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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Obstetrics and Gynecology, Ohio State University, Columbus, OH. Electronic address: Heather.Frey@osumc.edu.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Frey
authors.affiliation: Department of Obstetrics and Gynecology, Washington University in St Louis, St Louis, MO.
authors.forename: Molly J
authors.initials: MJ
authors.lastname: Stout
authors.affiliation: Department of Anthropology, Pennsylvania State University, University Park, PA.
authors.forename: Laurel N
authors.initials: LN
authors.lastname: Pearson
authors.affiliation: Department of Obstetrics and Gynecology, Washington University in St Louis, St Louis, MO.
authors.forename: Methodius G
authors.initials: MG
authors.lastname: Tuuli
authors.affiliation: Department of Obstetrics and Gynecology, Washington University in St Louis, St Louis, MO.
authors.forename: Alison G
authors.initials: AG
authors.lastname: Cahill
authors.affiliation: Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, VA.
authors.forename: Jerome F
authors.initials: JF
authors.lastname: Strauss
authors.affiliation: Department of Obstetrics and Gynecology, University of Tennessee Health Science Center, Memphis, TN.
authors.forename: Luis M
authors.initials: LM
authors.lastname: Gomez
authors.affiliation: Department of Obstetrics and Gynecology, Center for Research on Reproduction and Women's Heath, University of Pennsylvania School of Medicine, Philadelphia, PA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Parry
authors.affiliation: Departments of Biomedical and Health Informatics and Obstetrics and Gynecology, University of Missouri-Kansas City School of Medicine, Kansas City, MO.
authors.forename: Jenifer E
authors.initials: JE
authors.lastname: Allsworth
authors.affiliation: Department of Obstetrics and Gynecology, Washington University in St Louis, St Louis, MO.
authors.forename: George A
authors.initials: GA
authors.lastname: Macones
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000483:Alleles; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D019410:Interleukin-16 / Q000235:genetics; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D007752:Obstetric Labor, Premature / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D047928:Premature Birth / Q000235:genetics*; D051571:Protein Kinase C-alpha / Q000235:genetics; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics; D055815:Young Adult
chemical_list: D019410:Interleukin-16; C560823:TIMP2 protein, human; D019716:Tissue Inhibitor of Metalloproteinase-2; C496628:PRKCA protein, human; D051571:Protein Kinase C-alpha; D020778:Matrix Metalloproteinase 2
keywords: genetics; inflammation; preterm birth