(Circulation. 1999;99:3210-3212.)
© 1999 American Heart Association, Inc.
Editorials |
Polymorphism of the Lipopolysaccharide Receptor (CD14) and Myocardial Infarction
New Evidence for a Role of Gram-Negative Bacterial Infection?
From the University of California, San Francisco.
Correspondence to Richard J. Havel, MD, University of California, San Francisco, Box 0130, 505 Parnassus Ave, L-1337, San Francisco, CA 94143-0130.
Key Words: Editorials • genetics • myocardial infarction • epidemiology • immune system
Strong familial aggregation of coronary artery disease has long been recognized. Some of the increment of familial risk is attributable to established risk factors, such as plasma lipid levels, hypertension, smoking, and diabetes. Statistical regression studies, however, suggest that only 30% to 50% of the observed increment of coronary disease risk associated with a positive family history can be accounted for by canonical risk factors.1 2 Thus, significant factors remain to be discovered. These may involve retrieval of lipids from plaque, antioxidant defenses, endothelial dysfunction, abnormalities of platelet function, thrombogenesis and thrombolysis, and hereditary determinants of the inflammatory components of atherogenesis, among others.3
The idea that an inflammatory response directed at microorganisms might contribute to the atherogenic process is not new. In the last century, Virchow4 noted histopathological parallels between bacterial infection and atheromata. Recent reports have rekindled interest in the possibility that infection, particularly by Gram-negative bacteria, may contribute to the inflammatory component of atherosclerosis (including the major acute event of myocardial infarction) and that activation of monocytes may contribute to myocardial infarction as well as atherogenesis. Two European groups have now independently tested the hypothesis that genetic variations in the receptor for lipopolysaccharides (LPSs; endotoxins) produced by Gram-negative bacteria, CD14, may be a risk factor for myocardial infarction. Each group, one from Germany and the other from the Czech Republic, found a common polymorphism in the upstream, untranslated region of the CD14 gene. At the polymorphic site, cytosine or thymine is at position -260, within the Spl transcription factor binding site known to have a major influence on CD14 expression.5 Moreover, each group has reported evidence that expression of the T allele may be a risk factor for myocardial infarction.
The designs of the 2 studies were distinct. The German study of 2228 patients in Giessen and Bad Nauheim, all of whom had undergone diagnostic coronary angiography for suspected coronary heart disease (CHD), was reported this year.6 The genotype (CC, TC, or TT) was assessed by single-strand conformation or restriction fragment length analysis, and in some cases by both methods. The overall distribution was 28% CC, 50% CT, and 22% TT. No evidence for variation in this distribution was found according to extent or severity of disease or between those who had a history of myocardial infarction and those who did not. Moreover, the allele expression was unrelated to a number of established CHD risk factors. However, among normotensive TT homozygotes, the relative risk of past myocardial infarction was 1.4, and for normotensive nonsmokers it was 1.6, the latter value being statistically significant in both univariate and multivariate regression analysis. The relative risk (3.8) was highly significant for normotensive nonsmokers >62 years old but not for younger patients. The results of the subgroup analysis involving a small fraction of the total population in this study must be interpreted cautiously. Moreover, as noted by the authors, the T allele was overrepresented only in a subgroup of older patients and could therefore be a negative rather than positive risk factor.
The Czech report in this issue of Circulation7 was a case-control study involving 178 men (average age, 56 years) with myocardial infarction admitted to 2 coronary care units in 2 districts of central Bohemia. Controls were all from a nearby Czech district and represented a randomly selected 1% population sample: 135 men with an average age of 55 years. The Czech investigators identified the same common polymorphism in the promoter region of the CD14 gene by restriction fragment length analysis. Among patients, the frequency of the 3 genotypes was similar to that of the total group of Germans (29% CC, 43% CT, and 27% TT), but among controls the distribution was strikingly different (45% CC, 39% CT, and 16% TT). The differences in genotype and T allele frequency were highly significant. As in the German study, the CD14 polymorphism was unrelated to a number of established CHD risk factors, but surprisingly, none of these conventional risk factors differed significantly between the Czech patient and control groups.
