Genetic polymorphisms in sepsis and septic shock: role in prognosis and potential for therapy.
Genetic epidemiologic studies suggest a strong genetic influence on the outcome from sepsis, and genetics may explain the wide variation in the individual response to infection that has long puzzled clinicians. Several candidate genes have been identified as important in the inflammatory response and investigated in case-controlled studies, including the tumor necrosis factor (TNF)-alpha and TNF-beta genes, positioned next to each other within the cluster of human leukocyte antigen class III genes on chromosome 6. Other candidate genes for sepsis and septic shock include the interleukin (IL)-1 receptor antagonist gene, the heat shock protein gene, the IL-6 gene, the IL-10 gene, the CD-14 gene, the Toll-like receptor (TLR)-4 gene, and the TLR-2 gene, to name a few. In this review, we summarize the evidence for a genetic susceptibility to development of sepsis and death from sepsis, discuss design of clinical genetics studies relevant to the study of complex disorders, consider the candidate genes likely to be involved in the pathogenesis of sepsis, and discuss the potential for targeted therapy of sepsis and septic shock based on genetic variability.
Holmes
Cheryl L
CL
McDonald Research Laboratories/The iCAPTURE Centre, University of British Columbia, 1081 Burrard Street, Vancouver, BC, Canada V6Z 1Y6.
Russell
James A
JA
Walley
Keith R
KR
D000209:Acute-Phase Proteins / Q000235:genetics*; D000328:Adult; D000483:Alleles; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D016207:Cytokines / Q000235:genetics*; D005786:Gene Expression Regulation / Q000502:physiology; D005838:Genotype; D006360:Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D008233:Lymphotoxin-alpha / Q000037:antagonists & inhibitors / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D011486:Protein C / Q000037:antagonists & inhibitors / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics*; D012772:Shock, Septic / Q000188:drug therapy / Q000235:genetics*; D018746:Systemic Inflammatory Response Syndrome / Q000188:drug therapy / Q000235:genetics*; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics
D000209:Acute-Phase Proteins; D000911:Antibodies, Monoclonal; D016207:Cytokines; D006360:Heat-Shock Proteins; D008233:Lymphotoxin-alpha; D008562:Membrane Glycoproteins; D011486:Protein C; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha