Toll-like Receptor 4 Polymorphisms and Atherogenesis

doi:10.1056/NEJMoa012673

Volume 347:185-192		July 18, 2002		Number 3

Toll-like Receptor 4 Polymorphisms and Atherogenesis

Stefan Kiechl, M.D., Eva Lorenz, Ph.D., Markus Reindl, Ph.D., Christian J. Wiedermann, M.D., Friedrich Oberhollenzer, M.D., Enzo Bonora, M.D., Johann Willeit, M.D., and David A. Schwartz, M.D.

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ABSTRACT

Background The ability to mount a prominent inflammatory responseto bacterial pathogens confers an advantage in innate immunedefense but may signal an increased risk of atherosclerosis.We determined whether recently discovered genetic variants oftoll-like receptor 4 (TLR4) that confer differences in the inflammatoryresponse elicited by bacterial lipopolysaccharide are relatedto the development of atherosclerosis.

Methods As part of the five-year follow-up in the Bruneck (Italy)Study, we screened 810 persons in the study cohort for the TLR4polymorphisms Asp299Gly and Thr399Ile. The extent and progressionof carotid atherosclerosis were assessed by high-resolutionduplex ultrasonography.

Results As compared with subjects with wild-type TLR4, the 55subjects with the Asp299Gly TLR4 allele had lower levels ofcertain proinflammatory cytokines, acute-phase reactants, andsoluble adhesion molecules, such as interleukin-6 and fibrinogen.Although these subjects were found to be more susceptible tosevere bacterial infections, they had a lower risk of carotidatherosclerosis (odds ratio, 0.54; 95 percent confidence interval,0.32 to 0.98; P=0.05) and a smaller intima–media thicknessin the common carotid artery (regression coefficient, –0.07;95 percent confidence interval, –0.12 to –0.02;P=0.01).

Conclusions The Asp299Gly TLR4 polymorphism, which attenuatesreceptor signaling and diminishes the inflammatory responseto gram-negative pathogens, is associated with a decreased riskof atherosclerosis. This finding is consistent with the hypothesisthat innate immunity may play a part in atherogenesis.

Induction of inflammation is an important component in the defenseagainst microorganisms. Owing to the putative proatherogeniceffects of intravascular inflammation, we hypothesized thatan efficient innate immune defense may offer an early advantageat the expense of chronic vascular damage in later years.

The responsiveness of the individual innate immune system hasa complex genetic background and depends on the virulence ofgiven pathogens. Recently, a family of receptors — thetoll receptors — has been described that provides a criticallink between immune stimulants produced by microorganisms andthe initiation of host defense.¹^,²^,³^,⁴ Activation of these receptorsresults in the release of antimicrobial peptides, inflammatorycytokines, and costimulatory molecules that initiate adaptiveimmunity (Figure 1).² For infections with gram-negative bacteria,lipopolysaccharide is the main source of inflammation, and toll-likereceptor 4 (TLR4) is crucial in mediating its effects.¹^,²^,³^,⁴TLR4 is expressed on cardiomyocytes, macrophages, airway epithelia,and endothelial and smooth-muscle cells and in small amountsin most other tissues.²^,⁵ Although the relation between TLR4and lipopolysaccharide has been the most thoroughly investigated,TLR4 also interacts with other exogenous and endogenous ligands,including respiratory syncytial virus, heat-shock proteins,fibronectin, fibrinogen, and hyaluronic acid (Figure 1).²^,⁶^,⁷^,⁸^,⁹

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Figure 1. Toll-like Receptor 4 (TLR4).
Shown are candidate ligands, the means of regulation of receptor expression, mechanisms of signal transduction, and the functional importance in various tissues. It is likely but not yet certain that oxidized low-density lipoprotein (oxLDL) has a role as a ligand of TLR4. TLR2 denotes toll-like receptor 2, NF- ${kappa}$ B nuclear factor- ${kappa}$ B, TNF- ${alpha}$ tumor necrosis factor ${alpha}$ , APC antigen-presenting cell, and ICAM-1 intracellular adhesion molecule 1.

