Frank Stber, Malte Book, Sven Klaschik, Lutz Eric Lehmann,

Jens-Christian Schewe, and Stefan Weber

Department of Anaesthesiology and Intensive Care Medicine, University of Bonn, Bonn, Germany

The morbidity and mortality of critical illness is still principally determined by the incidence and course of
sepsis and its sequelae. Evidence-based efforts to improve the care of sepsis patients include the
Surviving Sepsis Campaign and the International Sepsis Forum, and new definitions and diagnostic
concepts are being evaluated with the aim of facilitating early diagnosis and evidence-based therapies.
Advances include the PIRO (predisposition, infection, response, organ dysfunction) concept, which is
designed to classify states of sepsis. PIRO recognizes that the incidence and outcome of sepsis are
affected by genetic predisposition, which has been suggested as a tool for risk stratification and even as
an inclusion criterion for therapeutic trials. Genomic variants may influence the individual phenotype,
including gene expression profiles and protein structure and concentration. Genomics research has
therefore entered the area of complex diseases, of which sepsis remains one of the greatest challenges in
acute medicine. Genomics and genotyping in the critically ill will be integrated into the field of functional
genomics, assisted by high-throughput automated technologies such as microarrays. However, standards
and quality-control measures need to be implemented and genotyping in intensive care must be tested in
large-scale genetic epidemiological studies. Advances in Sepsis 2004;4(1):116.
The importance of predisposition in the development and
prognosis of sepsis is recognized by the PIRO
(predisposition, infection, response, organ dysfunction)
concept [1]. The extent of the inflammatory response in an
individual is determined by genetic variations in the
endogenous mediators that constitute the inflammatory
pathways. Genes encoding proteins involved in the
transduction of inflammatory processes are candidates for
determining differences in the systemic inflammatory
response to infection and injury.
The capacity for production and release of inflammatory
mediators shows significant variation between individuals
and may contribute to a wide range of clinical manifestations
of inflammatory disease. But which genes and which
genomic variations should be used as diagnostic markers?
Will certain subgroups of patients benefit more than others
from anti-mediator strategies because of their predisposition
to high mediator release? Genetics may have a profound
impact on diagnostics and therapy in intensive care medicine
in the future [2].
Address for correspondence: F Stber, Department of Anaesthesiology
and Intensive Care Medicine, University of Bonn, Sigmund-FreudStrasse 25, 53105 Bonn, Germany.
Email: frank.stueber@ukb.uni-bonn.de

The search for candidate genes has been directed by the

current understanding of sepsis pathophysiology (reviewed
in [3]). Both pro- and anti-inflammatory responses
contribute to the outcome of patients with systemic
inflammation and sepsis; thus, all genes that encode
proteins involved in the transduction of inflammatory
processes are candidates. This group of genes is not
restricted to those encoding cytokines, but also includes
genes for numerous other effector molecules, such as
components of the coagulation system, heat shock proteins
(HSPs), and signal transduction molecules.
Impact of genomic variation on sepsis: An update
Cytokines released from immunocompetent cells are major
players in the inflammatory response to infection. Primary
proinflammatory cytokines, such as tumor necrosis factor
(TNF) and interleukin-1 (IL-1), induce production of
secondary pro- and anti-inflammatory mediators, such as
IL-6 and IL-10. These have been shown to contribute
substantially to the primary response to infection [3].
Variations at the TNF locus have been the main focus of
genomic research in sepsis. Biallelic polymorphisms defined
by restriction enzymes (NcoI, AspHI), single base changes
within the promoter regions (at positions 5308 and 5238),
and multiallelic microsatellites (TNFae) have all been

ADVANCES IN SEPSIS Vol 4 No 1 2004

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LEADING ARTICLE

Genomics and Genotyping in Severe Sepsis

FRANK STBER, MALTE BOOK, SVEN KLASCHIK ET AL.

