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Relevance of Mutations in the TLR4 Receptor in Patients With Gram-Negative Septic Shock
Eva Lorenz, PhD;
Jean Paul Mira, MD;
Kathy L. Frees;
David A. Schwartz, MD
Arch Intern Med. 2002;162:1028-1032.
ABSTRACT
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Background Septic shock remains a significant health concern worldwide, and despite
progress in understanding the physiological and molecular basis of septic
shock, the high mortality rate of patients with septic shock remains unchanged.
We recently identified a common polymorphism in toll-like receptor 4 (TLR4)
that is associated with hyporesponsiveness to inhaled endotoxin or lipopolysaccharide
in humans.
Methods Since TLR4 is a major receptor for lipopolysaccharide in mammals and
gram-negative bacteria are the prevalent pathogen associated with septic shock,
we investigated whether these specific TLR4 alleles
are associated with a predisposition to a more severe disease outcome for
patients with septic shock. We genotyped 91 patients with septic shock as
well as 73 healthy blood donor controls for the presence of the TLR4 Asp299Gly and TLR4 Thr399Ile mutations.
Results We found the TLR4 Asp299Gly allele exclusively
in patients with septic shock (P = .05). Furthermore,
patients with septic shock with the TLR4 Asp299Gly/Thr399Ile alleles had a
higher prevalence of gram-negative infections.
Conclusion Mutations in the TLR4 receptor may predispose people to develop septic
shock with gram-negative microorganisms.
INTRODUCTION
DESPITE SIGNIFICANT advances in understanding the molecular basis of
sepsis and its associated immunologic response, sepsis remains a problem worldwide
and is associated with a high mortality. Annually, septic shock, the most
severe form of sepsis, causes the death of more than 100 000 people in
the United States.1-2 Gram-negative
bacteria are the most common pathogens associated with bacterial infections
in diseases such as meningitis. Endotoxin or lipopolysaccharide (LPS), the
main component of the cell wall of gram-negative bacteria, has been shown
to elicit an inflammatory response that mimics all of the features described
in septic shock.3 In vivo and in vitro, LPS
activates macrophages and monocytes, as shown by increased secretion of cytokines
such as tumor necrosis factor (TNF)  , interleukin (IL) 1, IL-6, and
IL-8.4-5 Activation of an innate
immune mechanism causes proinflammatory cytokine release to be magnified to
dangerous levels, resulting in hypotension, organ failures, and even death
in a significant number of patients.1-2
A likely target for novel therapeutic intervention is the initial recognition
of pathogens and the initiation of an early innate immune response.
The molecular events leading to cell recognition and response to LPS
are becoming more clearly defined. Recently, the toll family of proteins,
which consists of at least 10 type 1 transmembrane receptor proteins, has
been identified.6 The toll proteins share a
highly homologous cytoplasmic domain, similar to the IL-1 receptor, a very
short transmembrane domain, and an extracellular portion consisting of a various
number of leucine-rich repeats.7 Toll-like
receptor 4 (TLR4), in particular, has been shown to be a major LPS recognition
receptor.8 In vivo, mouse strain C3H/HeJ (which
has a proline-to-histidine substitution at amino acid 712 of TLR4) and C57BL/10ScCR (which has a deletion of the TLR4 locus and does not express TLR4 RNA)
are both hyporesponsive to LPS.9 In addition,
macrophages and B cells from TLR4-/-
mice are unable to mount a cellular response to LPS.10-11
In vitro data from transfection of mammalian cell lines further proved that
TLR4 is able to enhance the LPS responsiveness of cells, a process augmented
by CD14 and leading to activation of transcription factors nuclear factor– B
and activator protein 1.12 These findings indicate
that TLR4 is a recognition molecule for gram-negative pathogens and specifically
LPS.