The recent characterization of the human TLR4 polymorphismsAsp299Gly and Thr399Ile, which impair the efficacy of lipopolysaccharidesignaling and the capacity to elicit inflammation,¹⁰ offersa good opportunity for a critical evaluation of the hypothesisthat innate immunity plays a part in atherogenesis. For thatpurpose, we assessed the two TLR4 variants in a random sampleof the general population and analyzed the relations among thesepolymorphisms, the level of systemic inflammation, the riskof severe infections, and the development of atherosclerosis.

Methods

Study Subjects

The Bruneck Study is a prospective population-based survey ofthe epidemiology and pathogenesis of atherosclerosis.¹¹^,¹²^,¹³The study protocol was reviewed and approved by the appropriateethics committees, and all study subjects gave their writteninformed consent. At the 1990 base-line evaluation, the studypopulation was recruited as a random sample, stratified accordingto sex and age, of all inhabitants of Bruneck, Italy (125 womenand 125 men in each of the following age groups: 40 to 49 years,50 to 59 years, 60 to 69 years, and 70 to 79 years). A totalof 93.6 percent of those recruited participated, and data assessmentwas completed for 919 subjects. Between 1990 and the reevaluationin the summer of 1995 (the first five-year period) 63 subjectsdied or moved away. Among survivors who remained in Bruneck,follow-up was 96.5 percent complete (826 subjects had completedata for the first period). Blood specimens for DNA extractionwere drawn as part of the follow-up in 1995. No adequate polymerase-chain-reaction(PCR) products were obtainable from 16 samples, so 810 men andwomen were included in the main analysis. Of these subjects,94 died between the summer of 1995 and the summer of 2000 (thesecond five-year period). During the second period, 100 percentof the subjects (810) were followed up for newly diagnosed cardiovasculardisease, and 94.3 percent of the 716 survivors (675 subjects)underwent sonographic reevaluation.

Clinical History Taking and Examination

Hypertension was defined as a blood pressure (mean of threemeasurements) of 160/95 mm Hg or higher or the use of antihypertensivedrugs. Subjects were considered to have diabetes mellitus ifthey had a fasting glucose level of at least 140 mg per deciliter(7.7 mmol per liter), a glucose level two hours after oral glucosechallenge of at least 200 mg per deciliter (11.1 mmol per liter),or both.

Information on severe acute infections of bacterial origin includingpneumonia, pyelonephritis, peritonitis, diverticulitis, andsepsis was collected during the second five-year follow-up periodfrom a detailed self-reported medical history, medical recordsprovided by general practitioners, death certificates, and reviewsof the data bases of the Bruneck Hospital, which is the onlyhospital in the district. Chronic infections were assessed byan extensive screening procedure, as detailed previously.¹⁴

Assessment of newly diagnosed (fatal and nonfatal) cardiovasculardisease during the second period was based on the patient'smedical history, a detailed review of the data bases of theBruneck Hospital and of death certificates, and the resultsof clinical and various laboratory examinations.¹⁵ Myocardialinfarction was considered confirmed when the World Health Organizationcriteria for definite disease status were met.¹⁶ Stroke andtransient ischemic attack were classified according to the criteriaof the National Survey of Stroke.¹⁷ The diagnosis of peripheralartery disease required a positive response to the Rose questionnaire,with the vascular nature of problems confirmed by standard diagnosticprocedures.

Laboratory Methods

Blood samples were drawn after an overnight fast and 12 hoursof abstinence from smoking.¹⁸ In subjects with acute infection,the drawing of blood was delayed for at least six weeks —that is, until at least four to five weeks after recovery fromthe infectious illness. Markers of infection and inflammationwere measured with commercial assays as follows: C-reactiveprotein, ${alpha}$ 1-antitrypsin, and ceruloplasmin by nephelometry (Behring);soluble vascular-cell adhesion molecule 1, soluble intracellularadhesion molecule 1, and E-selectin by enzyme-linked immunosorbentassay (R&D Systems and Bender); soluble interleukin-2 receptorby enzyme immunoassay (T Cell Diagnostics); neopterin by radioimmunoassay(Henning), and interleukin-6 by enzyme amplified sensitivityimmunoassay (Biosource).

DNA Extraction and TLR4 Genotyping

Genomic DNA was prepared from frozen whole blood with the useof a blood DNA isolation kit (Genomic Prep, Amersham PharmaciaBiotech). Subsequent allele-specific PCR amplification for theTLR4 alleles Asp299Gly and Thr399Ile was performed accordingto a previously described protocol.¹⁹ Genotypes were assignedby independent investigators who were unaware of the patients'identities and phenotypes.

