A genetic association study of maternal and fetal candidate genes that predispose to preterm prelabor rupture of membranes (PROM).
OBJECTIVE
We sought to determine whether maternal/fetal single-nucleotide polymorphisms (SNPs) in candidate genes are associated with preterm prelabor rupture of membranes (pPROM).


METHODS
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.


CONCLUSIONS
DNA variants in a maternal gene involved in extracellular matrix metabolism doubled the risk of pPROM.
Romero
Roberto
R
Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health/Department of Health and Human Services, Bethesda, MD, USA. prbchiefstaff@med.wayne.edu
Friel
Lara A
LA
Velez Edwards
Digna R
DR
Kusanovic
Juan Pedro
JP
Hassan
Sonia S
SS
Mazaki-Tovi
Shali
S
Vaisbuch
Edi
E
Kim
Chong Jai
CJ
Erez
Offer
O
Chaiworapongsa
Tinnakorn
T
Pearce
Brad D
BD
Bartlett
Jacquelaine
J
Salisbury
Benjamin A
BA
Anant
Madan Kumar
MK
Vovis
Gerald F
GF
Lee
Min Seob
MS
Gomez
Ricardo
R
Behnke
Ernesto
E
Oyarzun
Enrique
E
Tromp
Gerard
G
Williams
Scott M
SM
Menon
Ramkumar
R
D000328:Adult; D001324:Autoantigens / Q000235:genetics; D016022:Case-Control Studies; D002821:Chorioamnionitis / Q000473:pathology; D003094:Collagen / Q000235:genetics; D024042:Collagen Type I; D024141:Collagen Type IV / Q000235:genetics; D019332:Endothelin-1 / Q000235:genetics; D005260:Female; D005322:Premature Rupture of Fetal Membranes / Q000235:genetics*; D005333:Fetus; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008957:Models, Genetic; D009035:Mothers; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011347:Procollagen; D020033:Protein Isoforms; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics; D018078:Receptors, Prostaglandin E / Q000235:genetics; D058306:Receptors, Prostaglandin E, EP1 Subtype; D017422:Sequence Analysis, DNA; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics; D023084:alpha-Defensins / Q000235:genetics
D001324:Autoantigens; D024042:Collagen Type I; D024141:Collagen Type IV; D019332:Endothelin-1; C545635:PTGER1 protein, human; D011347:Procollagen; D020033:Protein Isoforms; D018019:Receptors, Corticotropin-Releasing Hormone; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D023084:alpha-Defensins; C057112:type IV collagen alpha3 chain; D019716:Tissue Inhibitor of Metalloproteinase-2; D003094:Collagen