The cloning of TLR4 and its identification
as a primary LPS receptor in mammals prompted us recently to investigate whether
mutations in TLR4 would modulate the response to
LPS in humans. Using a reliable model of LPS-induced airflow obstruction,13 we demonstrated that specific mutations in TLR4 (Asp299Gly and Thr399Ile) are associated with a diminished
airway response to inhaled LPS in normal human volunteers.14
Since mice that contain mutations in TLR4 are
hyporesponsive to LPS and are also more susceptible to gram-negative bacterial
challenge, we hypothesized that the mutations in human TLR4 associated with hyporesponsiveness to inhaled endotoxin would
also enhance the susceptibility of humans to gram-negative sepsis. To investigate
this hypothesis, we studied the distribution of mutations in TLR4 in healthy blood donors and in patients with septic shock. Our
findings indicate that, although the overall frequency of TLR4 mutations was similar in both populations, within the septic shock
group patients with TLR4 mutations had more severe
disease and an increased frequency of gram-negative infections. In addition,
mutations of TLR4 involving only the 299 residue
occurred exclusively in those with septic shock, and all of the patients with
this isolated mutation had gram-negative septic shock. These findings indicate
that mutations of the TLR4 receptor may predispose
individuals to gram-negative septic shock.
SUBJECTS AND METHODS
STUDY SUBJECTS
The patient samples were collected as part of a multicenter study conducted
in 7 academic adult intensive care units in France between March 1, 1996,
and November 30, 1997. The protocol was approved by the institutional review
board of Cochin University Hospital, Paris, France. Informed consents were
obtained from control subjects and patients or their relatives.
The control group comprised 73 healthy unrelated white blood donors
to the Cochin University Hospital blood bank; 42 of the controls had been
previously genotyped for a study on TNF- polymorphisms.15
An additional 31 healthy blood donors were collected as control subjects for
this study. The septic shock group, defined by the criteria of the consensus
conference,16 included 91 intensive care unit
(ICU) patients. Of these patients, 88 had been included in a previously published
study on the effect of TNF- polymorphism on septic shock,15
and 3 patients were entered into the study after June 1997.
To be eligible for enrollment, the patients with septic shock had to
be white and to have 6 of the following inclusion criteria of septic shock
within a 12-hour period: (1) clinical evidence of infection; (2) hyperthermia
(temperature >38°C) or hypothermia (temperature <35.6°C); (3) tachycardia
(heart rate >90 beats/min); (4) tachypnea (respirations 120/min) or need for
mechanical ventilation; (5) use of vasopressor to maintain systolic blood
pressure higher than 90 mm Hg, or hypotension, defined as systolic blood pressure
less than 90 mm Hg for more than 30 minutes or a decrease in systolic blood
pressure of more than 40 mm Hg from previously established values for more
than 30 minutes (hypotension had to be present at enrollment and refractory
to an intravascular volume challenge of at least 500 mL); and (6) evidence
of inadequate organ function or perfusion within 12 hours of enrollment, as
manifested by at least 1 of the following syndromes (previously described):
acute deterioration of the patient's mental status; arterial hypoxemia (PaO2/fraction of inspired oxygen <280); plasma lactate concentration
above the normal range or metabolic acidosis; oliguria; and disseminated intravascular
coagulation. The exclusion criteria were the following: (1) age greater than
80 years; (2) cardiac failure (class III or IV); (3) liver insufficiency (Child
class C); (4) bone marrow aplasia (white blood cell count <500/µL);
or (5) immunosuppression (positive human immunodeficiency virus serologic
result, current immunosuppressive therapy including corticosteroids [equivalent
prednisone >0.5 mg/kg per day], or cancer).
Patients were followed up throughout their stays in the ICU. Age, sex,
primary site of infection, infection-related organisms, and severity indexes
including Simplified Acute Physiology Score (SAPS II),17
which uses a total of 15 variables to assess the severity of ICU patients,
and Organ System Failure score,18 were collected
at each patient's entry into the ICU. All the samples and information used
in the study were coded and patient confidentiality was preserved according
to the guidelines for studies of human subjects.
