Genetic variation associated with preterm birth in African-American women

Heather A. Frey, Molly J. Stout, Laurel N. Pearson, Methodius G. Tuuli, Alison G. Cahill, Jerome F. Strauss, Luis Gomez Carbajal, Samuel Parry, Jenifer E. Allsworth, George A. Macones

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Background Preterm birth is considered a multifactorial condition; however, emerging evidence suggests that genetic variation among individuals may have an important role. Prior studies have suggested that single-nucleotide polymorphisms associated with genes related to the immune system, and particularly the maternal inflammatory response, may be associated with an increased risk of preterm delivery. Objective The objective of the study was to identify single-nucleotide polymorphisms associated with spontaneous preterm birth <37 weeks within a cohort of African-American women. Study Design This is a secondary analysis of a randomized trial that evaluated periodontal disease and preterm birth. Women were enrolled between 6 and 20 weeks’ gestation at 3 prenatal care clinics between 2004 and 2007. Maternal DNA samples were collected and analyzed using a custom 1536 single-nucleotide polymorphismgenotyping array designed to assess genes involved in inflammation. Women were included in this study if they self-identified as African American. We excluded women with a multiple gestation or an indicated preterm delivery. We performed allele- and genotype-based analyses to evaluate the association between spontaneous preterm birth and tag single-nucleotide polymorphisms. We used a logistic regression to adjust for prior preterm birth in our genotype-based analysis. In a subgroup analysis, we compared women who delivered at <34 weeks’ gestation to women who delivered at term. Within the microarray, we identified ancestry informative markers and compared global ancestry estimates among women who delivered preterm with those who delivered at term. Results Of the 833 African-American women in the study with genotype data, 77 women (9.2%) had a spontaneous preterm birth, whereas 756 women delivered at term. In an allele-based analysis, 4 single-nucleotide polymorphisms related to the genes for protein kinase C-α (PRKCA) were associated with increased risk of spontaneous preterm birth <37 weeks, whereas a single single-nucleotide polymorphism related to fms-related tyrosine kinase 1 (FLT1) was associated with spontaneous preterm birth <34 weeks. A genotype-based analysis revealed similar associations between single-nucleotide polymorphisms related to the PRKCA genes and spontaneous premature delivery. Additionally, single-nucleotide polymorphisms related to matrix metalloproteinase-2 (MMP2), tissue inhibitor of matrix metalloproteinase-2 (TIMP2), and interleukin 16 (IL16) genes were associated with spontaneous preterm birth <37 weeks in genotype-based analysis. Genetic variants related to MMP2, matrix metalloproteinase-1 (MMP1), and leukemia inhibitory factor receptor antisense RNA 1 (LIFR-AS1) genes were associated with higher rates of preterm birth <34 weeks. Ancestry estimates were similar between the women who had a spontaneous preterm birth and those who delivered at term. Conclusion We identified tag single-nucleotide polymorphisms related to 7 genes that are critical to inflammation, extracellular remodeling, and cell signaling that were associated with spontaneous preterm birth in African-American women. Specifically, we found a strong association with the PRKCA gene. Genetic variation in these regions of the genome may be important in the pathogenesis of preterm birth. Our results should be considered in the design of future genomic studies in prematurity.

Original languageEnglish (US)
Pages (from-to)235.e1-235.e8
JournalAmerican Journal of Obstetrics and Gynecology
Volume215
Issue number2
DOIs
StatePublished - Aug 1 2016

Fingerprint

Premature Birth
African Americans
Single Nucleotide Polymorphism
Genotype
Matrix Metalloproteinase 2
Genes
Pregnancy
Matrix Metalloproteinase 16
OSM-LIF Receptors
Interleukin-16
Alleles
Mothers
Inflammation
Tissue Inhibitor of Metalloproteinase-2
Antisense RNA
Matrix Metalloproteinase 1
Prenatal Care
Periodontal Diseases
Protein-Tyrosine Kinases
Protein Kinase C

All Science Journal Classification (ASJC) codes

  • Obstetrics and Gynecology

Cite this

Frey, H. A., Stout, M. J., Pearson, L. N., Tuuli, M. G., Cahill, A. G., Strauss, J. F., ... Macones, G. A. (2016). Genetic variation associated with preterm birth in African-American women. American Journal of Obstetrics and Gynecology, 215(2), 235.e1-235.e8. https://doi.org/10.1016/j.ajog.2016.03.008

Genetic variation associated with preterm birth in African-American women. / Frey, Heather A.; Stout, Molly J.; Pearson, Laurel N.; Tuuli, Methodius G.; Cahill, Alison G.; Strauss, Jerome F.; Gomez Carbajal, Luis; Parry, Samuel; Allsworth, Jenifer E.; Macones, George A.

