Original Contributions |
From the Max-Planck-Institut für Physiologische und Klinische Forschung, Kerckhoff-Klinik, Bad Nauheim (K.U.); the Institut für Klinische Chemie und Pathobiochemie (A.G., M.P.), the Institut für Humangenetik (M.K.), and Zentrum für Innere Medizin, Abteilung Kardiologie und Angiologie (H.T., W.H.), Justus-Liebig-Universität Giessen, Germany.
Correspondence to Werner Haberbosch, MD, Zentrum für Innere Medizin, Abteilung Kardiologie und Angiologie, Justus-Leibig-Universität Giessen, Klinikstraße 36, D-35385 Giessen, Germany. E-mail Werner.G.Haberbosch{at}innere.med.uni-giessen.de
| Abstract |
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Key Words: CD14 genetics coronary disease myocardial infarction risk factors
| Introduction |
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Endotoxin-activated monocytes produce proinflammatory
cytokines such as tumor necrosis factor-
, interleukin-1 and
interleukin-6, and growth factors.9 In stimulated
endothelial cells, expression of
endothelial leukocyte adhesion
molecule-1,10 intercellular adhesion
molecule-1,11 and vascular cell adhesion
molecule-112 is induced, accompanying cell adhesion to
endothelium.12 LPS increases the levels of
LDL and VLDL and supports the oxidation of LDL; HDL levels are
decreased.13 It stimulates smooth muscle cell
proliferation and migration by release of platelet-derived growth
factor by monocytes.14 Moreover, LPS promotes procoagulant
activity by induction of tissue factor expression in
monocytes15 and endothelial
cells.16 Cell activation, leukocyte adhesion to
endothelium and extravasure, smooth muscle cell
proliferation and migration, and altered lipoprotein
metabolism and coagulability are events with a marked
impact in the development of atherosclerosis (for
review, see Liao13). Assuming that LPS plays a
role in atherogenesis, its dependence on CD14 as a receptor molecule
led us to investigate CD14.
We wondered whether interindividual variations in susceptibility to LPS stimulation because of genetic polymorphisms of CD14 could contribute to a disposition to coronary artery disease (CAD) or myocardial infarction (MI). This is of interest, because in some patients there seems to be a genetic disposition in the absence of classic atherosclerotic risk factors.
| Methods |
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Individual histories were taken concerning diabetes mellitus, arterial hypertension, chest pain, and smoking habits. Whether MI had occurred in the patient's former history was assessed according to criteria of the World Health Organization. Body mass index (BMI) was calculated dividing weight in kilograms by height in meters squared. Levels of fibrinogen, cholesterol, apoA1, apoB, and apoE, Lp(a), triglycerides, and C-reactive protein were determined with standard laboratory procedures (after overnight fast).
Coronary angiography was performed according to the Judkins
method. Relevant CAD was defined as
50% coronary artery
stenosis and qualified as 1-, 2-, or 3-vessel disease. In
addition, the assessment of CAD was based on the Gensini score as
described elsewhere.17 18 Ventriculography gave
information about the ejection fraction and any impairment of left
ventricular function.
Within the study group, significant CAD (stenosis,
50%)
could be excluded in 501 patients (mean age, 58 years); 423 patients
had no or mild coronary artery sclerosis, defined by a Gensini
score <10; and 1175 patients had never had MI (mean age, 61 years).
These probands served as control groups for statistical
analyses.
Statistical Analysis
Statistics were calculated by using the SPSS software for
Windows 95 (Version 7). The deviation of continuous variables from
normal distribution was analyzed by the KolmogorovSmirnov
goodness-of-fit test. Their relation to the CD14 genotype was
checked by KruskalWallis 1-way ANOVA. Binary variables were
checked by
2 analysis, which was also
used to detect differences in allele distribution from
HardyWeinberg's equilibrium in subgroups with different clinical
conditions.
The following well-established risk factors for MI and CAD were
included in the calculations to check whether the CD14 genotype
also acts as an independent risk factor: age, cholesterol,
triglycerides, apoA1 (as protective factor), apoB, Lp(a),
fibrinogen, BMI, smoking, diabetes, and hypertension. Odds ratios (ORs)
were determined as relative risk of MI or severe CAD associated with
the CD14 genotype (with the T allele or with T
homozygosity). Two-tailed probability values (significance, <0.05) and
95% CI values were calculated by Pearson's
2
test and multiple regression or logistic regression with regard to the
above-mentioned risk factors.
