Bench-to-bedside review: Association of genetic variation with sepsis

Susceptibility and response to infectious disease is, in part, heritable. Initial attempts to identify the causal genetic polymorphisms have not been entirely successful because of the complexity of the genetic, epigenetic, and environmental factors that influence susceptibility and response to infectious disease and because of flaws in study design. Potential associations between clinical outcome from sepsis and many inflammatory cytokine gene polymorphisms, innate immunity pathway gene polymorphisms, and coagulation cascade polymorphisms have been observed. Confirmation in large, well conducted, multicenter studies is required to confirm current findings and to make them clinically applicable. Unbiased investigation of all genes in the human genome is an emerging approach. New, economical, high-throughput technologies may make this possible. It is now feasible to genotype thousands of tag single nucleotide polymorphisms across the genome in thousands of patients, thus addressing the issues of small sample size and bias in selecting candidate polymorphisms and genes for genetic association studies. By performing genome-wide association studies, genome-wide scans of nonsynonymous single nucleotide polymorphisms, and testing for differential allelic expression and copy number polymorphisms, we may yet be able to tease out the complex influence of genetic variation on susceptibility and response to infectious disease

Genetic determinants of the host response to infection in critically ill adults with systemic inflammatory response syndrome

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.Medicine, Faculty ofMedicine, Department ofExperimental Medicine, Division ofGraduat

Novel polymorphism of interleukin-18 associated with greater inflammation after cardiac surgery

Introduction: Interleukin (IL)-18 is a key modulator of the cytokine response that leads to organ dysfunction and prolonged intensive care unit (ICU) stay after cardiopulmonary bypass surgery. We hypothesised that variation in the pro-inflammatory gene IL-18 is associated with adverse clinical outcome because of a more intense inflammatory response. Methods: Haplotypes of the IL-18 gene were inferred from genotypes of 23 Coriell Registry subjects. Four haplotype tag single nucleotide polymorphisms (-607 C/A, -137 G/C, 8148 C/T and 9545 T/G) identified four major haplotype clades. These polymorphisms were genotyped in 658 Caucasian patients undergoing cardiopulmonary bypass surgery. Clinical phenotypes were collected by retrospective chart review. Results: Patients homozygous for the T allele of the 9545 T/G polymorphism had an increased occurrence of prolonged ICU stay (6.8% for TT genotype versus 2.7% for GG or GT genotype; p = 0.015). Patients homozygous for the T allele also had increased occurrence of low systemic vascular resistance index (62%) compared with the GG and GT genotypes (53%; p = 0.045). Patients homozygous for the T allele had increased serum IL-18 concentrations 24 hours post-surgery (p = 0.018), increased pro-inflammatory tumour necrosis factor alpha concentrations (p = 0.014) and decreased anti-inflammatory serum IL-10 concentrations (p = 0.018) 24 hours post-surgery. Conclusions: The TT genotype of the IL-18 9545 T/G polymorphism is associated with an increased occurrence of prolonged ICU stay post-surgery and greater post-surgical inflammation. These results may be explained by greater serum IL-18, leading to greater pro-versus anti-inflammatory cytokine expression.Critical Care Medicine, Division ofMedicine, Faculty ofMedicine, Department ofReviewedFacult