Genetic determinants of the inflammatory response.
OBJECTIVE
Despite substantial advances in our understanding of the biology of sepsis and inflammation, improvements in clinical outcomes have been more sporadic and, with few notable exceptions, are related to improvements in supportive care rather than to specific therapies. As a result, morbidity, mortality, and cost remain high. Investigation into the genetic determinants of this response span a broad spectrum and include those aimed at deciphering the mechanisms and involved pathways on a molecular level, to those aiming to identify how genetic variation may be clinically important. While it is clear that gene sequencing and manipulation of experimental models have provided insight into the biology of the inflammatory response to infection, these technologies and their application to the study of naturally occurring human genetic variation have yet to provide the same insight or clinical benefit. The purpose of this review is to summarize what is known about the genetic determinants of the inflammatory response. We make particular reference to this broad scope of investigation introduced above but with a focus on the present status of studies examining the role of human genetic variation in the risk for and outcome from severe bacterial infection, or sepsis.


RESULTS
Using the examples of two candidate genes tumor necrosis factor-alpha (TNF-alpha) and toll-like receptor 4 (TLR4), we illustrate the spectrum of studies concerning the genetic determinants of the inflammatory response. We highlight recent literature across this spectrum, focusing on genetic association studies examining the relationships between SNPs in these genes and sepsis risk and outcome. We then review the literature addressing discordant findings in basic experimental observations and studies of clinical association.


CONCLUSIONS
Naturally occurring genetic variants in important inflammatory mediators such as TNF-alpha and TLR4 appear to alter inflammatory responses in numerous experimental and a few clinical models of inflammation. However, inconsistencies exist in the literature regarding the association between these genetic variants and disease (eg, sepsis) susceptibility and prognosis. The main limitations relate to the translation of experimental observations into reproducible genotype-phenotype associations. The reasons for these are multifactorial and include deficiencies in study design (insufficient sample size), and the complexities introduced by background genetic heterogeneity.
Imahara
Scott D
SD
Department of Surgery, University of Washington and Harborview Medical Center, Seattle, Washington 98104, USA. imaharas@u.washington.edu
O'Keefe
Grant E
GE
D020022:Genetic Predisposition to Disease; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000235:genetics; D018805:Sepsis / Q000235:genetics*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha