Genetic association of Toll-like receptor 4 with cervical cytokine concentrations during pregnancy

Toll-like receptors (TLRs) are critical components of innate immunity, recognizing bacterial microorganisms and initiating local inflammatory responses. In this study, we assessed the impact of genetic variation in TLR genes on cervical concentrations of pro- and anti-inflammatory cytokines, and determined whether this relationship is influenced by bacterial vaginosis (BV). A total of 4 single nucleotide polymorphisms (SNPs) in TLR2 and 12 in TLR4 were examined for associations with 10 cervical pro- and anti-inflammatory cytokine concentrations in 91 African-American (AA) and 97 European-American (EA) women in the first trimester of pregnancy. In EAs, individuals with the TT genotype at rs1554973 (TLR4) had higher cervical concentrations of interleukin-1 beta (IL-1b) compared with those with the CT or TT genotypes (P=1.5 x 10(-5)), which remains significant after correction for multiple testing. This association was more significant in women with BV (P=5 x 10(-3)) than those without BV (P=0.02). This SNP was also associated with cervical concentrations of IL-1a, IL-6, IL-8 and IP10 (interferon-gamma-inducible protein 10) (P=6 x 10(-3), 0.03, 0.05, 6 x 10(-3), respectively). Our study demonstrates that TLR4 is an important mediator of pro-inflammatory cervical immune responses, particularly in EA women and especially in those with microbial disorders such as BV.