In: American Journal of Obstetrics and Gynecology, Vol. 215, No. 2, 01.08.2016, p. 235.e1-235.e8.

Research output: Contribution to journalArticle

Frey, HA, Stout, MJ, Pearson, LN, Tuuli, MG, Cahill, AG, Strauss, JF, Gomez Carbajal, L, Parry, S, Allsworth, JE & Macones, GA 2016, 'Genetic variation associated with preterm birth in African-American women', American Journal of Obstetrics and Gynecology, vol. 215, no. 2, pp. 235.e1-235.e8. https://doi.org/10.1016/j.ajog.2016.03.008
Frey HA, Stout MJ, Pearson LN, Tuuli MG, Cahill AG, Strauss JF et al. Genetic variation associated with preterm birth in African-American women. American Journal of Obstetrics and Gynecology. 2016 Aug 1;215(2):235.e1-235.e8. https://doi.org/10.1016/j.ajog.2016.03.008
Frey, Heather A. ; Stout, Molly J. ; Pearson, Laurel N. ; Tuuli, Methodius G. ; Cahill, Alison G. ; Strauss, Jerome F. ; Gomez Carbajal, Luis ; Parry, Samuel ; Allsworth, Jenifer E. ; Macones, George A. / Genetic variation associated with preterm birth in African-American women. In: American Journal of Obstetrics and Gynecology. 2016 ; Vol. 215, No. 2. pp. 235.e1-235.e8.
@article{86e15a54502e4ae6a0895c186d309f1a,
title = "Genetic variation associated with preterm birth in African-American women",
abstract = "Background Preterm birth is considered a multifactorial condition; however, emerging evidence suggests that genetic variation among individuals may have an important role. Prior studies have suggested that single-nucleotide polymorphisms associated with genes related to the immune system, and particularly the maternal inflammatory response, may be associated with an increased risk of preterm delivery. Objective The objective of the study was to identify single-nucleotide polymorphisms associated with spontaneous preterm birth <37 weeks within a cohort of African-American women. Study Design This is a secondary analysis of a randomized trial that evaluated periodontal disease and preterm birth. Women were enrolled between 6 and 20 weeks’ gestation at 3 prenatal care clinics between 2004 and 2007. Maternal DNA samples were collected and analyzed using a custom 1536 single-nucleotide polymorphismgenotyping array designed to assess genes involved in inflammation. Women were included in this study if they self-identified as African American. We excluded women with a multiple gestation or an indicated preterm delivery. We performed allele- and genotype-based analyses to evaluate the association between spontaneous preterm birth and tag single-nucleotide polymorphisms. We used a logistic regression to adjust for prior preterm birth in our genotype-based analysis. In a subgroup analysis, we compared women who delivered at <34 weeks’ gestation to women who delivered at term. Within the microarray, we identified ancestry informative markers and compared global ancestry estimates among women who delivered preterm with those who delivered at term. Results Of the 833 African-American women in the study with genotype data, 77 women (9.2{\%}) had a spontaneous preterm birth, whereas 756 women delivered at term. In an allele-based analysis, 4 single-nucleotide polymorphisms related to the genes for protein kinase C-α (PRKCA) were associated with increased risk of spontaneous preterm birth <37 weeks, whereas a single single-nucleotide polymorphism related to fms-related tyrosine kinase 1 (FLT1) was associated with spontaneous preterm birth <34 weeks. A genotype-based analysis revealed similar associations between single-nucleotide polymorphisms related to the PRKCA genes and spontaneous premature delivery. Additionally, single-nucleotide polymorphisms related to matrix metalloproteinase-2 (MMP2), tissue inhibitor of matrix metalloproteinase-2 (TIMP2), and interleukin 16 (IL16) genes were associated with spontaneous preterm birth <37 weeks in genotype-based analysis. Genetic variants related to MMP2, matrix metalloproteinase-1 (MMP1), and leukemia inhibitory factor receptor antisense RNA 1 (LIFR-AS1) genes were associated with higher rates of preterm birth <34 weeks. Ancestry estimates were similar between the women who had a spontaneous preterm birth and those who delivered at term. Conclusion We identified tag single-nucleotide polymorphisms related to 7 genes that are critical to inflammation, extracellular remodeling, and cell signaling that were associated with spontaneous preterm birth in African-American women. Specifically, we found a strong association with the PRKCA gene. Genetic variation in these regions of the genome may be important in the pathogenesis of preterm birth. Our results should be considered in the design of future genomic studies in prematurity.",
author = "Frey, {Heather A.} and Stout, {Molly J.} and Pearson, {Laurel N.} and Tuuli, {Methodius G.} and Cahill, {Alison G.} and Strauss, {Jerome F.} and {Gomez Carbajal}, Luis and Samuel Parry and Allsworth, {Jenifer E.} and Macones, {George A.}",
year = "2016",
month = "8",
day = "1",
doi = "10.1016/j.ajog.2016.03.008",
language = "English (US)",
volume = "215",
pages = "235.e1--235.e8",
journal = "American Journal of Obstetrics and Gynecology",
issn = "0002-9378",
publisher = "Mosby Inc.",
number = "2",

