Bench-to-bedside review: understanding genetic predisposition to sepsis (original) (raw)
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Contribution of genes polymorphism to susceptibility and outcome of sepsis
Egyptian Journal of Medical Human Genetics– Elsevier. 2010;11:97–103.
Sepsis and its sequelae are still a major cause of morbidity and mortality in intensive care units (ICU). The evidence that endogenous mediators actually mediate the individual’s response to infection has led to various approaches to assess the individual’s contribution to the course of the disease. The role of an individual’s genetic background and predisposition for the extent of inflammatory responses is determined by variability of genes encoding endogenous mediators that constitute the pathways of inflammation. Pro- and anti-inflammatory responses contribute to the susceptibility and outcome of patients with systemic inflammation and sepsis. Therefore, all genes encoding proteins involved in the transduction of inflammatory processes are candidate genes to determine the human genetic background that is responsible for interindividual differences in systemic inflammatory responses. Polymorphism of TNA a, TNFB, IL-10, IL-6, IL-1b, IL-1RN, HMGB1, TLR, PAI-1, DEFB1, HSP and MMP-9 has contribution to susceptibility and outcome of sepsis in some research. Examination of the association between genetic polymorphisms and sepsis promises to provide clinicians with new tools to evaluate prognosis, to intervene early and aggressively in treating high risk persons, and to avoid the use of therapies with adverse effects in treating low risk persons. Genomic information may be useful to use to identify groups of patients with a high risk of developing severe sepsis and multiple organ dysfunctions.
Genomic polymorphism and sepsis--is there a reason for optimism?
Prague medical report, 2008
There is no doubt that, in infectious disease, genetic predisposition plays a very important role in clinical outcome. Sepsis is a polygenic syndrome initiated by infection. A fact confounding the situation is that two factors--the macroorganism and the microorganism--are at play at the same time; hence of genotype effect must be assessed in light of their interaction. From a phylogenetic point of view, infectious disease is a companion of man throughout their life and its role in terms of function of the system of innate immunity is perceived as a beneficial one. However, the presence of a major antigen load by the infectious agent results in pathological responses at the levels of the macroorganism. Assessment of the severity of the inflammatory process on the basis of genetic predisposition is a most challenging issue. Genetic polymorphisms in the immune response to infection have been shown to be associated with clinical outcomes. The advancement of single nucleotide polymorphis...
Genetic Factors of the Disease Course After Sepsis: Rare Deleterious Variants Are Predictive
EBioMedicine, 2016
Sepsis is the dysregulated host response to an infection which leads to life-threatening organ dysfunction that varies by host genomic factors. We conducted a genome-wide association study (GWAS) in 740 adult septic patients and focused on 28 day mortality as outcome. Variants with suggestive evidence for an association (p ≤ 10 −5) were validated in two additional GWA studies (n = 3470) and gene coding regions related to the variants were assessed in an independent exome sequencing study (n = 74). In the discovery GWAS, we identified 243 autosomal variants which clustered in 14 loci (p ≤ 10 −5). The best association signal (rs117983287; p = 8.16 × 10 −8) was observed for a missense variant located at chromosome 9q21.2 in the VPS13A gene. VPS13A was further supported by additional GWAS (p = 0.03) and sequencing data (p = 0.04). Furthermore, CRISPLD2 (p = 5.99 × 10 −6) and a region on chromosome 13q21.33 (p = 3.34 × 10 −7) were supported by both our data and external biological evidence. We found 14 loci with suggestive evidence for an association with 28 day mortality and found supportive, converging evidence for three of them in independent data sets. Elucidating the underlying biological mechanisms of VPS13A, CRISPLD2, and the chromosome 13 locus should be a focus of future research activities.
