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Journal of the American College of Cardiology
© 2007 by the American College of Cardiology Foundation
Published by Elsevier Inc.
Vol. 50, No. 12, 2007
ISSN 0735-1097/07/$32.00
doi:10.1016/j.jacc.2007.06.012
STATE-OF-THE-ART PAPER
C-Reactive Protein Gene Polymorphisms, C-Reactive
Protein Blood Levels, and Cardiovascular Disease Risk
Fadi G. Hage, MD, Alexander J. Szalai, PHD
Birmingham, Alabama
C-reactive protein (CRP), a blood marker of inflammation and a hallmark of the acute-phase response, has been
shown to be a powerful and specific predictor of cardiovascular event risk in populations of otherwise healthy
persons. Here we review what is known about CRP gene polymorphisms, discuss how these might affect the
epidemiology of CRP and our understanding of CRP’s contribution to cardiovascular disease, and examine their
potential clinical usefulness. Evidence shows that certain subtle variations in the CRP gene sequence, mostly
single nucleotide polymorphisms, predictably and strongly influence the blood level of CRP. Some of these variations are associated with clinical correlates of cardiovascular disease. If future studies can establish with certainty that CRP influences cardiovascular biology, then CRP gene profiling could have clinical utility. (J Am Coll
Cardiol 2007;50:1115–22) © 2007 by the American College of Cardiology Foundation
C-reactive protein (CRP) was discovered in 1930 by Tillet
and Francis during their studies of patients with acute
pneumonia (1). They found that when serum from febrile
patients was mixed with a cell-wall component of pneumococci that they called “Fraction C,” a precipitate formed.
This property was subsequently found to be due to reactivity
of CRP, present at high levels in “acute-phase” sera, with a
polysaccharide in the pneumococcal cell wall (Cpolysaccharide). C-reactive protein was the first of many
acute-phase reactants subsequently discovered (2), but today
elevation of CRP is still considered the hallmark of the
acute-phase response.
C-reactive protein is a member of the phylogentically
ancient and conserved pentraxin family of proteins. Human
CRP (Fig. 1) consists of 5 noncovalently bound subunits of
206 amino acids, each arranged symmetrically around a
central pore. The molecule has a ligand recognition face that
contains a Ca2⫹-dependent binding site, as well as an
effector molecule binding face that is able to initiate fluidphase pathways of host defense (by activating the complement system) and cell-mediated pathways (by activating
complement and by binding to the Fc receptors of immunoglobulin G) (3) (Fig. 1). The rise in blood CRP after
tissue insult or injury is rapid and robust, with levels
increasing by as much as 1,000-fold above baseline within
24 h. This behavior makes blood CRP an ideal clinical
marker of a patient’s general health status, and it has thus
been used for decades (4). The recent introduction of
From the Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
Manuscript received March 14, 2007, revised manuscript received May 7, 2007,
accepted June 5, 2007.
“high-sensitivity CRP” assays, technologies that allow clinicians to detect the low levels of blood CRP in ostensibly
healthy people, has resulted in accumulation of vast
amounts of data linking blood CRP to various kinds of
cardiovascular diseases (5). At the same time, new evidence
from animal models indicates that CRP might actually have
a pathogenic role in vascular disease (6 –9).
It has long been recognized that environmental variables
and patient behaviors and traits such as smoking, infections,
age, gender, lipid levels, and blood pressure can contribute
to variation in baseline CRP level1 (10). Indeed, obesity is a
major determinant of CRP levels in humans, and elevated
levels of CRP predict the development of type 2 diabetes
mellitus and the metabolic syndrome (11,12). Elevated
CRP levels in these conditions are related to insulin resistance (13), and weight loss can reduce CRP levels (14).
Newer evidence indicates an additional and substantial
genetic component (10,15,16). The realization that CRP
genetic polymorphisms do exist and that certain of these
directly and predictably influence steady-state blood CRP
level could be of substantial clinical importance, because
genetic predisposition to high baseline CRP might account
for a significant proportion of people with a higher than
average risk of heart disease (17). Herein we review the
available evidence showing that a variety of CRP gene
polymorphisms are statistically associated with blood CRP
level, that certain of these are biologically functional in that
they directly alter CRP blood levels, and that some CRP
variants are linked to a risk of heart and blood-vessel disease.