MUTATION DETECTION
To determine the TLR4 genotype of the samples
with respect to residues 299 and 399, the genomic DNA was amplified with primers
(forward primer: 5'-tctagagggcctgtgcaatt-3'; reverse primer, 5'-tgaaaactcactcatttgtttcaa-3')
that span the region containing the 2 polymorphisms. Polymerase chain reaction
conditions were as follows: 5-minute initial denaturation at 95°C, followed
by 30 cycles (95°C for 30 seconds, 55°C for 30 seconds, and 72°C
for 1 minute). After polymerase chain reaction amplification, fragments were
purified (Gel Purification Kit; Qiagen, Valencia, Calif) and sequenced. The
sequence of the genomic DNA from each subject was determined with an automated
DNA sequencer (Model 377; Perkin Elmer, Norwalk, Conn). The sequence analysis
was performed blinded to the phenotype of the study subjects.
STATISTICAL ANALYSIS
The statistical analysis was designed to determine whether specific
mutations in the TLR4 gene were associated with several
factors related to septic shock. We used a Fisher 1-sided exact test (consistent
with our hypothesis) to determine whether specific mutations of the TLR4 gene occurred more frequently in cases than controls.19 Similar comparisons were made between TLR4 allele type and disease characteristics among those with septic
shock. A Mann-Whitney test was used to determine the significance of continuous
variables.19
RESULTS
We studied 91 patients with septic shock and 73 healthy control subjects.
The control subjects were on average younger (mean, 36.9 years; SD, 11.6 years)
than the patients (average age, 57.7 years; SD, 15.0 years). The sex was evenly
distributed between both study populations. Eleven patients (12%) and 8 control
subjects (11%) had either the 299 or the 399 mutation in TLR4 (Table 1), a frequency
similar to what we reported previously.14 When
the populations were tested for occurrence of the TLR4
mutation (Asp299Gly/Thr399Ile), we observed a similar prevalence of the double
mutation Asp299Gly Thr399Ile in both the patients with septic shock and the
control group (Table 1). However,
the TLR4 Asp299Gly mutation in the absence of a cosegregating
mutation at residue 399 was found to occur only in the septic shock group.
Importantly, 5 patients with septic shock (5.5%) had the Asp299Gly TLR4 mutation, while this occurred in none of the control subjects
(P = .05) (Table
1).
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Table 1. Characteristics of the Study Subjects*
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Among the patients with septic shock, we investigated the relationship
between specific TLR4 alleles and clinical characteristics
of the disease process. While no significant differences were observed for
age, sex, or treatment site (medical or surgical ICU) (data not reported),
infections due to gram-negative organisms ranged from about 35% for patients
carrying the wild-type TLR4 locus or the TLR4 Asp299Gly/Thr399Ile allele to 80% in patients with only the TLR4 Asp299Gly allele (P = .06; Table 2). When we looked at gram-negative
organisms occurring with/without polymicrobial infections, the numbers increased
to 50% in the TLR4 wild-type group and to 100% in patients with the TLR4 Asp299Gly
allele (P = .04; Table 2), whereas the percentage remained unchanged for patients
carrying the TLR4 Asp299Gly Thr399Ile mutation.
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Table 2. Association of TLR4 Genotype With
Certain Bacteria in Study Subjects With Septic Shock*
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We next investigated the relationship between the different alleles
of TLR4 and the primary sites of infection (Table 3). Although we found that meningitis
occurred more frequently in those with both the TLR4
Asp299Gly and the Thr399Ile mutations, the number of study subjects was small,
and this association was no longer evident when the analysis was limited to
patients with gram-negative sepsis. Since our in vitro data had suggested
that the mutation at residue 299 had a more severe effect on TLR4 function,14 we tested whether the
different TLR4 mutations had an effect on disease
severity as measured by SAPS II, Organ System Failure score, and mortality
(Table 4). No significant differences
were observed between the TLR4 genotype and SAPS
II values or mortality. While patients with the TLR4
Asp299Gly allele had a higher Organ System Failure value than the other groups
(Table 4), the difference was
not significant (P = .24).
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Table 3. Association of TLR4 Genotype With
Specific Disease in Study Subjects With Septic Shock*
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Table 4. Association of TLR4 Genotype With
Survival and Severity of Disease in Study Subjects With Septic Shock*
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Of note, the only patient who was homozygous for the TLR4 Asp299Gly allele in our study population was a 15-year-old girl
who died of Escherichia coli pyelonephritis. This
patient was admitted to the ICU with altered mental status, fever (temperature,
41°C), and abdominal pain. She was found to have pyelonephritis and was
treated with fluids and appropriate antibiotics. Despite these treatments,
she developed a dramatic septic shock and multiorgan failure (adult respiratory
distress syndrome, anuria, refractory shock) and died at day 3 of hospitalization.