investigated. Polymorphisms within the TNF promoter

region may be important in the regulation of the TNF gene
[4,5], while the rare TNF2 allele (A at position 308) has
been linked to high TNF promoter activity [4]. However,
some of the association studies that have been carried out
have low statistical power as a consequence of enrolling
low numbers of patients. Study designs similar to the
transmission disequilibrium test (TDT) used in state-of-theart genetic epidemiological investigations are required to
confirm the results. Genetic epidemiologists currently favor
association studies in complex diseases that do not allow
sampling of DNA from family members and where the
disease phenotype depends on an environmental impact,
such as injury or infection [6]. Family members do not all
face the same environmental risks and thus do not form a
comparable study group within the TDT design.
Compared with genomic variations in the promoter
region, intronic polymorphisms are more difficult to
associate with possible functional relevance. Initial studies
have suggested that single nucleotide polymorphisms may
affect the incidence and/or outcome of sepsis [7,8]. Various
studies have associated TNF polymorphisms with particular
sepsis phenotypes [815]. Genomic TNF variations have
been associated with mediastinitis [9] and the development
of organ dysfunction induced by systemic inflammation
following major surgery [10]. Association studies of the
impact of these polymorphisms on the incidence and
outcome of severe sepsis and septic shock have been carried
out, although their results are conflicting, partly due to low
statistical power because of the low numbers of patients
recruited [1115]. Trauma patients carrying the
TNF2/TNFB2 risk allele haplotype were found to be
protected from sepsis following polytrauma [12], and a
variety of other studies have suggested that TNF
polymorphisms are positively associated with the incidence
and/or outcome of severe sepsis or septic shock
[710,12,15,16]. Moreover, one study of 160 patients
undergoing major surgery identified a positive association
between the TNF-b NcoI polymorphism and the composite
outcome of severe complications [13]. However, no
large-scale, well-powered epidemiological study of genetic
predisposition in sepsis has been published so far.
The question of whether a particular genotype is clearly
associated with a high proinflammatory response in clinical
Gram-negative infection and severe sepsis cannot yet be
answered. In the ex vivo studies published to date, different
conditions of cell culture and cytokine induction have
contributed to varying results. Bayley and colleagues have
recently published a review of the functional impact of
genomic variations within the TNF locus that asked whether
there is a future for TNF promoter polymorphisms [5]. Most

12

of the published studies discussed found that genomic TNF

variations have no impact on TNF expression or presented
conflicting evidence. In terms of genetic epidemiology, it
does not matter whether TNF promoter variations affect
promoter activity; a marker may still have a strong
association with disease due to linkage to other genes or
variations. However, in terms of molecular biology, it is
important to understand the influence of a genomic
variation on gene function. This knowledge can strengthen
the role of the gene as a candidate marker and gives insight
into gene regulation.
As more genetic information on different markers from
different candidate genes becomes available, studies of
combined gene effects and genegene interactions will
become a further tool for studying genetic predisposition.
A combination of TNF high responders and IL-10 low
responders to an inflammatory stimulus was found to have
the highest death rate in a study of patients with acute renal
failure [17,18]. The definition of high or low responder was
established by testing the responses of genotyped
individuals to defined ex vivo stimuli (e.g. stimulation of
peripheral blood cells with lipopolysaccharide [LPS]), while
taking into account molecular studies on the effects of
genomic variation on gene function. Evidently, a patients
genetic predisposition ultimately will be described by a set of
genomic markers, which may even vary with the cause of
severe sepsis, for example between pancreatitis and
nosocomial pneumonia [17,20].
IL-1 is a potent proinflammatory cytokine that is
released by macrophages involved in the systemic
inflammatory response. It is capable of inducing the
symptoms of septic shock and organ failure in animal
models and is regarded as a primary mediator of the
systemic inflammatory response. Despite the finding that a
homozygous TaqI genotype correlates with high IL-1b
secretion, genotyping of patients with severe sepsis did not
reveal that this genotype had any association with the
incidence or outcome of the disease [20,21]. An IL-6
promoter variation at position 5174 has also been the
subject of initial association studies. However, although
a positive association was demonstrated between this
variation and sepsis in adults [22] and low birth-weight
neonates [23], large confirmatory studies are needed.
Major efforts have been made in cytokine research to
disclose the mechanisms of endotoxin-mediated effects.
There are also a number of noncytokine mediators, such
as nitric oxide, that significantly contribute to the toxicity
of endotoxin.
Intracellular HSPs may provide protection against the
cellular stress induced by endotoxin and its mediators. HSPs
act as molecular chaperones, facilitating protein synthesis