1
Because of the highly skewed distribution of human CRP blood levels, the
population statistic most often reported in the epidemiologic literature is the median.
Mean CRP levels and transformed CRP levels are also reported.
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Hage and Szalai
CRP Gene Polymorphisms
Abbreviations
and Acronyms
JACC Vol. 50, No. 12, 2007
September 18, 2007:1115–22
Localization and
Structure of the CRP Gene
CABG ⴝ coronary artery
bypass graft
On the basis of the amino acid
sequence of the protein, WhiteCRP ⴝ C-reactive protein
head et al. (18) synthesized
IL ⴝ interleukin
CRP-specific oligonucleotides
SLE ⴝ systemic lupus
and used these to screen a human
erythematosus
liver c-deoxyribonucleic acid liSNP ⴝ single nucleotide
brary. The clone pCRP1 was
polymorphism
thus isolated, sequenced, and
used as a probe to localize the
human CRP gene to chromosome 1. This launched the
era of CRP genetics. C-reactive protein was subsequently
mapped to the proximal long arm of chromosome 1 in the
1q23.2 region (19,20) (Fig. 2). The CRP gene sequence
was simultaneously determined in 1985 by 2 different
groups (21,22), both reporting that it is composed of 1
intron separating 2 exons (Fig. 2). The first exon encodes
a signal peptide and the first 2 amino acids of the mature
protein. This is followed by a 278-nucleotide-long intron
that includes a GT repeat sequence. The second exon
encodes the remaining 204 amino acids, followed by a
stop codon. Goldman et al. (23) were the first to show
that the GT stretch in the intron is polymorphic in
length.
Once the CRP gene was identified and its sequence
reported, several groups investigated its proximal promoter region and how this regulates messenger ribonu-
Figure 1
Blood CRP Circulates as a Pentamer
One face of the pentamer supports multipoint attachment to ligands and
ligand-decorated surfaces; the other face binds C1q and Fc␥R. Only some of
the many C-reactive protein (CRP) ligands are listed. HDL ⫽ high-density
lipoprotein; oxLDL ⫽ oxidized low-density lipoprotein.
Figure 2
The CRP Gene Is Located on Chromosome 1
The gene per se is comprised of 2 exons (red boxes) separated by a single
intron encoding a dinucleotide (gt) repeat. Exon 1 encodes an 18 amino acid
leader peptide (green box) and the first 2 amino acids of the mature protein.
The cross-hatched box demarcates the position of a reported alternative transcript. CRP ⫽ C-reactive protein; UTR ⫽ untranslated regions (yellow boxes).
cleic acid production. Several reviews of that subject are
available (3,24,25). Fundamentally, regulation of CRP
expression occurs mostly at the transcriptional level, with
interleukin (IL)-6 being the major inducer and IL-1
acting synergistically to enhance the effect (26). Accordingly, certain polymorphisms of the IL-1 (27,28) and
IL-6 (29) genes associate with differences in blood CRP
level. Both IL-1 and IL-6 polymorphisms have been linked
to myocardial infarctions and stroke (30,31) and to mortality after acute coronary syndromes (32). Studies using mice
expressing human CRP from the human CRP promoter
have shown that although IL-6 is necessary for the induction of the CRP gene, it is not by itself sufficient (33,34). In
humans, CRP blood levels are generally higher in females
than in males (35), whereas in mice, expression of the
human CRP transgene exhibits the opposite pattern (33). It
is important to note that in vitro studies of regulation of
CRP gene expression have focused solely on primary hepatocytes, hepatocyte cell lines, or a variety of transfected cell
lines (3,24,25). With the recent realization that CRP can be
locally produced by the vasculature (7,36), however, this
area needs to be reinvestigated to determine whether the
same regulatory mechanisms are operating in cells of nonhepatic origin.
