Toll-like Receptor 2 Polymorphism Is Associated With Preterm Birth

Abstract

ABSTRACT:Evidence is increasing for a role of polymorphisms in maternal or fetal innate immune response genes in preterm birth. Toll-like receptors (TLRs) are important receptors in the innate immunity. The genotype distribution of two TLR2 single nucleotide polymorphisms (SNPs) and one TLR4 SNP were determined among 524 neonates and associated with gestational age (GA). Genomic DNA was isolated from prospectively collected blood samples and polymorphisms in TLR2 (T-16934A, RS4696480 and Arg753Gln, RS5743708) and TLR4 (Thr399Ile, RS4986791) were determined using sequence specific primers by PCR. Allele frequencies of two TLR2 SNPs and one TLR4 SNP were analyzed according to prematurity. Analysis among 305 infants, after exclusion of infants born after multiple pregnancy or because of preeclampsia, revealed significantly shorter GAs for infants carrying two polymorphic TLR2 alleles (-16934TA/AA and 753ArgGln/GlnGln) compared with infants carrying one polymorphic and one wild-type allele or two wild-type alleles (median GA 30.6 wk versus 34.1-36.8 wk, respectively, p Ͻ 0.02). Carriage of two variant TLR2 alleles potentially leads to aberrant innate immune responses, which may have contributed to very preterm birth. (Pediatr Res 62: 474-476, 2007) P reterm birth remains a major public health concern because of its associated perinatal morbidity and mortality (1). Evidence is increasing of an important role of polymorphisms in maternal or fetal immune response genes in preterm birth (2,3). Several single nucleotide polymorphisms (SNPs) in immune response genes, particularly in proinflammatory cytokine genes, have been investigated for their contribution to the etiology of preterm birth (2-5). The innate immune system's rapid recognition of pathogens is mediated through toll-like receptors (TLRs) and binding of a microbe to a TLR leads to activation of several inflammatory pathways (6 -9). SNPs in TLR genes may affect TLR function, contributing to a modulated inflammatory response. Up-regulation of TLRs may be one of the mechanisms by which intrauterine inflammation signals parturition and triggers preterm labor (10). This is supported by the fact that the majority of pregnancies that end with very preterm birth are more likely to be complicated by chorioamnionitis and/or neonatal infection acquired by vertical transmission from the mother (11,12). Moreover, an increased frequency of two TLR4 polymorphisms has been found in a population of preterm Finnish infants when compared with term control infants (5). The most important TLR4 ligand is LPS from Gram-negative microorganisms.We hypothesize that polymorphisms in the TLR2 and TLR4 genes result in modulation of fetal inflammatory responses, which trigger preterm birth. To address this issue, we determined the genotype distribution of two common TLR2 (T-16934A, Arg753Gln) and two cosegregating TLR4 (Asp299Gly and Thr399Ile) SNPs among 524 infants admitted to the neonatal intensive care unit of our hospital and associated this with gestational age (GA). METHODS Patient...

A TIR domain receptor–associated protein (TIRAP) variant SNP (rs8177374) confers protection against premature birth

“…18 Our study concurs with the findings of the Finnish study. Krediet et al 19 found a significantly higher frequency of the TLR2 (rs5743708) polymorphism in premature neonates of o30 weeks gestation, which was not replicated in our study. Krediet and colleagues' study population was predominantly Caucasian and they excluded babies whose mothers had pre-eclampsia.…”

Congenital toxoplasmosis: candidate host immune genes relevant for vertical transmission and pathogenesis

“…This potentially leads to aberrant innate immune responses, which may contribute to early preterm birth. 75 Individuals possessing the TLR4 co-segregating polymorphisms, Asp299Gly and Thr399Ile, are hyporesponsive to lipopolysacharide and are more susceptible to Gram-negative bacterial infections. 73,76,77 Those fetuses carrying the low-expression alleles of these receptors would hypothetically be more susceptible to die either by uncontrolled parasite replication/invasion or impaired trophoblast growth.…”

The Role of Toll-like Receptors in Perinatal Brain Injury

“…[34][35][36] Several studies have shown an association between preterm birth and TLR polymorphisms. [37][38][39] Animal studies have demonstrated a strong link between the TLR4 agonist LPS and brain injury, in fetal and newborn animals. 40 The direct involvement of TLRs has been examined in newborn animals.…”