A genetic association study of maternal and fetal candidate genes that predispose to preterm prelabor rupture of membranes (PROM)

• Published in: American journal of obstetrics and gynecology Vol. 203; no. 4; pp. 361.e1 - 361.e30
• Main Authors: Romero, Roberto, MD, Friel, Lara A., MD, PhD, Velez Edwards, Digna R., PhD, Kusanovic, Juan Pedro, MD, Hassan, Sonia S., MD, Mazaki-Tovi, Shali, MD, Vaisbuch, Edi, MD, Kim, Chong Jai, MD, Erez, Offer, MD, Chaiworapongsa, Tinnakorn, MD, Pearce, Brad D., PhD, Bartlett, Jacquelaine, MS, Salisbury, Benjamin A., PhD, Anant, Madan Kumar, PhD, Vovis, Gerald F., PhD, Lee, Min Seob, PhD, Gomez, Ricardo, MD, Behnke, Ernesto, MD, Oyarzun, Enrique, MD, Tromp, Gerard, PhD, Williams, Scott M., PhD, Menon, Ramkumar, PhD
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01-10-2010; Elsevier
• Subjects: Adult; alpha-Defensins - genetics; Autoantigens - genetics; Biological and medical sciences; Case-Control Studies; chorioamnionitis; Chorioamnionitis - pathology; Collagen - genetics; Collagen Type I; Collagen Type IV - genetics; Delivery. Postpartum. Lactation; Diseases of mother, fetus and pregnancy; Disorders; DNA variants; Endothelin-1 - genetics; extracellular matrix; Female; Fetal Membranes, Premature Rupture - genetics; Fetus; Gene Frequency; Genetic Association Studies; genetic association study; genomics; Genotype; Gynecology. Andrology. Obstetrics; haplotype; Haplotypes; high dimensional biology; Humans; Infant, Newborn; Male; matrix metalloproteinase; Medical sciences; Models, Genetic; Mothers; Obstetrics and Gynecology; parturition; Polymorphism, Single Nucleotide; Pregnancy; Pregnancy. Fetus. Placenta; prematurity; preterm prelabor rupture of membranes; Procollagen; Protein Isoforms; Receptors, Corticotropin-Releasing Hormone - genetics; Receptors, Prostaglandin E - genetics; Receptors, Prostaglandin E, EP1 Subtype; Sequence Analysis, DNA; single-nucleotide polymorphism; Tissue Inhibitor of Metalloproteinase-2 - genetics; DNA variants; haplotype; high dimensional biology; prematurity; preterm prelabor rupture of membranes; chorioamnionitis; parturition; genetic association study; genotype; genomics; matrix metalloproteinase; single-nucleotide polymorphism; extracellular matrix; Pregnancy; Pregnancy disorders; Mother; Gynecology; Premature rupture of membrane; Delivery disorders; Fetus; Genetics; Candidate gene; Fetoplacental membrane; Obstetrics
• ISSN: 0002-9378; 1097-6868
• DOI: 10.1016/j.ajog.2010.05.026

Objective We sought to determine whether maternal/fetal single-nucleotide polymorphisms (SNPs) in candidate genes are associated with preterm prelabor rupture of membranes (pPROM). Study Design A case-control study was conducted in patients with pPROM (225 mothers and 155 fetuses) and 599 mothers and 628 fetuses with a normal pregnancy; 190 candidate genes and 775 SNPs were studied. Single locus/haplotype association analyses were performed; false discovery rate was used to correct for multiple testing (q* = 0.15). Results First, a SNP in tissue inhibitor of metalloproteinase 2 in mothers was significantly associated with pPROM (odds ratio, 2.12; 95% confidence interval, 1.47–3.07; P = .000068), and this association remained significant after correction for multiple comparisons. Second, haplotypes for Alpha 3 type IV collagen isoform precursor in the mother were associated with pPROM (global P = .003). Third, multilocus analysis identified a 3-locus model, which included maternal SNPs in collagen type I alpha 2, defensin alpha 5 gene, and endothelin 1. Conclusion DNA variants in a maternal gene involved in extracellular matrix metabolism doubled the risk of pPROM.