Assessment of Atherosclerosis

The protocol for ultrasonography involved the scanning of theinternal carotid arteries (bulbus and distal segments) and thecommon (proximal and distal segments) carotid arteries on bothsides with a 10-MHz imaging probe.¹⁸ Atherosclerotic lesionswere defined according to two ultrasonographic criteria: thewall surface (the presence of protrusions or roughness on thearterial boundary) and the wall texture (whether or not it wasechogenic). The maximal axial diameter of plaques was assessedin each of the eight vessel segments, and an atherosclerosisscore was calculated by summing all diameters (intraobservercoefficient of variation in a random subgroup ["reproducibilitysample"] consisting of 100 persons in the Bruneck population,13.5 percent).¹⁸ In addition, the development of new carotidplaques (new cases of atherosclerosis) was assessed in all subjects(kappa coefficients in the reproducibility sample, >0.8).¹¹^,¹²The intima–media thickness was quantified at the far wallof plaque-free sections of the common carotid arteries as thedistance between the interface of the lumen and the intima andthe interface of the media and the adventitia (intraobservercoefficient of variation in the reproducibility sample, 7.9percent).¹²

Statistical Analysis

Analysis of variance was used to compare levels of circulatingmediators of inflammation in subjects with wild-type TLR4, thosewith the Asp299Gly allele, and those with both the Asp299Glyallele and the Thr399Ile allele. In supplementary analyses,the levels in subjects with wild-type TLR4 were compared withthose in the other two groups combined. The association of TLR4polymorphisms with newly diagnosed carotid atherosclerosis wasexamined by logistic-regression analysis with a test proceduredetermined by the maximum-likelihood estimator.²⁰ A base modelwas adjusted only for age, sex, and presence or absence of atherosclerosisat base line. Multiple regression analyses were adjusted fora fixed set of covariates that were assessed in previous analysesof the vascular risk profiles of the Bruneck study population.¹³Genetic categories were modeled as sets of indicator variables.The presence of differential effects of TLR4 variants on therisk of atherosclerosis in various subgroups was tested by theinclusion of interaction terms. Logistic-regression models weresupplemented and confirmed by linear regression analyses inwhich the log-transformed atherosclerosis score or the intima–mediathickness was used as a continuous outcome variable. Finally,crude and adjusted hazard ratios for newly diagnosed cardiovasculardisease were calculated by Cox models.²¹ All P values are two-sided.

Results

Of the 810 men and women tested, 53 were heterozygous for theAsp299Gly TLR4 allele, and 2 were homozygous, for an allelicfrequency of 3.1 percent and a carriage rate of 6.0 percent(with adjustment for the age and sex distribution of the generalpopulation in Bruneck). In 46 of these subjects (25 men and21 women), cosegregation of the Thr399Ile polymorphism was observed,whereas 9 subjects (7 men and 2 women) had an isolated Asp299Glypolymorphism.

As compared with the carriers of the wild-type TLR4, subjectswith the Asp299Gly allele (alone or in combination with theThr399Ile allele) had lower levels of some of the inflammatorycytokines, acute-phase reactants, soluble adhesion molecules,and other mediators of inflammation that we tested (Table 1).In contrast, no associations were observed between TLR4 genotypesand common vascular risk factors or lifestyle factors.

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Table 1. Associations between Common Polymorphisms of Toll-like Receptor 4 and Levels of Markers of Inflammation in the 810 Subjects.

Carriers of TLR4 polymorphisms appeared to be more susceptibleto bacterial infections. In the current study population, 53subjects (6.5 percent) had severe acute infections of putativebacterial origin during the second five-year period. The frequencyof such infectious illness was substantially higher among subjectswith the Asp299Gly allele but not the Thr399Ile allele (3 of9 [33 percent]) and subjects with both polymorphisms (5 of 46[11 percent]) than among those with wild-type TLR4 (45 of 755[6 percent]; P=0.002 by the chi-square test). In contrast, chronicinfections occurred at similar rates in the various groups (4of 9 [44 percent], 16 of 46 [35 percent], and 242 of 755 [32percent], respectively; P=0.69 by the chi-square test).