In this review we will not discuss further IL-6, IL-1,
gender hormones, or any other of the multitude of transacting factors and their genes that might themselves be
polymorphic and might participate in CRP gene regulation.
Rather, we will focus on the CRP gene per se and
systematically discuss its many polymorphic cis-acting elements. We will in turn examine evidence that the CRP gene
coding and promoter region is polymorphic, that this
sequence variation affects how much blood CRP is made,
and that this in turn affects CRP’s association to cardiovascular disease.
Hage and Szalai
CRP Gene Polymorphisms
JACC Vol. 50, No. 12, 2007
September 18, 2007:1115–22
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SNP in the CRP Gene
Table 1
SNP in the CRP Gene
Gene Region
Promoter
Intron
Exon 2
3= untranslated
3= flanking
SNP Position Commonly
Reported in the Literature
⫺757
⫺717
NCBI refSNP ID
Relative Allele
Frequency*
Nucleotide Associated
With Higher
CRP Blood Level
rs3093059
T⬎C
T
(47,58,60,72)
rs2794521
T⬎C
T
(46,49,52,57,58,66,67)
Association Studies†
⫺409
rs3093062
G⬎A
G
(51)
⫺390
rs3091244
C⬎T⬎A
T
(16,51,52,55,67,68,70,71)
⫹29
rs1417938
A⬎T
A
(49,50,60,67,72)
⫹1059
rs1800947
G⬎C
G
(50,52,60–63,65,67,71,72)
⫹219
rs3093066
C⬎A
C
(49)
⫹1444
rs1130864
C⬎T
T
(46–48,52,67,69,71)
⫹1846
rs1205
C⬎T
C
(65–67,69,72)
⫹2911
rs3093068
C⬎G
G
(69)
*Alleles are reported in order from most frequent to least frequent as listed on the National Center for Biotechnology Information (NCBI) website. Depending on the deoxyribonucleic acid strand sequenced,
allele designations may differ from those commonly reported in the literature. †References to articles discussed in the text that studied the association of the indicated single nucleotide polymorphism (SNP)
to C-reactive protein (CRP) blood level or disease status.
refSNP ⫽ reference single nucleotide polymorphism.
The CRP Gene Is Polymorphic
Pankow et al. (37) estimated that the interindividual variation in blood CRP level is 35% to 40% heritable. This has
since been confirmed in twin studies (38 – 40). For example,
MacGregor et al. (39) compared monozygotic versus dizygotic twin pairs and found that, although CRP was associated with body mass index, smoking status, and hormone
replacement therapy, there was a greater correlation of CRP
level among monozygotic than dizygotic twins, with an
estimated heritability of 52%. Similarly, Retterstol et al. (40)
found in monozygotic twins the within-pair correlation
coefficient for CRP level was 0.40. Soon after it was
established that differences in CRP level associate with
genetic differences, efforts were made to identify different
CRP gene polymorphisms to determine whether they directly affect the protein’s blood level. We have already
mentioned that soon after the gene was sequenced, a
polymorphism in the length of the GT repeat in the CRP
intron was identified (23,41). Some time later, Cao and
Hegele reported (42) the first coding region variation, i.e., a
single nucleotide polymorphism (SNP) in exon II of CRP.
That SNP, ⫹1059 G/C (rs1800947) (Table 1),2 is silent at
the amino acid level (CTG¡CTC, Leu¡Leu), and the
rarer C allele was reportedly found in Caucasians but not
Inuits (43). Pronounced ethnic and race effects are now
known to be a general characteristic of the distribution of
CRP gene polymorphs. Indeed, a recent systematic resequencing of the CRP gene revealed as many as 40 SNPs
forming as many as 29 different haplotypes, with by far the
highest nucleotide diversity observed in African Americans
(44). It is indisputable that the CRP gene is polymorphic.
2
Throughout the text, SNPs are identified using the terminology most commonly
used in the literature. Wherever possible each is also cross-referenced to the NCBI
database using the reference (ref)SNP ID number or ‘rs’ number.