}

TY - JOUR

T1 - Genetic variation associated with preterm birth in African-American women

AU - Frey, Heather A.

AU - Stout, Molly J.

AU - Pearson, Laurel N.

AU - Tuuli, Methodius G.

AU - Cahill, Alison G.

AU - Strauss, Jerome F.

AU - Gomez Carbajal, Luis

AU - Parry, Samuel

AU - Allsworth, Jenifer E.

AU - Macones, George A.

PY - 2016/8/1

Y1 - 2016/8/1

N2 - Background Preterm birth is considered a multifactorial condition; however, emerging evidence suggests that genetic variation among individuals may have an important role. Prior studies have suggested that single-nucleotide polymorphisms associated with genes related to the immune system, and particularly the maternal inflammatory response, may be associated with an increased risk of preterm delivery. Objective The objective of the study was to identify single-nucleotide polymorphisms associated with spontaneous preterm birth <37 weeks within a cohort of African-American women. Study Design This is a secondary analysis of a randomized trial that evaluated periodontal disease and preterm birth. Women were enrolled between 6 and 20 weeks’ gestation at 3 prenatal care clinics between 2004 and 2007. Maternal DNA samples were collected and analyzed using a custom 1536 single-nucleotide polymorphismgenotyping array designed to assess genes involved in inflammation. Women were included in this study if they self-identified as African American. We excluded women with a multiple gestation or an indicated preterm delivery. We performed allele- and genotype-based analyses to evaluate the association between spontaneous preterm birth and tag single-nucleotide polymorphisms. We used a logistic regression to adjust for prior preterm birth in our genotype-based analysis. In a subgroup analysis, we compared women who delivered at <34 weeks’ gestation to women who delivered at term. Within the microarray, we identified ancestry informative markers and compared global ancestry estimates among women who delivered preterm with those who delivered at term. Results Of the 833 African-American women in the study with genotype data, 77 women (9.2%) had a spontaneous preterm birth, whereas 756 women delivered at term. In an allele-based analysis, 4 single-nucleotide polymorphisms related to the genes for protein kinase C-α (PRKCA) were associated with increased risk of spontaneous preterm birth <37 weeks, whereas a single single-nucleotide polymorphism related to fms-related tyrosine kinase 1 (FLT1) was associated with spontaneous preterm birth <34 weeks. A genotype-based analysis revealed similar associations between single-nucleotide polymorphisms related to the PRKCA genes and spontaneous premature delivery. Additionally, single-nucleotide polymorphisms related to matrix metalloproteinase-2 (MMP2), tissue inhibitor of matrix metalloproteinase-2 (TIMP2), and interleukin 16 (IL16) genes were associated with spontaneous preterm birth <37 weeks in genotype-based analysis. Genetic variants related to MMP2, matrix metalloproteinase-1 (MMP1), and leukemia inhibitory factor receptor antisense RNA 1 (LIFR-AS1) genes were associated with higher rates of preterm birth <34 weeks. Ancestry estimates were similar between the women who had a spontaneous preterm birth and those who delivered at term. Conclusion We identified tag single-nucleotide polymorphisms related to 7 genes that are critical to inflammation, extracellular remodeling, and cell signaling that were associated with spontaneous preterm birth in African-American women. Specifically, we found a strong association with the PRKCA gene. Genetic variation in these regions of the genome may be important in the pathogenesis of preterm birth. Our results should be considered in the design of future genomic studies in prematurity.

