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

Abstract

Objective-To determine whether maternal/fetal 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; FDR was used to correct for multiple testing (q*=0.15)].Results-1) A SNP in TIMP2 in mothers was significantly associated with pPROM(OR=2.12 95% CI [1.47-3.07], p = 0.000068), and this association remained significant after correction for multiple comparisons; 2) Haplotypes for COL4A3 in the mother were associated with pPROM (global p = 0.003); 3) Multilocus analysis identified a three locus model, which included maternal SNPs in COL1A2, DEFA5, and EDN1.Conclusion-DNA variants in a maternal gene involved in extracellular matrix metabolism doubled the risk of pPROM.

Mid-trimester preterm premature rupture of membranes (PPROM): etiology, diagnosis, classification, international recommendations of treatment options and outcome

“…The single-nucleotide polymorphism of the tissue inhibitor of MMP-2 in mothers and haplotypes for alpha-3 type-IV collagen isoform precursor are associated with a higher rate of PPROM [51,52]. Fujimoto et al investigated, whether polymorphism at −1607 MMP-1 promoter in the MMP-1 is functionally significant for MMP-1 expression in amnion cells and in case of PPROM [53].…”

Antimicrobial peptides and pregnancy

“…A SNP has also been identified within the maternal a-defensin HD5 gene that has been identified as part of a locus that is associated with preterm premature rupture of the membranes (Romero et al 2010). The presence of bacterial vaginosis in the reproductive tract has been shown to reduce the Placenta SLPI (Denison et al 1999) Elafin/trappin-2 (King et al 2007a(King et al , 2007b HBD1-3 (King et al 2007a(King et al , 2007b Fetal skin LL37 (Marchini et al 2002) Vernix SLPI (Akinbi et al 2004) HNP1-3 (Akinbi et al 2004) LL37 (Tollin et al 2005) Vagina ELAFIN (Pfundt et al 1996) Cervicovaginal secretions SLPI (Stock et al 2009) Elafin/trappin-2 (Stock et al 2009) Cervix SLPI (Helmig et al 1995) Cervical mucus plug SLPI (Helmig et al 1995 concentration of AMPs compared with cervicovaginal fluid from healthy women; however, when effective treatment of the bacterial vaginosis is administered, the levels of antimicrobials are normalized suggesting that reduction is due to the presence of the disease (Valore et al 2006).…”

Positive and negative effects of cellular senescence during female reproductive aging and pregnancy

“…Consistent with this idea, cellular senescence in fetal membranes is implicated in pregnancy complications, such as preterm premature rupture of the membranes (pPROM) (Menon et al 2014a). In relation to pregnancies with preterm birth without rupture of membranes (PTB with no ROM), pPROM pregnancies also have elevated amniotic fluid (AF) inflammatory markers (Athayde et al 1998(Athayde et al , 1999, high salivary collagenolytic activity (a surrogate for lower uterine segment activity) (Menon et al 2006), elevated AF F2-Isoprostane concentrations (a marker for oxidative stress) (Menon et al 2011a), shortened fetal leukocyte and placental DNA telomere length (a marker of cellular senescence) (Menon et al 2012), and distinct single nucleotide polymorphisms (SNPs) associated with common inflammatory pathway genes , Romero et al 2010a. Hence, cellular senescence in fetal membranes is suggested to promote pregnancy complications.…”