CRP Gene Polymorphisms Associate
With Differences in CRP Blood Levels
Ours was the first group to report an association between
CRP gene polymorphism and baseline blood CRP (45). We
examined the relationship between GT repeat alleles and
blood protein levels in patients with systemic lupus erythematosus (SLE) versus healthy control patients and
therein identified 13 alleles ranging in length from 9 to 25
repeats (GT9 to GT25). Two of these, GT16 and GT21,
accounted for more than 75% of all the alleles found. The
statistical relationship between CRP genotype and CRP
blood level was best described by a sine-wave model having
a periodicity of 5 GT repeats, with the GT16 and GT21
variants associated with lowest CRP levels (Fig. 3). No
particular GT allele was associated with SLE (45).
Soon after our study was published, Brull et al. (46)
reported their own findings. They measured blood CRP in
healthy men before and after 48 h of endurance exercise, and
in patients before and after coronary artery bypass graft
(CABG) surgery and screened each of their respective CRP
genes. Two new polymorphisms were identified; a
⫺717G/A SNP (rs2794521) in the CRP promoter and a
⫹1444C/T SNP (rs1130864) in the 3= untranslated region.
The former did not associate with CRP, but ⫹1444TT
homozygotes had significantly higher CRP at baseline, after
exercise training, and after CABG. The ⫹1444C/T SNP by
itself accounted for 3.7% of the total variance in baseline
blood CRP. Later the same group reported that CRP was
higher in periodontal patients carrying the ⫹1444T versus
the C allele (47), and another group showed that healthy
young men with the ⫹1444TT genotype had 64% higher
blood CRP than those with the ⫹1444CC genotype (48).
Many other CRP polymorphisms with association to
blood CRP level have since been reported. Thus, Obisesan
et al. (49) identified association between a ⫺717A/G SNP
and CRP levels before and after exercise training: blood
CRP was higher in ⫺717AA homozygotes. A similar
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Figure 3
Hage and Szalai
CRP Gene Polymorphisms
Association Between Baseline CRP and
the GT Repeat Polymorphism in the CRP Gene
Each circle and whisker is the mean ⫾ SEM for baseline (age-adjusted) CRP
obtained from the indicated number of individuals. The correlation coefficient
(r ) for the sine-wave regressions is given. The arrows point to the common
GT16 and GT21 variants having the lowest (approximately equal) CRP levels.
CRP ⫽ C-reactive protein.
JACC Vol. 50, No. 12, 2007
September 18, 2007:1115–22
values in individuals carrying ⫺390TT. Both SNPs reside
within E-box elements we named E-box 1 and E-box 2,
respectively. Using electrophoretic mobility shift assays, we
proved that both E-boxes are functional and that transcription factors are capable of binding E-box 1. Importantly, the
SNP in E-box 1 affects its ability to interact with transcription factors. We also showed that individuals with a
⫺409G/⫺390T haplotype (the only haplotype found that
encoded a high transcription factor binding version of
E-box 1 and a transcription factor binding version of E-box
2) had highest blood CRP, whereas individuals with
⫺409A/⫺390T (weak transcription factor binding versions
of both E-boxes) had the lowest (Fig. 4A). Individuals with
either of the 2 remaining haplotypes had intermediate CRP
levels. Finally, using CRP promoter-firefly luciferase reporters, we confirmed that transcription at baseline and in
response to IL-6 was different for the different E-box
haplotypes (Fig. 4B). Impressively, carriers of the ⫺409G/
⫺390T haplotype who never smoked still had higher CRP
levels than ⫺409G/⫺390C carriers who currently did (51).