Next, we estimated the potential effects of TLR4 polymorphismson carotid-artery disease with the use of three distinct ultrasonographicmeasures of the severity and progression of atherosclerosis:intima–media thickness in the common carotid artery (measuredin 1995) — a frequently used surrogate measure for systemicvessel disease; an atherosclerosis summary score¹⁸ (calculatedin 1995); and the person-based model of atherosclerosis progressiondeveloped specifically for the Bruneck Study (applied duringthe first five-year period).¹¹^,¹² Results of these analysesare summarized in Figure 2. Whatever measure of atherosclerosiswas applied, the Asp299Gly TLR4 allele emerged as a significantprotective factor. Beneficial effects appeared to be more pronouncedin the 9 subjects with the isolated Asp299Gly polymorphism thanin the 46 subjects with both Asp299Gly and Thr399Ile. The age-and sex-adjusted mean intima–media thickness was 1006µm in subjects with wild-type TLR4 and 937 µm inthose with the Asp299Gly allele (difference, 69 µm). Correspondingvalues for the atherosclerosis score were 4.26 mm and 3.03 mm(difference, 1.23 mm).

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Figure 2. Associations between Common Toll-like Receptor 4 Polymorphisms and Measures of the Severity and Progression of Atherosclerosis.
Odds ratios and regression coefficients were adjusted for age and sex (open squares) and for levels of low-density and high-density lipoprotein cholesterol and of lipoprotein(a), presence or absence of hypertension, smoking status, level of alcohol consumption, ferritin level, presence or absence of diabetes, and presence or absence of microalbuminuria (solid squares). The P values given were derived from the multiple regression analyses. Separate models were fitted for the comparison of subjects without the Asp299Gly allele (Asp299Gly^–) and the combined group of subjects with the Asp299Gly allele (Asp299Gly⁺) (model 1) and for the comparisons of subjects without the Asp299Gly allele, those with both the Asp299Gly allele and the Thr399Ile allele (Asp299Gly⁺, Thr399Ile⁺), and those with Asp299Gly only (Asp299Gly⁺, Thr399Ile^–) (model 2). Horizontal bars represent the 95 percent confidence intervals.

All of the above results were virtually unchanged when the statisticalmodels were adjusted for common vascular risk factors (Figure 2).There was no evidence of differential effects of TLR4 polymorphismsin subgroups defined according to the level of risk or lifestylefactors.

To demonstrate the consistency of our findings over a longerperiod, the computations were repeated with data from the secondfive-year follow-up period. These analyses yielded associationsbetween TLR4 polymorphisms and atherosclerosis similar to thosefound in the original evaluation. Despite the fact that fewerstudy subjects (675) were involved, most relations found werestatistically significant. The regression coefficients for thecomparison between subjects with the Asp299Gly allele and thosewith wild-type TLR4 were as follows: intima–media thickness(measured in 2000), –0.046 (95 percent confidence interval,–0.090 to –0.001; P=0.04) with adjustment for ageand sex, and –0.042 (95 percent confidence interval, –0.085to 0.001; P=0.06) according to the multivariate model; five-yearchanges in the intima–media thickness (during the secondfollow-up period), –0.050 (95 percent confidence interval,–0.099 to –0.001; P=0.05), with adjustment for ageand sex, and –0.053 (95 percent confidence interval, –0.102to –0.004; P=0.03) according to the multivariate model.The odds ratio for newly diagnosed atherosclerosis (during thesecond follow-up period) was 0.47 (95 percent confidence interval,0.22 to 1.03; P=0.06) with adjustment for age and sex; accordingto the multivariate analysis, the odds ratio was 0.43 (95 percentconfidence interval, 0.24 to 0.94; P=0.04).

Subjects with the Asp299Gly allele were less likely to havecardiovascular disease during the second follow-up period: theage- and sex-adjusted hazard ratio was 0.16 (95 percent confidenceinterval, 0.02 to 1.24; P=0.08). Similar proportions of thesubjects who died during the second period (8 of 94 [8.5 percent])and of those who survived (47 of 716 [6.6 percent]) had theAsp299Gly polymorphism; however, none of the 8 deaths in subjectswith the polymorphism had cardiovascular causes, whereas 28of the 86 deaths in subjects with wild-type TLR4 had cardiovascularcauses (P=0.10 by Fisher's exact test).