Genetic influence on bloodstream infections and sepsis
International Journal of Antimicrobial Agents, 2008
Bloodstream infections (BSIs) are a major burden in health care today, associated with considerable morbidity, mortality and costs. They are either caused by direct influx of pathogens via devices into the blood (primary BSI) or by bacterial spillover from infected distant organs (secondary BSI). The recognition of invading microbes by sensing of conserved molecular patterns is pivotal for the host in staging an adequate immune response to eradicate the pathogen. Moreover, a balanced immune response is crucial to avoid over inflammation followed by additional damage to the host. This complex host response pattern is controlled by soluble proteins and cellular receptors, which have recently been found to contain substantial individual genetic variations. Single nucleotide polymorphisms have been shown to affect susceptibility to and the course of numerous diseases. A large number of genes and their products are involved in the host reaction to BSIs, and genetic variation in these molecules alters the frequency and course of these events. Here we summarise recent findings on genetic variations in molecules of the innate immune system and other systems as well as their connection with susceptibility to BSIs and sepsis and the way the host stages a beneficial response to infection.
2018
The purpose of this study was to determine the impact of baseline systemic inflammation (pro-inflammatory cytokine, anti-inflammatory cytokine, and their ratio), genetic variability, and environment on the development of health care associated infections (HAI) among sepsis patients during their ICU stay (up to 28 days). Methods: A prospective observation study was conducted at the Veterans Affairs Medical Center in the Medical Intensive Care Unit over an 18 month period. A total of 78 patients were enrolled within 72 hours of presenting to the ICU with sepsis. Patient were excluded if they were receiving immunosuppressants (chemotherapy or greater than one mg/kg of prednisone or equivalent dose), immunosuppressed (AIDS, cancer), or had liver failure (Child Pugh category C or higher). Baseline plasma and buccal swabs were collected. Patients were followed prospectively through their ICU stay (or for a maximum of 28 days) for the development of HAI as defined by CDC guidelines. Primary variables included baseline IL-6 and IL-10 levels, IL-6 SNP rs1800795, IL-10 SNP rs1800896, APACHE II, invasive devices, and development of HAI. Results: A total of 17 HAI were identified with 64% caused by Candida. There were no significant differences in levels of pro-inflammatory cytokine, anti-inflammatory cytokine, or their ratio among subjects who did and did not develop at least one HAI during their ICU stay. There were also no significant differences in rs1800795 or rs1800896 genotypes for those who did and did not develop HAI; however, racial differences were detected in genotypes among white and black patients with sepsis who did and did not develop HAI. There was a significant difference in rs1800795 genotype among black patients with sepsis who did not develop HAI compared to whites patients with sepsis who did not develop HAI (p = 0.006). Specifically, black patients had a lower CG (17.4% vs. 42.1%) and higher GG (82.6% vs. 42.1%) than white patients. There were no racial differences when comparing white and black sepsis patients who developed HAI (p = 1.0). In a series of Cox regression analyses investigating timing to first HAI among those who did and did not develop HAI during ICU stay, the final model included only APACHE II, cumulative invasive device score, and IL-6 rs1800795. Conclusion: This study provides evidence of a genetic risk for development of HAI. Despite best evidenced based practices some patients will develop HAI. Strict aseptic technique is essential to preventing infection. In addition to eliminating invasive devices as quickly as possible, patients with a high severity of illness may need to be isolated to lower their risk. Early administration of antibiotics not only provides prompt treatment for the initial infection but also lowers risk for subsequent infections. vii TABLE OF CONTENTS CHAPTER 1.