Kovacs et al. (52) also identified and studied the triallelic
⫺390C/T/A SNP. They examined the correlation between
correlation was reported for a ⫹219G/A SNP (rs3093066)
in the 3= untranslated region: GG homozygotes had higher
CRP levels at baseline and after exercise (49). Impressively,
in a multivariate analysis, the ⫺717A/G and ⫹219G/A
SNPs together accounted for almost 9% of the total variation in CRP blood level (49). Finally, a ⫹29A/T SNP
(rs1417938) was found to be significantly associated with
baseline CRP level: individuals with the A allele had higher
blood CRP, a relationship that persisted even after controlling for clinical characteristics (50). It is now clear that
polymorphisms in the CRP gene associate with differences
in CRP blood level.
Some CRP Gene Polymorphisms Are Functional
None of the polymorphisms so far discussed has been shown
to be functional, that is, to directly contribute to differences
in baseline CRP blood level among individuals. Few studies
have actually pursued this question, and in the absence of
evidence, the common assumption made is that CRP
polymorphisms alter the structure of neighboring deoxyribonucleic acid and thus impede or bolster its translation to
messenger ribonucleic acid, or that known polymorphisms
are in linkage disequilibrium with yet-to-be identified
functional polymorphisms. To investigate this issue, we
sequenced the CRP promoter in 287 healthy individuals
and identified 2 SNPs, a biallelic one at nucleotide
⫺409G/A (rs3093062) and a triallelic one at ⫺390C/T/A
(rs3091244) (51). Blood CRP was lowest in people with the
⫺409AA genotype, intermediate in ⫺409GA, and highest
in ⫺409GG, and there was a tendency toward high CRP
Figure 4
Association of CRP Promoter
Haplotype With Baseline CRP
Baseline C-reactive protein (CRP) concentration for the indicated number of
individuals having the various haplotypes (A) and the corresponding relative
luciferase light units (the ratio of firefly vs. Renilla luciferase activity) (B) is
reported as the mean ⫹ SEM (bars and whiskers). The numbers above the
bars give the fold-increase in promoter activity relative to the steady state.
IL ⫽ interleukin. Modified with permission from Szalai et al. (51).
JACC Vol. 50, No. 12, 2007
September 18, 2007:1115–22
this SNP, a biallelic one at ⫺717A/G, the ⫹1059G/C SNP
in exon 2, and the ⫹1444C/T SNP in the 3= flanking
region. That study confirmed that the triallelic SNP correlated with baseline CRP. In the large Framingham Heart
Study (16), 9 of 13 CRP SNPs were found to be associated
with blood CRP after adjustment for clinical covariates. Of
these 9, only the triallelic SNP remained associated with
blood CRP after accounting for correlation among SNPs.
Finally, because CRP level after an acute coronary syndrome
is predictive of recurrent events (53,54), Danik et al. (55)
evaluated patients with acute coronary syndrome and found
that the highest CRP blood level was associated with a
⫺757T/C SNP (rs3093059) and again with the ⫺390C/
T/A SNP. The evidence from our initial study (51) and
independent additional studies thus points to at least 1 CRP
gene polymorphism that might truly be functional: ⫺390C/
T/A.
CRP Gene Polymorphism
Associates With Disease Status
Some of the most compelling reports of a strong association
between CRP polymorphism and disease status did not
include measurement of blood CRP level as a variable. For
example, Roy et al. (56) linked one poly(GT) allele (likely
GT16) (Fig. 3) to increased susceptibility to infection with
Streptococcus pneumonia, and Wolford et al. (57) found that
⫺717TT was associated with an increased prevalence of
type 2 diabetes mellitus. More recently, it was reported (58)
that having the C allele at the ⫺717T/C locus was significantly associated with training-induced improvements in
the insulin-sensitivity index.
Not all such studies revealed a gene– disease association.
Thus, although baseline CRP is a good predictor of restenosis (59), investigation of the ⫹1059G/C and ⫹29T/A
SNPs found no association with restenosis risk after angioplasty (60). These data consistently point toward an association of CRP polymorphisms with blood CRP levels. The
strength and direction of this association appear to depend
on the type of disease, however, and the polymorphisms
may or may not associate with disease risk.
The Big Question:
Does CRP Gene Polymorphism Alter
CRP Blood Levels and Thus Disease Status?
