Toll-like receptor 9 polymorphisms are associated with severity variables in a cohort of meningococcal meningitis survivors
- Equal contributors
1 Laboratory for Immunogenetics, Department of Medical Microbiology and Infection Control, VU University Medical Center, Amsterdam,, 1007 MB, The Netherlands
2 Institute for Public Health Genomics (IPHG), Department of Genetics and Cell Biology, Research Schools CAPHRI (School for Public Health and Primary Care) and GROW (School for Oncology & Developmental Biology), Faculty of Health, Medicine & Life Sciences, University of Maastricht, Maastricht, The Netherlands
3 Department of Pediatric Infectious Diseases, Immunology and Rheumatology, VU University Medical Center, Amsterdam,, 1007 MB, The Netherlands
4 Department in Surgery, Antonius Hospital Nieuwegein, Nieuwegein, The Netherlands
5 Department of Pediatrics, Maastricht University Medical Center (MUMC+), Maastricht, 6202 AZ, The Netherlands
BMC Infectious Diseases 2012, 12:112 doi:10.1186/1471-2334-12-112Published: 11 May 2012
Genetic variation in immune response genes is associated with susceptibility and severity of infectious diseases. Toll-like receptor (TLR) 9 polymorphisms are associated with susceptibility to develop meningococcal meningitis (MM). The aim of this study is to compare genotype distributions of two TLR9 polymorphisms between clinical severity variables in MM survivors.
We used DNA samples of a cohort of 390 children who survived MM. Next, we determined the genotype frequencies of TLR9 -1237 and TLR9 +2848 polymorphisms and compared these between thirteen clinical variables associated with prognostic factors predicting adverse outcome of bacterial meningitis in children.
The TLR9 -1237 TC and CC genotypes were associated with a decreased incidence of a positive blood culture for Neisseria (N.) meningitidis (p = 0.014, odds ratio (OR) 0.5. 95% confidence interval (CI) 0.3 – 0.9). The TLR9 +2848 AA mutant was associated with a decreased incidence of a positive blood culture for N. meningitidis (p = 0.017, OR 0.6, 95% CI 0.3 – 0.9). Cerebrospinal fluid (CSF) leukocytes per μL were higher in patients carrying the TLR9 -1237 TC or CC genotypes compared to carriers of the TT wild type (WT) (p = 0.024, medians: 2117, interquartile range (IQR) 4987 versus 955, IQR 3938). CSF blood/glucose ratios were lower in TLR9 -1237 TC or CC carriers than in carriers of the TT WT (p = 0.017, medians: 0.20, IQR 0.4 versus 0.35, IQR 0.5). CSF leukocytes/μL were higher in patients carrying the TLR9 +2848 AA mutant compared to carriers of GG or GA (p = 0.0067, medians: 1907, IQR 5221 versus 891, IQR 3952).
We identified TLR9 genotypes associated with protection against meningococcemia and enhanced local inflammatory responses inside the central nervous system, important steps in MM pathogenesis and defense.