Common polymorphisms in the complement system and susceptiblity to bacterial meningitis.
OBJECTIVE
Risk factors for susceptibility to bacterial meningitis have been identified, but basic causes of inter-individual differences in susceptibility are largely unknown.


METHODS
To determine the effect of genetic variation in the complement system on susceptibility to bacterial meningitis we performed a prospective nationwide genetic association study in patients with community-acquired bacterial meningitis. We genotyped 17 common SNPs (minor allele frequencies >5%) in genes coding for complement components and evaluated functional consequences by measuring complement levels in the cerebrospinal fluid.


RESULTS
From March 2006 to June 2009 we included 636 adults with community-acquired bacterial meningitis. DNA was available for 439 patients and 302 controls. Rs1047286 (Pro314Leu) in complement component 3 was associated with reduced susceptibility to bacterial meningitis after correction for multiple testing: the protective Leu/Leu genotype was found in 5 of 435 patients (1%) compared to 15 of 302 controls (5%; odds ratio [OR] 4.50, 95% confidence interval [CI] 1.62-12.50, p = 0.0017). Rs1047286 is in strong linkage disequilibrium with Rs2230199 (C3 Arg102Gly), of which the Arg/Arg genotype was associated with higher CSF levels of C3 and lower levels of C5a and terminal complement complex (TCC; soluble C5b-9), indicating decreased consumption of C3 and less activation of the complement system. Rs1047286 was associated with susceptibility albeit not significantly after Bonferroni correction (OR 1.37, 95% CI 1.01-1.87; p = 0.04).


CONCLUSIONS
This study shows an association between a common single nucleotide polymorphism in C3 and susceptibility for community-acquired bacterial meningitis.
Department of Neurology, Center of Infection and Immunity Amsterdam-CINIMA, Academic Medical Center, University of Amsterdam, PO Box 22660, 1100DD Amsterdam, The Netherlands.
Kirsten S
KS
Adriani
Matthijs C
MC
Brouwer
Madelijn
M
Geldhoff
Frank
F
Baas
Aeilko H
AH
Zwinderman
B
B
Paul Morgan
Claire L
CL
Harris
Arie
A
van der Ende
Diederik
D
van de Beek
D000328:Adult; D000368:Aged; D002555:Cerebrospinal Fluid / Q000382:microbiology; D017714:Community-Acquired Infections; D003176:Complement C3 / Q000134:cerebrospinal fluid / Q000235:genetics*; D003182:Complement C5 / Q000134:cerebrospinal fluid / Q000235:genetics; D003165:Complement System Proteins / Q000134:cerebrospinal fluid / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D016920:Meningitis, Bacterial / Q000235:genetics*; D008875:Middle Aged; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide
D003176:Complement C3; D003182:Complement C5; D003165:Complement System Proteins