Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data
BMJ 2011; 342 doi: https://doi.org/10.1136/bmj.d548 (Published 15 February 2011) Cite this as: BMJ 2011;342:d548
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C reactive protein as a marker, not factor, of risk of cardiovascular
disease.
In the study on the Association between C reactive protein and
coronary heart disease by the C Reactive Protein Coronary Heart Disease
Genetics Collaboration (CCGC), published 15 February 2011 in the BMJ, both
the authors and the editorialist conclude that CRP is unlikely to have
even a small causal role in coronary heart disease.
There have been several genetic studies done on the role of CRP as
cardiovascular risk factor or marker, and all of themes have a similar
conclusion.
In other recent study, done by the leader researchers on CRP in the
world, and published on Circulation online at February 7, 2011, the
authors found loci that are implicated in pathways related to the
metabolic syndrome, the immune system, or that play a role in
inflammation. They also found a locus with significant interaction with
the body mass index. But they also conclude that there was no evidence for
these genetic variants explaining the association of CRP with coronary
heart disease.
And the statins, like simvastatin, reduce the risk of cardiovascular
events in similar proportion at different levels of CRP, but independent
of these levels (Lancet 5 Feb 2011).
In other words, CRP is a marker of cardiovascular risk due to
inflammation, metabolic activity or metabolic syndrome, excess in body
mass index or obesity, or immune response. But CRP by itself is not a risk
factor.
In 1999 (Lancet, 13 March), we published our findings on the high
correlation between elevated body mass index and/or resting heart rate
(elevated Pulse Mass Index) and the global cardiovascular risk according
to the Framingham Heart Study.
We correlated the pulse with the BMI, because the resting heart rate
reflects the oxidative metabolic rate and activity of the sympathetic
nervous system seen in obesity, hyperinsulinemia, the metabolic syndrome,
inflammation or under stress and smoking, among other known cardiovascular
risk factors.
In the meantime, both, Body Mass Index and Resting Heart Rate, are
widely accepted as cardiovascular risk factors, and the Pulse Mass Index
is the global marker or expression of these risk factors.
The determination of CRP will continue to be important in the global
evaluation of cardiovascular risk, but clearly as a marker and not risk
factor by itself.
Prof. Enrique Sanchez Delgado, MD
Hospital Metropolitano Vivian Pellas, Managua, Nicaragua
Competing interests: No competing interests
The baseline level of inflammation, as assessed by the plasma
concentration of C-reactive protein (CRP), predicts the long-term risk of
a first MI. The study of polymorphisms in the CRP gene are associated
with marked increases in CRP levels and thus with a predicted increase in
the risk of ischemic vascular disease. Nevertheless, these polymorphisms
are not associated with an increased risk of ischemic vascular disease.
(1)
Recent advances in genetic technology have expanded our ability to
catalogue allelic variants in large sets of candidate genes related to
premature coronary artery disease. A total of 398 families were identified
in 15 participating medical centres. They fulfilled the criteria of
myocardial infarction, revascularization, or a significant coronary artery
lesion diagnosed before 45 years in men or 50 years in women. A total of
62 vascular biology genes and 72 single-nucleotide polymorphisms were
assessed. The conclusions of the genetic study have identified the
potential of multiple novel variants in the thrombospondin gene family to
be associated with familial premature myocardial infarction. (2)
Recently Ripatti et al. (3) aimed to establish the correlation
between the 13 single nucleotide-polymorphisms and coronary heart disease.
The conclusions of the authors were the genetic score improved risk in
subjects who were an intermediate risk on the basis of traditional risks
factors.
Therefore the use of genomic factors for individual disease risk
prediction in combination with conventional coronary risk factors remains
still unclear. In fact in 66185 participants from 15 population-based
study Dehghan et al. (4) found there was no evidence for these genetic
variants explaining the association of CRP with coronary heart disease.
In this context we read with interest the current study by the
authors (5) with a large study of population including 47.000 patients
suffering from CHD showed that genetically raised concentration of CRP is
unrelated to conventional risk factors of CHD.
In summary, we would like to ask to the authors if consider absolute
need test yet CRP or other inflammatory process in prediction of long term
coronary heart disease risk.
References
1.Pearson, TA, Mensah, GA, Alexander, RW, et al. Markers of
inflammation and cardiovascular disease: application to clinical and
public health practice: A statement for healthcare professionals from the
Centers for Disease Control and Prevention and the American Heart
Association. Circulation 2003; 107: 499.
