The tumor necrosis factor polymorphism TNF (-308) is associated with susceptibility to meningococcal sepsis, but not with lethality.
OBJECTIVE
To determine whether the promoter polymorphism tumor necrosis factor (TNF) (-308) is associated with susceptibility to or death from meningococcal sepsis. DESIGN, SETTING, PATIENTS, AND PARTICIPANTS: Association study involving 1321 patients with microbiologically proven invasive meningococcal disease presenting to hospitals throughout United Kingdom during 1998-2001, among whom 134 died. Controls were derived from 1280 northern English blood donors.


METHODS
DNA from patients and controls was genotyped at TNF (-308). After analysis, DNA was subsequently genotyped at eight other markers in strong linkage disequilibrium with TNF (-308); these markers were IkappaBL (-62), BAT3, LST1, NOTCH4 (+1297), NOTCH4 (+3061), CCHCR1 (+436), CCHCR1 (+2271), and LTalpha. To confirm functional relevance of TNF (-308) in the context of meningococcal disease, TNF secretion by, and TNF messenger RNA expression of macrophages derived from volunteers with known TNF (-308) genotype after exposure to Neisseria meningitidis were measured.


RESULTS
Among cases of meningococcal disease, likelihood of death was shown to be influenced by the age of the affected individual and also with the infecting serogroup, but was not influenced by genotype at TNF (-308) or the other linked markers. However, patients with meningococcal disease, irrespective of whether they died, were more likely to be homozygous for the rare allele at TNF (-308) (odds ratio = 1.93, 95% confidence interval 1.08-3.46), and less likely to be heterozygous for this marker (odds ratio = 0.79, 95% confidence interval 0.64-0.97), compared with the control cohort. There was no association of susceptibility to disease with the other markers studied. Macrophages derived from volunteers homozygous for the rare allele at TNF (-308) expressed higher levels of TNF messenger RNA and secreted higher concentrations of TNF compared with common homozygotes after exposure to N. meningitidis.


CONCLUSIONS
Genotype at TNF (-308) modifies cellular TNF secretion in response to N. meningitidis and may influence susceptibility to meningococcal disease, but does not influence the likelihood of death after infection.
Read
Robert C
RC
Section of Infection, Inflammation and Immunity, University of Sheffield Medical School, Sheffield, United Kingdom. r.c.read@sheffield.ac.uk
Teare
Dawn M
DM
Pridmore
Alison C
AC
Naylor
Simone C
SC
Timms
James M
JM
Kaczmarski
Edward B
EB
Borrow
Raymond
R
Wilson
Anthony G
AG
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D008589:Meningococcal Infections / Q000235:genetics* / Q000401:mortality*; D008875:Middle Aged; D011110:Polymorphism, Genetic; D018805:Sepsis / Q000235:genetics* / Q000401:mortality*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D055815:Young Adult
D014409:Tumor Necrosis Factor-alpha