A TLR5 (g.1174C > T) variant that encodes a stop codon (R392X) is associated with bronchopulmonary dysplasia

Pediatr Pulmonol. 2012 May;47(5):460-8. doi: 10.1002/ppul.21568. Epub 2011 Nov 4.

Abstract

Current evidence supports a major role for inherited factors in determining bronchopulmonary dysplasia (BPD) susceptibility. The Toll-like receptor (TLR) family of proteins maintain pulmonary homeostasis in the developing lung by aiding pathogen recognition and clearance, regulating inflammation, and facilitating reparative tissue growth. We hypothesized that sequence variation in the TLR pathway genes would alter the susceptibility/severity of BPD in preterm infants. Very low birth-weight infants were recruited prospectively in a multi-center study involving collection of blood samples and clinical information. Nine TLR pathway single-nucleotide polymorphisms were genotyped using a multiplexed single-base extension assay. BPD outcomes were compared among infants with and without the variant allele using Chi-square or Fisher's exact tests. In our cohort (n = 289), 66 (23.6%) infants developed BPD, out of which 32 (11.2%) developed severe BPD. The TLR5 (g.1174C > T) variant was associated with BPD (P = 0.03) and severe BPD (P = 0.004). The TIRAP (g.2054C > T) variant was associated with BPD (P = 0.04). Infants heterozygous for the X-linked IRAK1 (g.6435T > C) variant had a lower incidence of BPD compared to infants homozygous for either the reference or variant allele (P = 0.03). In regression models that controlled for potential epidemiological confounders, the TIRAP variant was associated with BPD, and the TLR5 variant was associated with severe BPD. Our data support the hypothesis that aberrant pathogen recognition in premature infants arising from TLR pathway genetic variation can contribute to BPD pathogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bronchopulmonary Dysplasia / epidemiology
  • Bronchopulmonary Dysplasia / genetics*
  • Codon, Terminator / genetics*
  • Cohort Studies
  • Female
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Heterozygote
  • Humans
  • Incidence
  • Infant, Newborn
  • Infant, Premature
  • Infant, Very Low Birth Weight
  • Interleukin-1 Receptor-Associated Kinases / genetics
  • Male
  • Pilot Projects
  • Polymorphism, Single Nucleotide
  • Prospective Studies
  • Severity of Illness Index
  • Toll-Like Receptor 5 / genetics*

Substances

  • Codon, Terminator
  • TLR5 protein, human
  • Toll-Like Receptor 5
  • IRAK1 protein, human
  • Interleukin-1 Receptor-Associated Kinases