Zee et al. (61) examined the relationship of ⫹1059G/C
with blood CRP and risk of arterial thrombosis. In a large
cohort of healthy American men (726 case-control pairs),
12% were found to carry the C allele, and those turned out
to have lower median CRP values compared with individuals having the GG genotype. No correlation with arterial
thrombosis was found (61). Likewise, in the British
Women’s Heart and Health Study (62), carriers of ⫹1059C
had lower blood CRP, but this did not affect blood pressure,
pulse pressure, or hypertension. In contrast, Balistreri et al.
(63) found that CRP blood level was higher in subjects with
Hage and Szalai
CRP Gene Polymorphisms
1119
the C allele, and there was a higher frequency of ⫹1059C in
patients with a history of acute myocardial infarction compared with healthy control patients. In a nested-case control
study of SLE (64), certain alleles of the intronic GT repeat
were found to be associated with vascular events (myocardial
infarction, stroke, peripheral arterial thrombosis, CABG,
angina or claudication). Systemic lupus erythematosus patients with these vascular events were more likely than SLE
patients without them to have blood CRP in the highest
quintile of measured values, and these patients had a higher
prevalence of the GT20 variant (64). In another study of
SLE patients, Russell et al. (65) directly sequenced the CRP
gene in British families and found a correlation between
baseline blood CRP, the ⫹1059G/C SNP, and a
⫹1846G/A SNP (rs1205) in the 3= flanking region. The
latter was associated with SLE and the presence of antinuclear antibodies.
Other efforts to associate CRP gene polymorphism with
blood CRP level and disease status are noteworthy. For
example, in Han Chinese subjects, although neither
⫺717A/G nor ⫹1846 A/G was found to correlate with
blood CRP, the frequency of the ⫺717A allele was significantly higher among patients with coronary heart disease
than control patients. Impressively, in that study, individuals carrying the A allele had an odds ratio for coronary heart
disease of 6.8 compared with those not carrying that allele
(66). This finding has since been confirmed, as the same
SNP was found to correlate with occurrence of myocardial
infarction or thromboembolic stroke in the Physician’s
Health Study (67). In a very recent and thorough examination of 7,159 individuals from the Third National Health
and Nutrition Examination Survey, several CRP SNPs were
found to be associated with CRP levels, but only the
functional ⫺390C/T/A SNP was linked to both CRP levels
and to increased prevalence of coronary heart disease (68).
One interpretation of the findings of these studies, which
were performed independently using diverse and unrelated
populations, is that there are some CRP sequence polymorphisms that influence expression of the protein that might
also affect cardiovascular well being.
All of the known CRP gene SNPs are in high-linkage
disequilibrium, so tag SNPs have been used to define
extended CRP haplotypes. Using this approach, Kardys
et al. (69) found that although CRP blood level was
associated with incident coronary heart disease and varied
with CRP haplotype, the different CRP haplotypes themselves were not associated with coronary heart disease. In
another tag SNP investigation of subjects from the NHLBI
Family Heart Study, a trend toward a significant association
of CRP haplotypes with blood CRP was reported. In this
case, the ⫺757T/C and ⫺390C/T/A SNPs showed the
strongest association. Again, however, none of the CRP
haplotypes or tag SNPs showed an association with intimamedia thickness as measured by ultrasound (70). Another
study examining the correlation of various CRP SNPs to
CRP blood level and arterial pulse wave velocity (71) found
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CRP Gene Polymorphisms
statistically significant association between CRP levels and
⫺390C/T/A and ⫹1444C/T, and there was association
of ⫹1059G/C with pulse-wave velocity. Finally, in the
Cardiovascular Health Study, ⫹1846C/T, ⫹29A/T,
⫹1059G/C, and ⫺757T/C were variably associated with
blood CRP. Not surprisingly, given that the distribution of
CRP alleles differed among the races, the disease risk also
differed among the races. Thus, in Caucasians ⫹29A/T was
associated with increased risk of stroke and cardiovascular
mortality and ⫹1059G/C and ⫹1846C/T were associated
with cardiovascular mortality, whereas in African Americans ⫺757T/C was associated with myocardial infarctions
(72). At least some of the large-scale investigations using tag
SNP approaches have provided some evidence that sequence differences in the CRP gene alter both CRP blood
levels and disease risk.
