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

Abstract

To investigate whether single nucleotide polymorphisms (SNPs) in genes encoding the Toll-like receptor (TLR) signaling pathway modulate susceptibility to preterm birth (PTB). Prospective case-control study examining the contribution of nine TLR SNPs to PTB (<37 weeks) and PTB <32 weeks. Genotyping was done on neonatal blood using a multiplexed single-base extension assay. Chi-square test, Fischer's exact test and classification trees were used for data analysis. Preterm infants (n=177) were more likely to be African American (P=0.02), and were more likely to be born to mothers who smoked (P=0.007), had pregnancy-induced hypertension (PIH; P=0.002) and placental abruption (P=0.0004) when compared with term infants (n=146). The TLR2, TLR4, TLR5, TLR9, nuclear factor-kappa B1 (NFκB1), NFκBIA and IRAK1 variants were not associated with PTB whereas the TIR domain receptor-associated protein (TIRAP) variant was more prevalent in term infants when compared with preterm infants born <32 weeks (P=0.004). PTB <32 weeks was more prevalent in infants without the TIRAP variant whose mothers had PIH and did not smoke (P=0.001). Presence of the TIRAP variant protected against PTB <32 weeks (P=0.015) in Caucasian infants. In our study, a TLR pathway adapter variant (TIRAP (rs8177374)) protected against PTB<32 weeks, supporting our hypothesis that genetic variation in the innate immune signaling pathway contributes to altered risk of PTB.