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GENOMICS AND GENOTYPING IN SEVERE SEPSIS

and folding and restructuring partially denatured proteins.

However, the utility of HSP polymorphisms for determining
predisposition in sepsis remains to be proven [24].
Coagulation factor polymorphisms have regained attention
following the demonstration that Activated Protein C is the
first anticoagulant agent to effectively lower mortality in
sepsis [25].
Plasminogen activator inhibitor-1 (PAI-1) is a potent
procoagulatory protein with genomic variation in its
promoter. Homozygotes of the PAI-1 4G allele have increased
plasma levels of PAI-1 and increased procoagulatory activity
compared with 5G allele homozygotes or heterozygotes.
Patients who are 4G homozygotes are at high risk of a poor
outcome in meningococcal disease [26], with a relative risk of
dying from meningococcal sepsis of 2.7 (95% confidence
interval 1.64.7), compared with heterozygotes and 5G
homozygotes. Logistical regression indicated a 40% reduction
in the odds of dying for 4G/5G patients and a 91% reduction
for 5G/5G patients compared with 4G homozygotes [27].
The PAI-1 promoter polymorphism was found to have a
similar effect in trauma patients [28]. The thrombinactivatable fibrinolysis inhibitor (TAFI) gene also shows
genomic variation, at position 325. An initial positive
association study showed an increased mortality in
patients with meningococcal disease who have this
polymorphism [29]. Genegene interaction effects between
TAFI and PAI-1 variants are worthy of study, as the risk
may be additive.
Candidate genes of innate immunity
The mechanism of transduction of the LPS signal into the
cell was unknown until the discovery of Toll-like receptors
(TLRs). These are analogs of the Drosophila Toll receptor
that transduces signals for the elaboration of innate immune
responses against bacteria and fungi. TLRs were first
identified in mice [30]. A single base-pair mutation resulting
in an amino acid change in murine TLR4 rendered the
extensively studied CH3/HeJ mouse strain highly resistant to
LPS challenge [31]. Thus far, 10 members of this protein
family (TLRs110) have been identified in mammals. TLRs1,
3, and 59 are orphan receptors. However, TLR2 has been
found to transduce peptidoglycan stimulation by Grampositive organisms [32] and TLR4 appears to have a key role
in the LPS-induced signaling pathway [33]. Both toxic and
microbial animal models of sepsis provide evidence for a
genetic component of sepsis. The canonical toxic
(endotoxic) model involves administration of bacterial LPS
to animals, although the fidelity of the model to authentic
sepsis is disputed. The acute inflammatory response initiated
by endotoxemia is one of several responses to clinical
infection. The first evidence for a genetic predisposition to

