Variation in the TLR4 gene influences the risk of organ failure and shock posttrauma: a cohort study.
BACKGROUND
Genetic variation contributes to risk and outcomes of sepsis. We sought to determine whether variation in inflammation related genes is associated with severity of sepsis in trauma patients.


METHODS
A cohort of severely injured Caucasian patients was studied and genotyped for candidate single nucleotide polymorphisms (SNPs). These were toll-like receptor 4 (TLR4) A896G, tumor necrosis factor-alpha G-308A, interleukin-6 G-174C, interleukin-1beta C-31T, and cluster of differentiation marker 14C-159T. SNP genotypes among patients with sepsis and complicated sepsis were analyzed by chi2 and logistic regression. Six haplotype-tagging SNPs in the TLR4 gene were subsequently examined to analyze their influence on TLR4 A896G SNPs relationship to sepsis severity.


RESULTS
We enrolled 598 patients. Complicated sepsis developed in 147 (25%). Adjusting for independent risk factors, carriage of the variant TLR4 896 G allele was associated with decreased risk of complicated sepsis (odds ratio = 0.3, 95% confidence interval, 0.1-0.7, p = 0.008). Furthermore, two haplotypes seemed to better characterize this risk than the variant TLR4 896G allele. The variant TLR4 896G allele is linked to one common haplotype, which seems to confer a considerably reduced risk of complicated sepsis. (aOR = 0.2 95% confidence interval, 0.05-0.7, p = 0.01).


CONCLUSIONS
Variation within TLR4 gene is associated with severity of posttraumatic sepsis. This risk may not be solely related to TLR4 A896G SNP. It is likely that other, uncharacterized variations in the TLR4 gene contribute to sepsis severity. A thorough evaluation of variability within the TLR4 gene is needed to characterize sepsis risk.
Shalhub
Sherene
S
Department of Surgery, University of Washington, Harborview Medical Center, Seattle, Washington 98104, USA. shalhub@u.washington.edu
Junker
Christopher E
CE
Imahara
Scott D
SD
Mindrinos
Michael N
MN
Dissanaike
Sharmila
S
O'Keefe
Grant E
GE
D000483:Alleles; D002056:Burns / Q000235:genetics*; D016009:Chi-Square Distribution; D015331:Cohort Studies; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015601:Injury Severity Score; D007375:Interleukin-1 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D018950:Lipopolysaccharide Receptors / Q000235:genetics; D016015:Logistic Models; D008297:Male; D009102:Multiple Organ Failure / Q000235:genetics*; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012306:Risk; D012769:Shock / Q000235:genetics*; D051197:Toll-Like Receptor 4 / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D007375:Interleukin-1; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha