

doi = "10.1055/s-0039-1678535",

language = "English (US)",

volume = "37",

pages = "281--290",

journal = "American Journal of Perinatology",

issn = "0735-1631",

publisher = "Thieme Medical Publishers",

number = "3",

}

TY - JOUR

T1 - Sex-Specific Genetic Susceptibility to Adverse Neurodevelopmental Outcome in Offspring of Pregnancies at Risk of Early Preterm Delivery

AU - Varner, Michael W.

AU - Costantine, Maged M.

AU - Jablonski, Kathleen A.

AU - Rouse, Dwight J.

AU - Mercer, Brian M.

AU - Leveno, Kenneth J.

AU - Reddy, Uma M.

AU - Buhimschi, Catalin

AU - Wapner, Ronald J.

AU - Sorokin, Yoram

AU - Thorp, John M.

AU - Ramin, Susan M.

AU - Malone, Fergal D.

AU - Carpenter, Marshall

AU - O'Sullivan, Mary J.

AU - Peaceman, Alan M.

AU - Dudley, Donald J.

AU - Caritis, Steve N.

PY - 2020/2/1

Y1 - 2020/2/1

N2 - 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 (MgSO 4) 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 MgSO 4 -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 MgSO 4 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.

AB - 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 (MgSO 4) 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 MgSO 4 -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 MgSO 4 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.

KW - genetic

KW - interleukin-6

KW - neurodevelopmental delay

KW - polymorphisms

KW - preterm birth

KW - sex

KW - single-nucleotide polymorphisms

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

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