title: MMP-8 genotypes influence the inflammatory response in human endotoxemia.
abstract: Clinical studies have reported associations between MMP-8 genotypes and clinical outcomes without exploring underlying mechanisms. This study aims to understand the influence of the rs1940475 SNP on downstream chemokine and cytokine response in human endotoxemia. Rs1940475 was genotyped in 44 healthy Caucasian males, who were challenged with an intravenous bolus of 2 ng/kg lipopolysaccharide (LPS). Plasma levels of tumor necrosis factor (TNF), interleukin (IL)-6, IL-8, and macrophage inflammatory protein (MIP)-1α were measured at baseline and 2, 4, 6, and 24 h after LPS infusion with high-sensitivity enzyme immunoassays. Peak TNF levels at 2 h after LPS infusion were significantly higher in subjects with AA genotype compared to subjects with AG or GG genotypes (185 pg/mL [IQR, 154-234] vs. 94 pg/mL [IQR, 65-125] vs. 107 pg/mL [IQR, 80-241], respectively; p = 0.03 between groups). Peak IL-6 levels were trend-wise higher in subjects with AA genotype compared to those with AG or GG genotypes (566 pg/mL [IQR, 294-644] vs. 278 pg/mL [IQR, 184-539] and 329 pg/mL [IQR, 240-492], respectively; p = 0.15 between groups). In contrast, peak MIP-1α at 2 h was highest in GG genotype carriers compared to those with AG or AA genotypes (602 pg/mL [IQR, 449-727] vs. 389 pg/mL [IQR, 375-490] and 510 pg/mL [425-813], respectively; p < 0.03 between groups). AA genotype carriers had highest peak TNF and IL-6 levels after LPS challenge, whereas peak MIP-1α levels were highest in GG carriers. This indicates that the rs1940475 SNP modifies the host response to inflammatory stimuli, which may in part explain previously shown associations with clinical outcomes.
authors.affiliation: Department of General Anesthesiology and Critical Care Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: Judith M
authors.initials: JM
authors.lastname: Rella
authors.forename: Bernd
authors.initials: B
authors.lastname: Jilma
authors.forename: Astrid
authors.initials: A
authors.lastname: Fabry
authors.forename: A Murat
authors.initials: AM
authors.lastname: Kaynar
authors.forename: Florian B
authors.initials: FB
authors.lastname: Mayr
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D015415:Biomarkers / Q000097:blood; D001777:Blood Coagulation; D054405:Chemokine CCL3 / Q000097:blood; D019446:Endotoxemia / Q000097:blood / Q000201:enzymology* / Q000208:ethnology / Q000235:genetics* / Q000276:immunology; D004731:Endotoxins / Q000008:administration & dosage; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D064368:Healthy Volunteers; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood*; D015850:Interleukin-6 / Q000097:blood; D016209:Interleukin-8 / Q000097:blood; D008297:Male; D020784:Matrix Metalloproteinase 8 / Q000235:genetics*; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D015415:Biomarkers; C515429:CCL3 protein, human; C508606:CXCL8 protein, human; D054405:Chemokine CCL3; D004731:Endotoxins; C508600:IL6 protein, human; D018836:Inflammation Mediators; D015850:Interleukin-6; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; C044101:endotoxin, Escherichia coli; C488762:MMP8 protein, human; D020784:Matrix Metalloproteinase 8