2.Topol EJ, McCarthy J, Gabriel S, et al. Single nucleotide
polymorphisms in multiple novel thrombospondin genes may be associated
with familial premature myocardial infarction. Circulation 2001 Nov
27;104(22):2641-4.
3.Ripatti S, Tikkanen E, Orho Melander M et al. A multilocus genetic
risk score for coronary heart disease: case-control and prospective cohort
analyses. Lancet 2010; 376: 1393-1400
4. Dehghan A, Dupuis J, Barbalic, M et al. Meta-Analysis of Genome-
Wide Association Studies in >80 000 Subjects Identifies Multiple Loci
for C-Reactive Protein Levels.Circulation 2011; Feb 7. [Epub ahead of
print]
5.C Reactive Protein Coronary Heart Disease Genetics Collaboration
(CCGC) Association between C reactive protein and coronary heart disease:
mendelian randomisation analysis based on individual participant data. BMJ
2011; 342-d548
Competing interests: No competing interests
C-reactive protein, biomarkers, and coronary heart disease
We agree with the letter by professor Enrico Sanchez Delgado and we
consider that C-reactive protein (C-RP) might represent a mediator of
vascular disease and several papers have been published in the last 10
years evaluating its role in coronary heart disease (CHD) 1,2
Nevertheless we have some concerns with the authors 3 of the non-
specificity of C-RP in CHD and we would be grateful if the authors could
provide additional information for a major clarity absolutely useful for
the general interest of the clinicians.
First, C-RP values have been measured in patients affected by stroke,
with the aim of understanding its role as predictor of further cardio-and
/ or cerebro - vascular events. 2 A study investigating 411 patients
showed the role of C-RP as biomarker predictor for incident ischemic
stroke, in relation with known risk factors (ABCD 2 score ), and Transient
Ischemic attacks (Corso and colleagues unpublished data). ROC curves were
plotted for two models: in Model 1the ABCD2 score was used and in Model 2
the ABCD2 score plus C-RP values were used. Analysis of the ROC curves
revealed the C-RP value 3 mg/L as the best cut-off point to predict the
occurrence of end-point events, optimizing the sensitivity- specificity
ratio (sensitivity = 0.60, specificity = 0.65, ASUC =0.66, 95% CI 63 to
69, p=0.0001).
C-RP levels were found to be an independent risk factor, as well as the
ABCD2 score.
Second, reports suggested that C-RP may predict response to
infliximab therapy in rheumatoid arthritis, ankylosing spondylitis,
Crohn's disease and psoriatic arthritis, sarcoidosis and to differentiate
sarcoidosis from Mycobacterium Tuberculosis.
Third, the curve analyses comparing ST2 marker to B type -natriuretic
peptide (BNP) amin terminal B-type natriuretic peptide (NT-pro BNP) and C
-RP for predicting death at 1 year after CHD showed a lower specificity of
C-RP that others markers of disease (Figure 1 adapted from Rheman and
colleagues)4
Finally in obesity patients the increase concentration of C-RP and
leptin was associated with measured risk of major cardiovascular events.
Crucially in a multivariate analysis leptin was an independent predictor
of cardiovascular disease whereas C-RP was not.
In summary we fill: i) currently available biomarkers in CHD have not
been much to helping us tailor our treatment, ii) a multi marker panel of
tests could be used to realize an algorithm to aid clinical-decision
making.
References
1.The Emerging Risk Factors Collaboration. C-reactive protein
concentration and risk of coronary heart disease, stroke, and mortality:
an individual participant meta-analysis- The Lancet 2009; 375:132-140
2.Ridker PM, Cook N. Clinical usefulness of very high and very low
levels of C-reactive protein across the full range of Framingham Risk
Scores. Circulation 2004; 109: 1955-1959
3.C Reactive Protein Coronary Heart Disease Genetics Collaboration
(CCGC) Association between C reactive protein and coronary heart disease:
mendelian randomisation analysis based on individual participant data. BMJ
2011; 342-d548
4.Rehman SU, Mueller T, Jannuzzi JL Jr. Characteristics of the novel
interleukin family biomarker ST2 in patients with acute heart failure. J
Am Coll Cardiol 2008; 28;52(18):1458-65
Competing interests: No competing interests