Molecular Analysis
Genomic DNA was isolated from EDTA-anticoagulated whole blood as
described elsewhere.19
Screening for Polymorphisms
Genomic DNA of 20 healthy volunteer blood donors was
investigated. We constructed overlapping PCR products of 155- to
204-bp length comprising the whole CD14 gene including a 344-bp
promoter region, its only intron of 88 bp, and the 5' and 3'
untranslated tails of cDNA. PCR products
overlapped for at least 40 bp. The
CD14 gene sequence was derived from Ferrero and
Goyert,20 the promoter sequence from Zhang et
al.21 The major site of transcription start was assumed,
according to Zhang et al,21 as position 1 of cDNA, the 3'
end of cDNA was assumed as published by Simmons et
al.2
Primers (of 18- to 22-bp length) and PCR conditions were designed by
using OLIGO primer analysis software (see Table 1
). PCR was run in a 20-µL volume in
96-well microtiter plates, using the Biometra UNO-Thermoblock.
Samples contained 100 ng of genomic DNA, 10 pmol of each primer, dNTPs
at 250 µmol/L each, and 1 U of Taq DNA polymerase in the
provided reaction buffer (Boehringer Mannheim). PCR conditions
comprised 3 minutes of denaturation at 94°C followed by 30 cycles of
30 seconds at 94°C, 1 minute of annealing at 59°C to 62°C and 30
seconds of extension at 72°C, and a final extension time of 5 minutes
at 72°C. If necessary, the concentration of magnesium chloride was
adjusted to 2.5 mmol/L (PCR products 10 and 12) or DMSO was
added to 0.05x (PCR product 12).
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Single-Strand Conformation Polymorphism (SSCP)
Analysis
For screening of PCR products, PCR was performed by adding
37 000 Bq (1 µCi) of [
-32P]dCTP
(Amersham) per reaction and reducing nonradioactive dCTP to 20
µmol/L. PCR products were denatured by mixing with a formamide
buffer and incubating at 94°C for 1 minute. SSCP analysis was
performed on 0.5x modified polyacrylamide gels (Serdogel,
Serva) in vertical electrophoresis in 0.6x Tris borate/EDTA buffer.
Gels were run at 4°C and at room temperature, and the probes were
visualized by autoradiography. For typing of 1285
individuals, nonradioactive PCR products of primer pair 2 were run
in horizontal electrophoresis on 17% to 5% polyacrylamide
gradient gels (49:1, acrylamide:bisacrylamide)
with 5% glycerin in 0.5x Tris borate/EDTA buffer. The 17%
polyacrylamide solution contained 4 g% saccharosis.
Gels were run at 25°C, and DNA bands were visualized by silver
staining.
Restriction Fragment Length Polymorphism Analysis
A new forward primer for PCR product 2 (see Table 1
)
was designed to obtain larger restriction fragments. PCR conditions did
not change. Typing of a further 943 probes was done by overnight
digestion of PCR products with 2 U of restriction endonuclease
HaeIII at 37°C. Digests were analyzed on 3%
NuSieve agarose gels and stained with ethidium bromide.
Sequence Analysis
Distinct PCR products were extracted from 1.2% agarose gels
(gel extraction kit, Qiagen) and directly sequenced by using the Thermo
Sequenase cycle sequencing kit (Amersham). We performed sequencing of
both strands with 5'-[
-32P]dATP-labeled
(Amersham) primers. PCR primers were radiolabeled with T4
polynucleotide kinase (USB). After 2 minutes of
denaturation at 94°C, 30 cycles of 20 seconds at 94°C, 30 seconds
at 60°C, and 20 seconds at 72°C were run. The sequencing reaction
was analyzed on 6% polyacrylamide gels (19:1,
acrylamide:bisacrylamide) with 7.5 mol/L urea
in 1x Tris borate/EDTA buffer. Gels were autoradiographed.
| Results |
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PCR product 2 comprises a T-to-C exchange at position -159,
ie, a promoter polymorphism (Figure 1
). Genotyping of this polymorphic
site in 2228 study patients was done by nonradioactive SSCP
analysis (Figure 2A
) and by
restriction fragment length polymorphism analysis (Figure 2B
); 100 probes were genotyped with both techniques,
which gave discordant results in 3 cases. In the SSCP gels no further
band shift was detected, indicating that a third allele is not
likely to exist.
|
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PCR product 13 bears a G-to-C exchange (1202 of cDNA), which changes codon 348 from CTG to CTC. This does not change the predicted amino acid leucine. The T-to-G polymorphic site in PCR product 14 has position 1497 in genomic DNA, which is 2 bp adjacent to the 3' end of cDNA. Polymorphisms of PCR products 13 and 14 were not investigated further.