Toll-like Receptor 1 Polymorphisms Affect Innate Immune Responses and Outcomes in Sepsis
American Journal of Respiratory and Critical Care Medicine, 2008
Rationale: Polymorphisms affecting Toll-like receptor (TLR)-mediated responses could predispose to excessive inflammation during an infection and contribute to an increased risk for poor outcomes in patients with sepsis. Objectives: To identify hypermorphic polymorphisms causing elevated TLR-mediated innate immune cytokine and chemokine responses and to test whether these polymorphisms are associated with increased susceptibility to death, organ dysfunction, and infections in patients with sepsis. Methods: We screened single-nucleotide polymorphisms (SNPs) in 43 TLR-related genes to identify variants affecting TLR-mediated inflammatory responses in blood from healthy volunteers ex vivo. The SNP associated most strongly with hypermorphic responses was tested for associations with death, organ dysfunction, and type of infection in two studies: a nested case-control study in a cohort of intensive care unit patients with sepsis, and a case-control study using patients with sepsis, patients with sepsis-related acute lung injury, and healthy control subjects. Measurements and Main Results: The SNP demonstrating the most hypermorphic effect was the G allele of TLR1 27202A/G (rs5743551), which associated with elevated TLR1-mediated cytokine production (P , 2 3 10 220). TLR1 27202G marked a coding SNP that causes higher TLR1-induced NF-kB activation and higher cell surface TLR1 expression. In the cohort of patients with sepsis TLR1 27202G predicted worse organ dysfunction and death (odds ratio, 1.82; 95% confidence interval, 1.07-3.09). In the case-control study TLR1 27202G was associated with sepsis-related acute lung injury (odds ratio, 3.40; 95% confidence interval, 1.59-7.27). TLR1 27202G also associated with a higher prevalence of gram-positive cultures in both clinical studies. Conclusions: Hypermorphic genetic variation in TLR1 is associated with increased susceptibility to organ dysfunction, death, and grampositive infection in sepsis.
Issues with Polymorphism Analysis in Sepsis
Clinical Infectious Diseases, 2005
Genetic variation has been shown to play a large role in determining susceptibility to and outcome of such complex diseases as sepsis. There is a much higher heritability of death due to infection than death due to cancer or heart disease. More than 8 million single nucleotide polymorphisms (SNPs) have been detected in the human genome, and there is very little understanding of their effect on gene expression and protein function. The use of haplotypes, which are inherited sets of linked SNPs, as the unit of genetic variation in association studies and the marking of these haplotypes with unique "tag SNPs" may help to narrow down the search for causal SNPs. Future studies must be large (thousands of patients) and must be carefully designed to avoid false associations resulting from ethnic differences in genotype frequencies and disease prevalence in order to find true, reproducible associations between genotype and phenotype. Functional studies and careful characterization of intermediate phenotypes must be done to lend biological plausibility to genotype-phenotype associations. Examination of the association between genetic polymorphisms and sepsis promises to provide clinicians with new tools to evaluate prognosis, to intervene early and aggressively in treating high-risk persons, and to avoid the use of therapies with adverse effects in treating low-risk persons.
Genomic landscape of the individual host response and outcomes in sepsis: a prospective cohort study
The Lancet. Respiratory medicine, 2016
Effective targeted therapy for sepsis requires an understanding of the heterogeneity in the individual host response to infection. We investigated this heterogeneity by defining interindividual variation in the transcriptome of patients with sepsis and related this to outcome and genetic diversity. We assayed peripheral blood leucocyte global gene expression for a prospective discovery cohort of 265 adult patients admitted to UK intensive care units with sepsis due to community-acquired pneumonia and evidence of organ dysfunction. We then validated our findings in a replication cohort consisting of a further 106 patients. We mapped genomic determinants of variation in gene transcription between patients as expression quantitative trait loci (eQTL). We discovered that following admission to intensive care, transcriptomic analysis of peripheral blood leucocytes defines two distinct sepsis response signatures (SRS1 and SRS2). The presence of SRS1 (detected in 108 [41%] patients in disc...
Polymorphisms in association with sucseptibility to severe sepsis
Laboratory Medicine
Background: This study investigates the allele and genotype distribution of a single nucleotide polymorphism located at position +16974A/C in 3'-untranslated region (UTR) and a complex polymorphism (IL-12Bpro) within the promoter region of IL-12B gene in association with susceptibility to severe sepsis.