Effects of genomic polymorphisms on the course of sepsis: is there a concept for gene therapy?

Abstract

Sepsis and its sequelae are still a major cause of morbidity and mortality on today's intensive care units. 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 variabilities of genes encoding endogenous mediators that constitute the pathways of inflammation. Primary responses in inflammation are mediated by proinflammatory cytokines such as tumor necrosis factor and interleukin 1. Conversely, anti-inflammatory mediators are released and may induce a state of immunosuppression in sepsis. Pro- and anti-inflammatory responses contribute to the 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 to injury. The genetically determined capacity of cytokine production and release, heat shock protein expression, nitric oxide synthase activity, gene polymorphisms of coagulation factors or factors of the innate immune system-like defensins, and other genes involved in inflammation may contribute to a wide range of clinical manifestations of an inflammatory disease. Genomic information may be used to identify groups of patients with a high risk of developing severe sepsis and multiple organ dysfunction, and determining which patients will benefit from antimediator strategies because of their genetic determination to high cytokine release in the inflammatory response will be the subject of future trials.