Distribution of the T/C Polymorphism of CD14 Promoter
Genotype distribution in the study group of 2228 male
probands (mean age, 62 years) was 631 CC (28%), 1104 CT (50%), and
493 TT (22%). Within the study group, we compared subgroups with
varying extents of CAD, defined as no, or 1-, 2-, or 3-vessel
disease. We also checked the subgroup with no or mild CAD (Gensini
score, <10) against that with severe CAD (Gensini score, >90).
Finally, groups with or without MI in their history were compared. In
the above-mentioned subgroups of the study population, the distribution
of genotypes did not differ significantly. Allele
distributions and their 95% CIs are depicted in Table 2
. We also checked the genotypes
in subgroups with or without impairment of left ventricular
function, which did not differ significantly. The distribution of
established risk factors [age, BMI, apoA1, apoB, apoE, total
cholesterol, Lp(a), triglycerides, fibrinogen,
diabetes mellitus, hypertension, and smoking] did not deviate in
subgroups of different genotypes.
|
Established Risk Factors and CAD or MI
Regarding the total study group, established risk factors could be
identified in multiple regression analysis (for CAD) and multiple
logistic regression analysis (for MI), ie, apoB for CAD
(P<0.0001) and MI (P<0.0002), Lp(a) for CAD
(P<0.02), fibrinogen for MI (P<0.05), diabetes
mellitus and hypertension for CAD (P<0.0001 each),
cigarette smoking for MI (P<0.002), age for CAD
(P<0.0001) and MI (P<0.002), and apoA1 as a
protective factor against CAD and MI (P<0.0001 each). The
level of total cholesterol was not detected as an
independent risk factor, but
hypercholesterolemia was treated significantly
more often in case groups of CAD (P<0.0001) and MI
(P<0.0005).
CD14 Promoter Polymorphism and Risk of CAD or MI
ORs were calculated for probands carrying the T allele as well
as for T-homozygous ones (considering a dominant or recessive effect of
the T allele). Again regarding the total study group, there was no
significant relative risk for either genotype. Calculations
referred to severeness of CAD (defined as multivessel disease or by
Gensini score) and MI. The C allele in no case showed a tendency of
a positive association with CAD or MI. In further calculations,
subgroups were formed as low-risk groups [excluding probands with
hypertension and/or smoking, and/or with continuous variables such
as BMI, fibrinogen, Lp(a), cholesterol,
triglycerides, apoB, and apoA1 beyond their average values
in the total study group]. In all cases, no relation of the CD14
promoter genotype to CAD or severeness of CAD could be
discerned.
For MI, however, there exists a relative risk of 1.4 (95% CI, 1.0 to
2.0) in T-homozygous normotensive subjects, by applying the
2 test (P<0.05). Multiple
regression analysis did not produce a significant value
(P=0.11, n=841). Subjects without hypertension and also not
smoking have a relative risk of MI of 1.6 (95% CI, 1.0 to 2.4;
P<0.05 in multiple logistic regression; n=173, 109 without
and 64 with infarction). After subdividing into groups of different
ages, it is noteworthy that only in normotensive patients older than 62
years was there a relative risk of MI when they were T homozygous
(OR=1.7; 95% CI, 1.0 to 2.9; P<0.05 by Pearson's
2 test, P=0.053 by multiple
logistic regression; n=379, 180 without and 199 with infarction). In
the small group of patients older than 62 years and without
hypertension and not smoking (n=76, 46 without and 30 with infarction),
the OR for MI and T homozygosity was 3.8 (95% CI, 1.6 to 9.0;
P<0.01 by multiple logistic regression). Relative risks
that were statistically significant are depicted in Table 3
. Checking high-risk groups, we did not
come to any significant ORs for an association with either
genotype.
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| Discussion |
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A significant correlation of T homozygosity with MI can be found in the low-risk group of normotensive patients without the smoking habit. Within the whole study group of 2228 probands, only 173 patients fulfill that criterion. Dividing these into categories of different ages, the association of MI and T homozygosity becomes stronger in the older patients of >62 years. As these subgroups are rather small and because they are arranged arbitrarily, the observed effect can be the result of mere coincidence. The association of the T genotype of the CD14 promoter with MI could be observed in any low-risk group as a tendency, but only significant data were presented.