Discussion

TLR4 is the transmembrane lipopolysaccharide receptor that initiatesthe innate immune response to common gram-negative bacteria,including Chlamydia pneumoniae and Helicobacter pylori —the two pathogens most commonly implicated in human atherogenesis.¹^,²^,³^,⁴^,²²^,²³Lipopolysaccharide binding activates the transcription factornuclear factor- ${kappa}$ B, ultimately leading to the synthesis and releaseof antimicrobial peptides, inflammatory cytokines and chemokines,and costimulatory molecules that provide a critical link toadaptive immunity (Figure 1).¹^,²^,³^,⁴ These inflammatory mediatorscan exert various atherogenic effects involving the expressionof adhesion molecules on endothelial cells, proliferation ofsmooth-muscle cells, activation of immune cells, and stimulationof the acute-phase response (Figure 1). Recently, numerous potentialactivators of TLR4 signaling and expression distinct from lipopolysaccharidehave been suggested (Figure 1).²^,⁶^,⁷^,⁸^,⁹^,²⁴^,²⁵

In this investigation, we demonstrated that the presence ofthe common Asp299Gly polymorphism of TLR4, which affects thecomposition and structure of the extracellular domain of thereceptor, predicted low levels of circulating inflammatory moleculesand conferred an increased risk of severe infections but a reducedrisk of atherosclerosis. The same polymorphism has been shownto attenuate human responsiveness to inhaled endotoxin in vivoand to interrupt TLR4-mediated lipopolysaccharide signalingin cellular-transfection studies and in airway epithelial cellsfrom heterozygous persons; the latter effect may be correctedby the addition of wild-type TLR4.¹⁰

Our findings have several implications. First, part of the low-gradesystemic inflammation that is measurable in healthy subjectsappears to be mediated by the TLR4 pathway. Circulating bacteriallipopolysaccharide, a potent ligand of TLR4, is detectable invirtually all healthy persons, albeit at highly variable concentrations.²⁶Toxic lipoteichoic acid from gram-positive bacteria, mycobacteriallipids, and proteins from respiratory syncytial virus are alsorecognized by TLR4, and it has been proposed that there is functional"cross-talk" among the members of the TLR family.²⁷^,²⁸^,²⁹ Therefore,the innate inflammatory defense against a broad palette of microorganismsmay rely on an intact TLR4 pathway, and the immune system iscommonly exposed to many of these pathogens. Recent findingsindicate that the importance of TLR4 may well extend beyondantimicrobial defense to other inflammatory processes inherentlyrelated to human atherogenesis (Figure 1).⁴^,⁸^,⁹^,²⁵ Human heat-shockprotein 60 has been shown to require functional TLR4 in orderto stimulate the production of tumor necrosis factor ${alpha}$ and nitricoxide.⁸ It has been proposed that heat-shock protein 60 actsas a "danger antigen" that, because of stimulation by variousendogenous and exogenous stress factors, is overexpressed andpartly released into the circulation, where it exerts inflammatoryeffects, thus driving the innate defense system to increasedalertness.²^,⁸ Moreover, oxidized low-density lipoprotein up-regulatesTLR4 messenger RNA expression in vitro, and the expression ofTLR4 by macrophages is preferentially increased in lipid-richplaques in humans.²⁵ In aggregate, these findings indicate thatTLR4 is stimulated by multiple agents that bridge inflammation,infection, and hyperlipidemia.

Second, diminished levels of intravascular inflammation andthe enhanced risk of severe bacterial infections observed insubjects with the Asp299Gly TLR4 polymorphism are clear indicationsof an attenuated innate immune defense. We have recently foundthat this allelic variant of TLR4 predisposes persons to septicshock with gram-negative microorganisms.³⁰