Subsequent bacteriologic analysis showed that the antibiotic treatment was
appropriate for a multisensitive E coli that was
cultured from her blood and urine.
Previously, the -308 TNF- polymorphism, TNF2, had been
shown to be associated with sepsis in this population.15
We therefore investigated whether the presence of the -308 TNF-
polymorphism altered the relationship between TLR4 polymorphisms and septic
shock. In the patient population, the values for the TNF2 polymorphism ranged
from 0% in the patients with the TLR4 Asp299Gly mutation
to 42.5% in the patients with wild-type TLR4 (P = .07). Stratifying the septic subjects by those with
(n = 32) and without (n = 59) the TNF2 (-308 TNF- polymorphism),
we did not observe any novel associations between the TLR4 alleles and the type or severity of septic shock.
COMMENT
Our findings demonstrate that mutations in the human TLR4 gene appear to be associated with an increased risk for septic
shock and a higher prevalence of gram-negative bacterial infection. These
findings suggest that mutations in the TLR4 gene,
which impair its responsiveness to LPS, could lead to an increased risk of
subsequent bacterial infections, analogous to the in vivo findings in the
mouse strain C3H/HeJ.20 This hypothesis could
explain our finding that the higher percentage of carriers for the TLR4 polymorphisms
may be associated with a higher risk of developing gram-negative sepsis in
the patient population. Even though the patient and control populations differed
significantly in age (see Table 1),
the difference in polymorphism frequency is not age related, and the occurrence
of the TLR4 Asp299Gly polymorphism exclusively in the patient population indicates
an association of specific TLR4 mutations with septic
shock. It is important to note that in previous studies the TLR4 Asp299Gly polymorphism occurred solely in combination with the
mutation at residue 399.14 The septic shock
population used in this study constitutes the first example, to our knowledge,
of a white population in which the TLR4 Asp299Gly
mutation occurs regularly in the absence of a second mutation at residue 399.
Moreover, 1 case in our study, that of a 15-year-old girl homozygous for the TLR4 Asp299Gly allele, who died of E
coli pyelonephritis, illustrates the potentially detrimental effects
of the TLR4 Asp299Gly mutation in a homozygous state.
It is possible that the increased severity of the 299 mutation in terms of
impairing protein function, as shown by our previous in vitro analysis,14 causes a more severe effect in carriers for this
mutation alone, making these patients more susceptible to bacterial infection.
The increased occurrence of the TLR4 Asp299Gly
genotype in the septic patients suggests that mutations of the TLR4 receptor enhance the susceptibility to gram-negative sepsis because
of a decrease in endotoxin responsiveness. These in vivo findings confirm
our in vitro studies that suggest that the mutations at residues 299 and 399
interrupt LPS signaling.14 In this previous
study, we demonstrated that the TLR4 Asp299Gly allele
and, to a much lesser degree, the TLR4 Thr399Ile
allele caused THP-1 cells to be hyporesponsive to LPS in culture. The difference
in mutation severity shown in vitro could potentially explain why the TLR4 Asp299Gly allele is more frequent in this septic shock
patient population than the TLR4 Thr399Ile allele
alone.
Since TLR4 is a transmembrane protein, it is not surprising to find
a putative signal peptide at the N-terminus, presumably responsible for proper
trafficking to the cell membrane.8 This raises
the possibility that sequence variants in the extracellular domain of TLR4
can disrupt trafficking of this receptor to the cell membrane and enhance
proteolysis.21 Mutations of this kind could
give rise to a range of phenotypes from almost normal to completely unresponsive,
depending on the severity of the trafficking defect, which would indirectly
affect receptor density on the cell surface. Potential other effects of the
mutant TLR4 receptor include decreased ligand binding or changes in the receptor
conformation that could impair signal transduction, once the ligand is bound.
