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Genetic determinants of the host response to infection in critically ill adults with systemic inflammatory response syndrome Sutherland, Ainsley M.


Background. Activation of a systemic inflammatory response to infection varies significantly between individuals with important clinical implications. Genotype contributes substantially to outcome of infectious disease. Hypothesis. Allelic variants of inflammatory and innate immunity genes affect protein levels and function and are predictive of outcome in critically ill adults who have systemic inflammatory response syndrome (SIRS). Methods. Clinical data for derivation and validation cohorts of critically ill Caucasian patients with SIRS were collected for 28 days after admission to ICU and also for cardiac surgery patients. A subgroup of cardiac surgery patients had blood drawn post-operatively for cytokine measurements. Haplotypes of candidate genes were inferred from publicly available data using PHASE and cladistic structure determined using MEGA2. A set of "haplotype tag" single nucleotide polymorphisms (htSNPs) that defined major haplotype clades of the candidate genes and previously examined SNPs were chosen for genotyping in the three cohorts. Main results. CD14 -159TT was associated with Gram-negative cultures in the derivation cohort and with mortality in the validation cohort. Mannose-binding lectin (MBL) haplotype pairs XO/O and O/O were associated with positive bacterial cultures and TLR2 - 16933AA was associated with sepsis and with Gram-positive cultures in the derivation cohort. The C/T/A clade of IRAK4 was associated with Gram-positive cultures in a large derivation cohort and with decreased B-lymphocyte response to CpG and a trend to decreased fibroblast response to LPS. Haplotype clades of IL-6 were associated with 28-day mortality and organ dysfunction in the derivation cohort, but not in the validation cohort. Haplotype clades of IL-6 were associated with post-surgical vasodilation in cardiac surgery patients, but not with altered serum levels of cytokines after cardiac surgery. Conclusions. Variation in the key inflammatory and innate immunity genes IL-6, CD14, MBL and TLR2 contribute to variation in individuals' responses to inflammatory stimuli.

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