AB - Background Preterm birth is considered a multifactorial condition; however, emerging evidence suggests that genetic variation among individuals may have an important role. Prior studies have suggested that single-nucleotide polymorphisms associated with genes related to the immune system, and particularly the maternal inflammatory response, may be associated with an increased risk of preterm delivery. Objective The objective of the study was to identify single-nucleotide polymorphisms associated with spontaneous preterm birth <37 weeks within a cohort of African-American women. Study Design This is a secondary analysis of a randomized trial that evaluated periodontal disease and preterm birth. Women were enrolled between 6 and 20 weeks’ gestation at 3 prenatal care clinics between 2004 and 2007. Maternal DNA samples were collected and analyzed using a custom 1536 single-nucleotide polymorphismgenotyping array designed to assess genes involved in inflammation. Women were included in this study if they self-identified as African American. We excluded women with a multiple gestation or an indicated preterm delivery. We performed allele- and genotype-based analyses to evaluate the association between spontaneous preterm birth and tag single-nucleotide polymorphisms. We used a logistic regression to adjust for prior preterm birth in our genotype-based analysis. In a subgroup analysis, we compared women who delivered at <34 weeks’ gestation to women who delivered at term. Within the microarray, we identified ancestry informative markers and compared global ancestry estimates among women who delivered preterm with those who delivered at term. Results Of the 833 African-American women in the study with genotype data, 77 women (9.2%) had a spontaneous preterm birth, whereas 756 women delivered at term. In an allele-based analysis, 4 single-nucleotide polymorphisms related to the genes for protein kinase C-α (PRKCA) were associated with increased risk of spontaneous preterm birth <37 weeks, whereas a single single-nucleotide polymorphism related to fms-related tyrosine kinase 1 (FLT1) was associated with spontaneous preterm birth <34 weeks. A genotype-based analysis revealed similar associations between single-nucleotide polymorphisms related to the PRKCA genes and spontaneous premature delivery. Additionally, single-nucleotide polymorphisms related to matrix metalloproteinase-2 (MMP2), tissue inhibitor of matrix metalloproteinase-2 (TIMP2), and interleukin 16 (IL16) genes were associated with spontaneous preterm birth <37 weeks in genotype-based analysis. Genetic variants related to MMP2, matrix metalloproteinase-1 (MMP1), and leukemia inhibitory factor receptor antisense RNA 1 (LIFR-AS1) genes were associated with higher rates of preterm birth <34 weeks. Ancestry estimates were similar between the women who had a spontaneous preterm birth and those who delivered at term. Conclusion We identified tag single-nucleotide polymorphisms related to 7 genes that are critical to inflammation, extracellular remodeling, and cell signaling that were associated with spontaneous preterm birth in African-American women. Specifically, we found a strong association with the PRKCA gene. Genetic variation in these regions of the genome may be important in the pathogenesis of preterm birth. Our results should be considered in the design of future genomic studies in prematurity.

UR - http://www.scopus.com/inward/record.url?scp=84963788650&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84963788650&partnerID=8YFLogxK

U2 - 10.1016/j.ajog.2016.03.008

DO - 10.1016/j.ajog.2016.03.008

M3 - Article

VL - 215

SP - 235.e1-235.e8

JO - American Journal of Obstetrics and Gynecology

JF - American Journal of Obstetrics and Gynecology

SN - 0002-9378

IS - 2

ER -