In the absence of any structural information on the extracellular domain of
the TLR4 receptor, the potential structural effect of the TLR4 mutation remains unclear, although the immunostaining of the airway
epithelial cells suggests an effect on receptor density.14
Another finding in this study is the high prevalence of gram-negative
infections in patients with TLR4 receptor mutations.
In addition to all patients with TLR4 receptor mutations
having a higher prevalence of gram-negative infections, the 5 patients carrying
the TLR4 Asp299Gly variant had solely gram-negative
infections. Although this finding may not be statistically significant in
a larger patient population, it could suggest that the increased severity
of the TLR4 Asp299Gly could more severely attenuate
the immune response to gram-negative infections among these individuals, thereby
increasing the susceptibility to infections. Since TLR4 and LPS binding is
an important first step in the defense against some gram-negative bacteria,
TLR4 plays a crucial role in mediating the cellular response to recognize
and eliminate these pathogens. The correlation between a potential lack of
receptor function and an increased susceptibility to infection is analogous
to what is seen in the TLR4-/- mice11 and the C3H/HeJ strain, which are both hyporesponsive
to LPS but more susceptible to gram-negative infections.20
The -308 TNF- polymorphism and the TLR4 Asp299Gly polymorphism appear to be independent predictors of septic
shock. While the -308 TNF- polymorphism was found to occur more
frequently among those with septic shock and found to be associated with enhanced
mortality,15 in the current study we found
that the TLR4 polymorphisms were associated with
gram-negative septic shock. The absence of an interaction between these genotypes
suggests that the effect of these polymorphisms on sepsis may be additive.
Future investigations examining the interaction between several biologically
relevant polymorphisms may provide important information to risk stratify
patients with life-threatening infections.
In summary, we show a potential link between mutations in the TLR4 receptor
and gram-negative septic shock. This preliminary finding warrants further
studies with a larger patient population to determine whether some of the
findings, such as a more severe disease phenotype, increased presence of gram-negative
bacteria in particular, will reach statistical significance.
AUTHOR INFORMATION
Accepted for publication September 6, 2001.
This study was supported by grants from the Department of Veterans Affairs
(Merit Review), Washington, DC; grants ES11375, ES07498, and ES09607 from
the National Institute of Environmental Health Sciences, Bethesda, Md; and
grant HL62628 from the National Heart, Lung, and Blood Institute, Bethesda.
Corresponding author and reprints: David A. Schwartz, MD, Pulmonary
and Critical Care Medicine, Duke University Medical Center, Research Drive,
Room 275 MSRB, DUMC Box 2629, Durham, NC 27710 (e-mail: david.schwartz{at}duke.edu).
From the Department of Medicine (Drs Lorenz and Schwartz and Ms Frees)
and the Department of Veterans Affairs Medical Center (Drs Lorenz and Schwartz),
The University of Iowa, Iowa City; and Medical Intensive Care Unit, Cochin
University Hospital, Paris, France (Dr Mira). Dr Schwartz is now with Pulmonary
and Critical Care Medicine, Duke University Medical Center, Durham, NC.
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ABSTRACT
Innate Immunity Influences Long-term Outcomes after Human Lung Transplant
Palmer et al.
Am. J. Respir. Crit. Care Med. 2005;171:780-785.
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Toll-like receptor 4 polymorphisms are associated with resistance to Legionnaires' disease
Hawn et al.
Proc. Natl. Acad. Sci. USA 2005;102:2487-2489.
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Bacterial Lipoprotein Induces Resistance to Gram-Negative Sepsis in TLR4-Deficient Mice via Enhanced Bacterial Clearance
O'Brien et al.
J. Immunol. 2005;174:1020-1026.
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Predictive Genomics of Adverse Events After Cardiac Surgery
Fox et al.
SEMIN CARDIOTHORAC VASC ANESTH 2004;8:297-315.
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Polymorphisms of genes involved in innate immunity: association with preterm delivery
Hartel et al.
Mol Hum Reprod 2004;10:911-915.
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TLR4 and TNF-{alpha} polymorphisms are associated with an increased risk for severe sepsis following burn injury
Barber et al.