The T allele may also work as a protective factor, because it occurs more frequently in older patients who have survived MI. But being a protective factor, its association with MI would be expected to be stronger in a high-risk group rather than in a low-risk group. What we initially had in mind, however, was to check whether that genetic variant of the CD14 gene represents a genetic risk factor, ie, contributes to the so-called familial risk in patients lacking a classic risk profile. Assuming that case, an association with MI in a large population should be stronger in low-risk patients who in addition are relatively young. The population that underlies our epidemiological study might omit that interesting collective of patients although it is rather extensive. In addition, it is noteworthy that this is a retrospective study design with regard to MI. A prospective study, with a case group of young low-risk patients going through acute MI, is in progress.
We also cannot exclude uncontrolled factors to be associated with the CD14 genotype. In particular, the control groups of probands without CAD and MI include many patients with valvular disease, which might falsify our results. On the other hand, one can conclude from the study design that all control patients are angiographically classified, which guarantees the most reliable results concerning CAD.
Familial or genetic risk may be comprised by a single factor responsible for, for example, a phenotypic metabolic disorder such as hyperhomocystinemia or familial hypercholesterolemia. On the other hand, genetic risk might be composed of several genetic markers that, isolated, have a functional impact that is scarcely measurable. Many polymorphisms already have been found with an isolated, only weak or controversial influence on coronary syndromes.22 23 24 25 26 27 There might be an additive effect of gene polymorphisms that concerns molecules involved in adhesive, coagulatory, and proliferative processes, or in vasoconstriction, and that is of a complexity beyond our knowledge until now.
Authors of several studies have suggested a role of chronic inflammation in genesis and progression of atherosclerosis. Acute-phase proteins like C-reactive protein and fibrinogen have been shown to be elevated in atherosclerosis, correlating with severeness of disease,28 and in MI.29 30 In animal experiments, local LPS application could be blamed for formation of atherosclerotic lesions.31 32
As this is an epidemiological study, we cannot provide evidence of whether the CD14 promoter polymorphism effects an altered expression of CD14 and susceptibility to LPS stimulation. According to investigations on the CD14 promoter by Zhang et al,21 the polymorphic base at -159 lies 49 bp adjacent to an experimentally detected binding site for transcription factor Sp1 at -110 and 1 bp adjacent to a putative Ap2 site at -158. Sp1 was found to be critical for the expression of CD14, whereas purified Ap2 did not interact with the CD14 promoter. Nuclear extracts of Mono Mac 6 cells interacted with 4 sites of the CD14 promoter, the nearest beginning at position -154. These experiments made use of a clone exhibiting a T at position -159 of the CD14 gene. One can speculate that with a C adjacent to the Ap2 consensus sequence, nuclear extracts would have interacted. In constructs of luciferase gene with truncated CD14 promoter, a construct up to position -227 had the highest promoter activity (including the polymorphic site), and a construct up to -128 had less activity (including only the Sp1 site). These findings suggest that the newly detected polymorphic site lies within or near a functional region of the CD14 promoter. Ongoing studies will show whether the T-159C polymorphism affects the expression of LPS receptor.
In conclusion, we found a new T/C polymorphism of the CD14 promoter at position -159. Homozygosity of the T allele is associated with a history of MI in the subgroup of older low-risk patients. Whether homozygosity of the T allele acts as a risk factor for MI or as a protective factor to survive MI must be clarified in further studies.
Received June 22, 1998; accepted August 31, 1998.