sepsis was provided by the LPS-resistant mouse. The genetic

locus of the LPS resistance was mapped to mouse
chromosome 4 and TLR4 was identified as a functionally
significant gene and gene product [34].
The presence of a functional TLR4 gene and gene
product appears to be one of several determinants of
outcome in endotoxemia. A survey of inbred laboratory
mice demonstrated a broad range of sensitivity to LPS, and
genetic analysis of inbred recombinant mice (genetically
defined crosses of the most and least sensitive of the
laboratory strains) identified five loci that appear to regulate
LPS sensitivity [35]. High-resolution mapping of these is in
progress. The data suggest that response to endotoxemia is
a definable multigenic characteristic of laboratory mice.
In humans, the work of Smirnova and colleagues has
revealed several genomic variations within the coding region
of TLR4 [36], although it remains to be evaluated
whether these polymorphisms affect the function of the
protein. If this is the case, the TLR4 gene is an important
candidate for determining the genomic contribution to
variability in innate immunity.
The first positive associations have been demonstrated in
sepsis patients. The TLR4 Thr399Ile polymorphism has been
suggested to predispose critically ill septic patients to Gramnegative infection [33], although the functional implications
of this variant remain controversial. Some researchers
have claimed that the polymorphism affects patient
responsiveness to LPS, but others have failed to confirm
these findings [37,38]. One study has identified a positive
association between the Thr399Ile polymorphism and
premature birth [39]. As the allele frequencies of this TLR4
polymorphism are low (610%), well-powered genetic
epidemiological studies will need to enroll many cases in
order to produce valid results. Other genetic markers are
also being investigated. A rare genomic variation has
recently been described at position 103 (A/G) of MD2, an
important adaptor molecule needed for adequate TLR4
function, causing an amino acid change at position 35
(Thr/Ala). This variant appears to lead to decreased
responses to LPS stimulation ex vivo [27]. Although the
population frequency of the allele is still to be determined,
MD2 is another candidate gene to be analyzed in genetic
studies of sepsis.
The role of CD14 genomic variants in LPS signaling and
the incidence and outcome of severe sepsis also needs
clarification [41]. Although some studies have not found a
significant association between genomic CD14 variations
and the development of severe sepsis following polytrauma
[33,42], one report has demonstrated an association
between CD14 polymorphisms and septic shock
susceptibility and mortality [43].

ADVANCES IN SEPSIS Vol 4 No 1 2004

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FRANK STBER, MALTE BOOK, SVEN KLASCHIK ET AL.

Perspectives of genotyping in the intensive care unit

How should researchers investigating the genetics of sepsis
go about finding the gene in a haystack [44]? They will
most probably not be able to depend on a single genomic
marker, but will need to find and define a combination of
them. Genotyping technology now includes reliable
microarray (genechip) systems. A microarray for
cytochrome P450 polymorphisms became commercially
available 1 year ago (AmpliChip CYP450, Roche, Basel,
Switzerland) and a genechip for risk assessment in the
intensive care unit, as well as for use in pharmacogenomics,
is on the verge of being realized. Necessary information on
genomic markers is still lacking, but major national and
international funding agencies have started to recognize the
importance of carrying out genetic epidemiological studies
in intensive care medicine and their potential to improve
healthcare. The first large-scale genotyping studies are in
progress and will help to resolve the initial confusion caused
by statistically underpowered small-scale studies. The results
of these studies should be used to help design prospective
studies to validate the classification of risk introduced by the
PIRO concept. The value of genomic risk markers needs to
be verified by prospective outcome studies. Moreover, the
question of whether groups of patients identified as high
risk by genomic markers may benefit from individualized
therapeutic strategies needs to be answered. If this is the
case, genotype information may be used as an inclusion
criterion for future therapeutic trials.

Currently, association study designs appear to be preferred

in genetic studies of complex diseases.
The increasing understanding of the genetics of the
inflammatory process raises the possibility of developing
valuable diagnostic tools and new therapeutic approaches for
severe sepsis. Possible genomic markers for risk stratification
of sepsis patients and for identification of individuals at
increased risk of developing organ failure have begun to be
evaluated. Many candidate genes remain to be studied and
the clinical significance of genomic markers must be tested.
Large-scale investigations to confirm the results of the initial
low-powered studies are underway. As funding agencies
realize the importance of genetic information on the diagnosis
and therapy of acute diseases such as sepsis, it can be hoped
that significant advances will be made in the near future.
Disclosures
The authors have no relevant financial interests to disclose.

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