A common human toll-like receptor 4 mutation is associated with increased mortality in children with invasive meningococcal disease

Abstract number: 1134_04_193

Knuf M.F., Faber P.J., Habermehl P.E., Gemmer G., Russo A., Murdoch C., Finn A., Mueller M., Zenz W., Meyer C., Zabel B.-U., Schmitt H.-J., Zepp F.

Objectives:  

Human Toll-like receptor 4 (TLR4) is the major endotoxin-signalling receptor of the innate immune system and is required for efficient recognition of gram-negative bacterial infections. We investigated a possible association between the common TLR4 mutation Asp299Gly and mortality due to invasive meningococcal disease in children.

Methods:  

197 children (ages 2–215 months, mean 59 months) with clinically and/or microbiologically proven invasive meningococcal disease from five different European countries were analysed for the Asp299Gly mutation by Lightcycler allele specific fluorescent hybridisation probe assays and direct sequencing. Genotyping results were correlated with fatal or none fatal outcome. Statistical analysis was performed applying Pearsons Chi-Square test (two-sided).

Results:  

The overall allele frequency of the Asp299Gly polymorphism was 9.4% (165 Asp/Asp, 27 Asp/Gly, 5 Gly/Gly) among the analysed patients with meningococcal disease. A total of 19 patients (9.6%) succumbed to the disease. Interestingly the heterozygous TLR4 Asp299Gly mutation was significantly associated with fatal disease outcome: In the none-survivor group 6 out of 19 patients (31%) had a heterozygous Asp299Gly polymorphism whereas this was only the case in 21 out of 178 patients (11.8%) in the survivor group (p = 0.029). There was no significant (p = 0.459) difference between the mutation in homozygous state in the survivor (5/178, 2.8%) and none-survivor group (0/19, 0%).

Conclusions:  

Our data suggest that the analysed TLR4 mutation Asp299Gly is associated with increased mortality in heterozygous state and might have an important impact on the clinical course and outcome of meningococcal disease in childhood.