Toll receptor 4 Asp299Gly polymorphism and its association with preterm birth and premature rupture of membranes in a South American population

Abstract

Preterm birth (PTB) is a worldwide health problem and remains the leading cause of perinatal morbidity and mortality. Systemic and local intrauterine infections have been implicated in the pathogenesis of preterm labor and delivery. Common pathways between PTB, premature rupture of ovular membranes (PROM) and altered molecular routes of inflammation have been proposed. There is evidence to support a genetic component in these conditions. Lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bacteria, is thought to play a key role in eliciting an inflammatory response. LPS is recognized by proteins of the innate immune system, including Toll-like receptor 4 (TLR4). Individuals from some European countries carrying the variant alleles resulting in an amino acid substitution (Asp299Gly) are at increased risk of Gram-negative infections and premature birth. The objective of this study was to determine if preterm newborns have different allele frequency of the Asp299Gly TLR4 variant from healthy term neonates in Uruguay. The impact of PROM was also examined. There was an increase in the risk for fetuses carrying the Asp299Gly substitution in TLR4 of being severely premature (<33 weeks) and to present PROM at the same time.

The Effect of Inflammation on Preterm Birth

“…However, in our study PTB was not linked directly to the presence of TLR4 variation. We did find an association between severe PTB (less than 34 weeks of gestation), PROM and the presence of the Asp299Gly variation (see also previous work; Rey et al, 2008), suggesting possible differences between the pathogenesis of severe and moderate preterm birth. Is it possible that genetic component plays a key role in severe preterm but not in moderate preterm?…”

“…However, more recently, genetic admixture analysis demonstrated a Native American and African contribution to the Uruguayan population of 10.4% and 5.6%, respectively (Hidalgo et al, 2005;Sans et al, 2006). The Uruguayan Asp299Gly observed frequency is lower than that of Europeans or Africans and equal to the admixed Chilean population (Rey et al, 2008), which suggests the effect of admixture on this gene. We published the first report concerning association between TLR4 and PTB or PPROM on a South American country and the data presented here confirm this link.…”

“…2.2 DNA extraction and Asp299Gly TLR4 genotyping DNA was extracted either from umbilical cords or from newborn cheek swabs by conventional methods (Rey et al, 2008). To detect Asp299Gly polymorphism, we used the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) strategy previously described by Lorenz et al (2001) (Figure 1a) and a High ResolutionMelting Analysis (HRM) developed in our laboratory ( Figure 1b).…”

Functional Screening of TLRs in Human Amniotic Epithelial Cells

“…To date, functional TLR4 has been implicated in PTL triggered by administration of heat-killed Escherichia coli to mice (49,50). In addition, an association between polymorphisms (Asp299Gly) in TLR4 and PTB has been reported (51,52). Human TLR4 mutations are associated with an increased risk of Gram-negative infections (53).…”

Πολυμορφισμοί Των TLR2 Και TLR4 Στη Χρόνια Αποφρακτική Πνευμονοπάθεια

“…Πράγµατι, σε φιλλανδικό πληθυσµό, διαπιστώθηκε συχνότερη παρουσία του 299Gly αλ-ληλίου µεταξύ πρόωρων νεογνών και µητέρων προώρων σε σχέση µε τα τελειόµηνα και τις µητέρες αυτών, οπότε συσχετίστηκε µε πρόωρο τοκετό [253]. Επιπλέον, πρόσφατα, η πα-ρουσία του πολυµορφισµού Asp299Gly σε έµβρυα συσχετίστηκε µε αυξηµένο κίνδυνο σοβα-ρής προωρότητας (<33 εβδοµάδες κύησης) και µε πρώιµη ρήξη των υµένων σε πληθυσµό της Ουρουγουάης [254]. Αντίθετα, σε Αµερικανούς αφρικανικής καταγωγής [255], καθώς και σε ένα γερµανικό πληθυσµό [256] δεν διαπιστώθηκε συσχέτισή του µε την πρόωρη ρήξη των υµένων.…”