Summary
We have attempted here to bring together for comparison
and contrast all of the published reports showing (or not
showing) that CRP gene polymorphisms associate with
CRP blood levels or/and that CRP gene polymorphisms
associate with cardiovascular disease risk. Some noteworthy
patterns emerged. There is now ample direct evidence that
some CRP gene polymorphisms affect the amount of CRP
produced and indirect evidence that this in turn might have
an impact on vascular disease. In the CRP gene, intron
variations in the GT repeat have been linked to changes in
blood CRP and the risk of vascular events, and the ⫹29A/T
SNP was linked to blood CRP level but not to restenosis. In
exon II, the often-studied ⫹1059G/C SNP has been shown
to correlate well with blood CRP and in at least 1 study to
associate with pulse-wave velocity. It does not correlate,
however, with arterial thrombosis, blood pressure, or restenosis. In the promoter region, the ⫺390C/T/A triallelic
SNP, the only functional CRP polymorphism so far described, has been shown to correlate with blood CRP and
recently has been directly linked to risk of cardiovascular
disease. The other SNPs in the promoter region have
variable association with CRP level but good correlation
with cardiac disease, diabetes mellitus, and insulin resistance. In the 3= untranslated and 3= flanking regions there
are other SNPs that also correlate with blood CRP, but
none that associate with cardiovascular disease (although
⫹1846C/T does associate with SLE). Importantly, nearly
10% of the total variation in CRP blood level can be
accounted for by the CRP gene SNPs. This is remarkable
given that CRP blood level is as much as 40% heritable. The
fact that most studies have not been able to link CRP
polymorphisms to events is not that surprising, despite their
clear relationship to blood CRP level and of the latter to
hard clinical end points. Given the modest proportion of
variation in blood CRP level that CRP polymorphisms
explain, it would take a very large study (several orders of
magnitude larger than those so far undertaken) to see a
JACC Vol. 50, No. 12, 2007
September 18, 2007:1115–22
direct relationship between a particular SNP or CRP
haplotype and actual clinical events.
Coronary artery disease is considered by many to be a
disease of inflammation (73), and blood CRP has been
shown to be a powerful predictor of cardiovascular events
(74,75). The effects of lifestyle and trans-acting factors not
withstanding, it is now increasingly apparent that certain
subtle variations in the CRP gene sequence predictably and
strongly influence blood CRP level. Furthermore, some of
these variations map to cis-acting elements that have already
been associated with clinical correlates of cardiovascular
disease; notable in this respect is the triallelic SNP at
position ⫺390. New CRP SNPs and novel gene-proteindisease associations will likely be reported at an increasing
pace, so the exact contribution of CRP gene polymorphisms
to the protein’s level and to disease status will continue to
define itself. However, reports that individual SNPs in CRP
might explain up to 10% of the variance in blood CRP level,
and that the heritability of blood CRP is 30% to 40%,
suggest that identifying an individual’s CRP SNPs might
one day be a practical and useful clinical approach for
prediction of cardiovascular event risk or for selecting
patients for treatment with CRP targeting drugs. Of course,
moving CRP genotyping to the clinical arena depends
entirely on obtaining proof that CRP participates in disease
processes in humans, and that proof is still not available. If
ultimately CRP is found to not contribute to cardiovascular
biology, its utility as a marker of inflammation will not be
diminished. Ongoing and future studies will no doubt settle
the issue, but until then, there will always be critics and
supporters of the position that CRP blood levels and CRP
gene polymorphisms really matter.
Reprint requests and correspondence: Dr. Fadi G. Hage, 306
Lyons-Harrison Research Building, 1530 3rd Avenue South,
Birmingham, Alabama 35294-0007. E-mail: [email protected].
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