J. Med. Genet. 2004;41:808-813.
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The Acute Respiratory Distress Syndrome
Piantadosi and Schwartz
ANN INTERN MED 2004;141:460-470.
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LARGE-SCALE CANDIDATE GENE STUDY OF LEPROSY SUSCEPTIBILITY IN THE KARONGA DISTRICT OF NORTHERN MALAWI
FITNESS et al.
Am J Trop Med Hyg 2004;71:330-340.
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Toll-Like Receptor 2 Represses Nonpilus Adhesin-Induced Signaling in Acute Infections with the Pseudomonas aeruginosa pilA Mutant
Lorenz et al.
Infect. Immun. 2004;72:4561-4569.
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Deficient host-bacteria interactions in inflammatory bowel disease? The toll-like receptor (TLR)-4 Asp299gly polymorphism is associated with Crohn's disease and ulcerative colitis
Franchimont et al.
Gut 2004;53:987-992.
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Toll-like receptors and the host defense against microbial pathogens: bringing specificity to the innate-immune system
Netea et al.
J. Leukoc. Biol. 2004;75:749-755.
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A novel assay to detect nucleotide receptor P2X7 genetic polymorphisms influencing numerous innate immune functions
Denlinger et al.
Innate Immunity 2004;10:137-142.
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Aberrant Toll Receptor Expression and Endotoxin Hypersensitivity in Mice Lacking a Functional TGF-{beta}1 Signaling Pathway
McCartney-Francis et al.
J. Immunol. 2004;172:3814-3821.
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The Interleukin-6 G(-174)C Promoter Polymorphism Does Not Determine Plasma Interleukin-6 Concentrations in Experimental Endotoxemia in Humans
Endler et al.
Clin. Chem. 2004;50:195-200.
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Toll-like receptor (TLR) 4 polymorphisms and COPD
Sabroe et al.
Thorax 2004;59:81-81.
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A Common Dominant TLR5 Stop Codon Polymorphism Abolishes Flagellin Signaling and Is Associated with Susceptibility to Legionnaires' Disease
Hawn et al.
J. Exp. Med. 2003;198:1563-1572.
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The Endotoxin Receptor TLR4 Polymorphism Is Not Associated With Diabetes or Components of the Metabolic Syndrome
Illig et al.
Diabetes 2003;52:2861-2864.
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Toll-Like Receptors in Health and Disease: Complex Questions Remain
Sabroe et al.
J. Immunol. 2003;171:1630-1635.
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Monocytes Heterozygous for the Asp299Gly and Thr399Ile Mutations in the Toll-like Receptor 4 Gene Show No Deficit in Lipopolysaccharide Signalling
Erridge et al.
J. Exp. Med. 2003;197:1787-1791.
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Variants of Toll-Like Receptor 4 Modify the Efficacy of Statin Therapy and the Risk of Cardiovascular Events
Boekholdt et al.
Circulation 2003;107:2416-2421.
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Assay of locus-specific genetic load implicates rare Toll-like receptor 4 mutations in meningococcal susceptibility
Smirnova et al.
Proc. Natl. Acad. Sci. USA 2003;100:6075-6080.
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Cutting Edge: A Toll-Like Receptor 2 Polymorphism That Is Associated with Lepromatous Leprosy Is Unable to Mediate Mycobacterial Signaling
Bochud et al.
J. Immunol. 2003;170:3451-3454.
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The clinical relevance of endotoxin in human sepsis: a critical analysis
Opal
Innate Immunity 2002;8:473-476.
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Polymorphisms in Toll-Like Receptor 4 Are Not Associated with Asthma or Atopy-related Phenotypes
Raby et al.
Am. J. Respir. Crit. Care Med. 2002;166:1449-1456.
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Role of Toll-like Receptor 4 Mutations in Gram-Negative Septic Shock
Yende et al.
Arch Intern Med 2002;162:2496-2496.
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Toll-like Receptor 4 Polymorphisms and Atherogenesis
Kiechl et al.
NEJM 2002;347:185-192.
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Mutations in TLR4 Receptor Associated with Gram-Negative Septic Shock
JWatch Infect. Diseases 2002;2002:9-9.
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