The Czech investigators also found that the density of CD14 among 38
healthy young men was significantly higher (by 
40%) on blood
monocytes from TT homozygotes than from the other 2
genotypes.
Taken alone, each study is suggestive that the T allele may be a new risk factor for myocardial infarction, and the Czech study provides a possible mechanism (increased CD14 expression) involving the Spl promoter site in the CD14 gene. The T allele is sufficiently common to exert a significant influence on the course of CHD in these 2 populations. That the German and Czech populations studies are genetically distinct is suggested by the location of the latter in central Bohemia. In some parts of Bohemia, German admixture may be substantial. In a northern Bohemian district, for example, the insertion/deletion polymorphism of the ACE gene is consistent with considerable German admixture. In central Bohemia, by contrast, the allele frequencies of this polymorphism differ and resemble those of some other Slavic countries (R. Poledne, personal communication, 1999). Thus, despite obvious differences in design, the findings suggest association of the T allele of CD14 with myocardial infarction in 2 European ethnic groups.
What possible mechanistic connection can be made between a receptor for
bacterial endotoxins and clinical coronary disease? Clearly
there is a large inflammatory component in atherogenesis.3
Furthermore, the decreased plaque stability that underlies acute
occlusive coronary syndromes is attributed chiefly to the
inflammatory response of macrophages.8 9 10 LPSs
present a protopathic threat to vertebrates, against which a
complex system of defense has evolved. LPSs are bound in plasma by the
LPS binding protein (LBP), a structural homologue of the plasma
phospholipid transfer and cholesteryl ester transfer
proteins.11 A significant portion of the LBP in human
plasma is complexed with HDLs.12 A membrane-anchored
protein, CD14, on monocytes, macrophages, and neutrophils binds
LPS,13 14 mediating cellular activation by endotoxins. Two
soluble splice variants of CD14 (sCD14) occur in plasma.15
The binding of LPS to sCD14 is greatly accelerated by
LPB.16 17 LPS can be transferred directly to HDLs by LBP,
but the transfer from sCD14 is much faster.16 This
reaction may serve to damp the potentially dangerous activation of
macrophages by LPS, because the LPS bound to HDLs does not
elicit activation. LPS bound to CD14, however, can elicit expression of
E-selectin by endothelial cells even though they lack
the membrane-anchored form of CD14.18 Further effects on
endothelium would be expected from cytokines
secreted by LPS-activated macrophages. LPS-mediated
activation of macrophages results in the release of several
inflammatory cytokines, including tumor necrosis factor-
and
interleukins 1 and 6, in addition to platelet-derived growth
factor, which can induce migration and proliferation of smooth muscle
cells.19 Endotoxins elicit transcription of
endothelial leukocyte adhesion molecule 1
(ELAM-1)20 and vascular cell adhesion molecule
(VCAM-1)21 by endothelial cells.
Furthermore, LPS-induced release of tissue factor by
macrophages and endothelial cells would have
procoagulant activity.22 23 The further finding that the
LPB is capable of transferring phospholipids to sCD1424
suggests that these proteins could affect the structure and speciation
of HDLs in addition to changes in the lipoproteins that may attend
their uptake of LPS. Thus, if the C(-260)
T polymorphism indeed
leads to differences in the density of the mCD14 on cells as described
by Hubacek et al,7 it could influence several inflammatory
and other processes that might be involved in a contribution by
bacterial endotoxins to atherogenesis. It will also be important to
determine the effect of the polymorphism on the content of sCD14 in
plasma.
The data from Czech and German populations clearly call for confirmation in other ethnic groups as well as in prospective studies. It could be of particular interest to test the association of the T allele with myocardial infarction in more isolated and genetically homogeneous ethnic groups known to be at high risk. In Finns, a recent study of Y chromosome haplotypes indicates a dual origin.25 Many Finns descended from early Asian immigrants have a common Y haplotype. Such an analysis among Finns might thus be concentrated on this distinctive genetic isolate, which predominates in northern Karelia and certain other provinces.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
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