Abstract
Host genetic variability may contribute to susceptibility of bacterial meningitis, but which genes contribute to the susceptibility to this complex disease remains undefined. We performed a genetic association study in 469 community-acquired pneumococcal meningitis cases and 2072 population-based controls from the Utrecht Health Project in order to find genetic variants associated with pneumococcal meningitis susceptibility. A HumanExome BeadChip was used to genotype 102,097 SNPs in the collected DNA samples. Associations were tested with the Fisher exact test. None of the genetic variants tested reached Bonferroni corrected significance (p-value <5 × 10−7). Our strongest signals associated with susceptibility to pneumococcal meningitis were rs139064549 on chromosome 1 in the COL11A1 gene (p = 1.51 × 10−6; G allele OR 3.21 [95% CI 2.05–5.02]) and rs9309464 in the EXOC6B gene on chromosome 2 (p = 6.01 × 10−5; G allele OR 0.66 [95% CI 0.54–0.81]). The sequence kernel association test (SKAT) tests for associations between multiple variants in a gene region and pneumococcal meningitis susceptibility yielded one significant associated gene namely COL11A1 (p = 1.03 × 10−7). Replication studies are needed to validate these results. If replicated, the functionality of these genetic variations should be further studied to identify by which means they influence the pathophysiology of pneumococcal meningitis.
Highlights
Acute bacterial meningitis is a life-threatening disease associated with substantial morbidity and mortality and ranks among the top 10 infectious causes of death[1,2]
Between 2006 and 2011, 656 patients with bacterial meningitis were included in the MeninGene study[21]
After quality control filters 408 pneumococcal meningitis patients and 2072 controls were included in the genetic associations analysis for meningitis disease susceptibility
Summary
Acute bacterial meningitis is a life-threatening disease associated with substantial morbidity and mortality and ranks among the top 10 infectious causes of death[1,2]. Genetic variation leading to difference in immune response has been identified to influence susceptibility to pneumococcal meningitis. Case-control studies mostly looking at variants in genes involved in the innate immune system have pointed out genetic variants associated with acquiring invasive pneumococcal disease[16,17,18,19,20]. In a Dutch case-control study genetic variations in the beta2-adrenoreceptor (ADRB2) and mannose binding lectin (MBL) genes were associated with susceptibility to pneumococcal meningitis[17,18]. These genetic association studies evaluated one or only few single-nucleotide www.nature.com/scientificreports/. The aim of our study was to identify new genetic variants involved in susceptibility to pneumococcal meningitis, genotyping over 240,000 genetic variants of which the majority is exonic or otherwise functional
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