Third, our study documents that a genetic variant renderingpersons susceptible to acute disseminated bacterial infectionconfers a decreased risk of atherosclerosis. Conversely, carriersof the wild-type allele, who are therefore capable of producinga prominent inflammatory response to virulent gram-negativepathogens, appear to have an increased risk of atherosclerosis.There are two sources of indirect support for our findings.On the one hand, the level of systemic inflammation, irrespectiveof its origin, has been shown to be a prominent predictor ofatherosclerosis in humans,³¹^,³²^,³³ and it has been conjecturedthat high levels of circulating endotoxin have similar predictivevalue.²⁶^,³⁴ On the other hand, proinflammatory polymorphismsof other (key) components of the inflammatory cascade, suchas polymorphisms of interleukin-6, E-selectin, tumor necrosisfactor ${alpha}$ , and CD14, have been linked to an increased risk ofcardiovascular disease.³⁵^,³⁶^,³⁷^,³⁸ It should, however, be notedthat our epidemiologic finding of a lower risk of atherosclerosisamong carriers of TLR4 polymorphisms lacks confirmation in animalstudies. In recent experiments by Wright and colleagues, therewas no difference in the extent of aortic atherosclerosis betweenstandard apolipoprotein-E–deficient mice and mice thatwere also deficient in TLR4 or mice raised in a germ-free environment.³⁹In this mouse model of atherogenesis, TLR4 appeared to be unrelatedto the emergence of vessel disease, at least in the absenceof standardized exposure to pathogens.

In interpreting our data, several limitations and potentialsources of bias should be considered. Individual measurementsof markers of inflammation may not necessarily reflect the long-termactivation of the inflammatory cascade. In the current study,however, some of the markers of inflammation were measured twiceor three times at five-year intervals, and the associationswith genetic TLR4 variants emerged consistently. We cannot excludethe possibility that TLR4 variants serve as markers of anotherimportant genetic abnormality without themselves being functionallyrelevant; none of the gene products encoded close to the TLR4region on chromosome 9 have yet been found to be related toatherosclerosis. Finally, a differential loss to follow-up couldhave influenced the finding of a reduced risk of atherosclerosisamong subjects with the Asp299Gly allele. Such a bias, however,appears unlikely, given the nearly complete follow-up, the smallnumber of Asp299Gly-positive subjects among those who died,and the underrepresentation of deaths from cardiovascular causesin the group with the Asp299Gly allele.

In conclusion, the common Asp299Gly TLR4 polymorphism, whichattenuates receptor signaling and diminishes the inflammatoryresponse to gram-negative pathogens and, potentially, to otherrelevant ligands, is associated with low levels of certain circulatingmediators of inflammation and a decreased risk of atherosclerosis.These data provide epidemiologic support for the concept thatan efficient innate immune defense against bacteria and associatedlong-term intravascular inflammatory stress are involved inthe development of atherosclerosis.

Supported by the Pustertaler Verein zur Prävention vonHerz- und Hirngefäßerkrankungen, the SanitätseinheitOst, and the Assessorat für Gesundheit and by grants fromthe National Institutes of Health (ES07498, ES09607, ES11375,HL62628, HL66611, and HL66604) and the Department of VeteransAffairs Merit Review Program.

We are indebted to Bernd Weiler, Guenter Weiss, Christina M.Reinisch, Stefan Dunzendorfer, Manfred Herold, Amanda Carlson,and Sangheeta Mohanty for their cooperation and technical assistance.

Source Information

From the Departments of Neurology (S.K., M.R., J.W.) and Internal Medicine (C.J.W.), University Clinic, Innsbruck, Austria; Wake Forest University Medical School, Winston-Salem, N.C. (E.L.); the Department of Internal Medicine, Bruneck Hospital, Bruneck, Italy (F.O.); the Department of Endocrinology and Metabolism, University of Verona, Verona, Italy (E.B.); and the Department of Medicine and Genetics, Duke University Medical Center and Veterans Affairs Medical Center, Durham, N.C. (D.A.S.).

Address reprint requests to Dr. Kiechl at the Department of Neurology, Innsbruck University Clinic, Anichstr. 35, A-6020 Innsbruck, Austria, or at stefan.kiechl{at}uibk.ac.at.

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Toll-like Receptor 4 Polymorphisms and Atherogenesis
Cooke G. S., Segal S., Hill A. V.S., the Tuberculosis, Genetics, and Environment (TBGENENV) and the Oxford Pneumococcal Surveillance Study Groups , Beutler B., Beutler E., Kiechl S., Willeit J., Schwartz D. A.
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N Engl J Med 2002; 347:1978-1980, Dec 12, 2002. Correspondence

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