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B. OSTERUD and E. BJORKLID Role of Monocytes in Atherogenesis Physiol Rev, October 1, 2003; 83(4): 1069 - 1112. [Abstract] [Full Text] [PDF] |
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P. J. Lindsberg and A. J. Grau Inflammation and Infections as Risk Factors for Ischemic Stroke Stroke, October 1, 2003; 34(10): 2518 - 2532. [Abstract] [Full Text] [PDF] |
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T Kondo, M Ohno, K Shimokata, S Iino, Y Inden, T Murohara, and M Hirai CD14 promoter polymorphism is associated with acute myocardial infarction resulting from insignificant coronary artery stenosis Heart, August 1, 2003; 89(8): 931 - 932. [Full Text] [PDF] |
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J. M. Fernandez-Real, M. Broch, C. Richart, J. Vendrell, A. Lopez-Bermejo, and W. Ricart CD14 Monocyte Receptor, Involved in the Inflammatory Cascade, and Insulin Sensitivity J. Clin. Endocrinol. Metab., April 1, 2003; 88(4): 1780 - 1784. [Abstract] [Full Text] [PDF] |
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P. Marques-Vidal, E. Mazoyer, V. Bongard, P. Gourdy, J.-B. Ruidavets, L. Drouet, and J. Ferrieres Prevalence of Insulin Resistance Syndrome in Southwestern France and Its Relationship With Inflammatory and Hemostatic Markers Diabetes Care, August 1, 2002; 25(8): 1371 - 1377. [Abstract] [Full Text] [PDF] |
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S. Kiechl, E. Lorenz, M. Reindl, C. J. Wiedermann, F. Oberhollenzer, E. Bonora, J. Willeit, and D. A. Schwartz Toll-like Receptor 4 Polymorphisms and Atherogenesis N. Engl. J. Med., July 18, 2002; 347(3): 185 - 192. [Abstract] [Full Text] [PDF] |
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W. Koenig, N. Khuseyinova, M. M. Hoffmann, W. Marz, M. Frohlich, A. Hoffmeister, H. Brenner, and D. Rothenbacher CD14 C(-260)->T polymorphism, plasma levels of the soluble endotoxin receptor CD14, their association with chronic infections and risk of stable coronary artery disease J. Am. Coll. Cardiol., July 3, 2002; 40(1): 34 - 42. [Abstract] [Full Text] [PDF] |
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R. Y.L. Zee, D. Bates, and P. M. Ridker A Prospective Evaluation of the CD14 and CD18 Gene Polymorphisms and Risk of Stroke Stroke, April 1, 2002; 33(4): 892 - 895. [Abstract] [Full Text] [PDF] |
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F Andreotti, I Porto, F Crea, and A Maseri Inflammatory gene polymorphisms and ischaemic heart disease: review of population association studies Heart, February 1, 2002; 87(2): 107 - 112. [Abstract] [Full Text] [PDF] |
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T. D. LeVan, J. W. Bloom, T. J. Bailey, C. L. Karp, M. Halonen, F. D. Martinez, and D. Vercelli A Common Single Nucleotide Polymorphism in the CD14 Promoter Decreases the Affinity of Sp Protein Binding and Enhances Transcriptional Activity J. Immunol., November 15, 2001; 167(10): 5838 - 5844. [Abstract] [Full Text] [PDF] |
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G. H. KOPPELMAN, N. E. REIJMERINK, O. COLIN STINE, T. D. HOWARD, P. A. WHITTAKER, D. A. MEYERS, D. S. POSTMA, and E. R. BLEECKER Association of a Promoter Polymorphism of the CD14 Gene and Atopy Am. J. Respir. Crit. Care Med., March 15, 2001; 163(4): 965 - 969. [Abstract] [Full Text] |
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M. Heesen, D. Kunz, R. Rossaint, and B. Blomeke Real-Time PCR Assay with Fluorescent Hybridization Probes for Rapid Genotyping of the CD14 Promotor Polymorphism Clin. Chem., November 1, 2000; 46(11): 1866 - 1867. [Full Text] [PDF] |
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D. Ito, M. Murata, N. Tanahashi, H. Sato, A. Sonoda, I. Saito, K. Watanabe, and Y. Fukuuchi Polymorphism in the Promoter of Lipopolysaccharide Receptor CD14 and Ischemic Cerebrovascular Disease Stroke, November 1, 2000; 31(11): 2661 - 2664. [Abstract] [Full Text] [PDF] |
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J. P. Kane and R. J. Havel Polymorphism of the Lipopolysaccharide Receptor (CD14) and Myocardial Infarction : New Evidence for a Role of Gram-Negative Bacterial Infection? Circulation, June 29, 1999; 99(25): 3210 - 3212. [Full Text] [PDF] |
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M.-L. Wong, B. Xie, N. Beatini, P. Phu, S. Marathe, A. Johns, P. W. Gold, E. Hirsch, K. J. Williams, J. Licinio, et al. Acute systemic inflammation up-regulates secretory sphingomyelinase in vivo: A possible link between inflammatory cytokines and atherogenesis PNAS, July 18, 2000; 97(15): 8681 - 8686. [Abstract] [Full Text] [PDF] |
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