Received: 21 January 2018 | Accepted: 30 April 2018

DOI: 10.1002/jcp.26791

REVIEW ARTICLE

Serum C‐reactive protein in the prediction of cardiovascular

diseases: Overview of the latest clinical studies
and public health practice

Amir Avan1* | Seyedeh Belin Tavakoly Sany2,3* | Majid Ghayour‐Mobarhan1 |

Hamid Reza Rahimi1 | Mohammad Tajfard2,3 | Gordon Ferns4

1
Department of Modern Sciences and
Technologies, School of Medicine, Mashhad Cardiovascular disease is the most common cause of morbidity and mortality globally.
University of Medical Sciences, Mashhad, Iran Epidemiological studies using high‐sensitivity assays for serum C‐reactive protein
2
Social Determinants of Health Research
have shown a consistent association between cardiovascular disease risk and serum
Center, Mashhad University of Medical
Sciences, Mashhad, Iran C‐reactive protein concentrations. C‐reactive protein is a biomarker for inflammation,
3
Department of Health Education and Health and has been established in clinical practice as an independent risk factor for
Promotion, Faculty of Health, Mashhad
University of Medical Sciences, Mashhad, Iran
cardiovascular disease events. There is evidence that serum C‐reactive protein is an
4
Medical Education and Metabolic Medicine excellent biomarker of cardiovascular disease and is also an independent and strong
Head, Department of Medical Education, predictor of adverse cardiovascular events. Further characterization of the impact
Brighton and Sussex Medical School,
University of Brighton Falmer Campus, and influence of lifestyle exposures and genetic variation on the C‐reactive protein
Brighton, UK
response to cardiovascular disease events may have implications for the therapeutic
Correspondence approaches to reduce cardiovascular disease events. This review summarizes the
Mohammad Tajfard, Department of Health
studies that have examined the association between serum C‐reactive protein and
Education and Health Promotion, Faculty of
Health, Mashhad University of Medical the risk of cardiovascular disease. We also discuss the impact of independent factors
Sciences, Mashhad, Iran.
and C‐reactive protein genetic polymorphisms on baseline plasma C‐reactive protein
Email: tajfardm@mums.ac.ir
levels.
Funding information
Mashhad University of Medical Sciences, KEYWORDS
Grant/Award Number: IR 940306
angiography, cardiovascular diseases (CVD), C‐reactive protein (CRP), inflammatory biomarkers

1 | INTRODUCTION associated with complete or partial arterial thrombosis and athero-

sclerotic plaque rupture (Christiansen, 2017; Xu et al., 2008). CVD is
Cardiovascular disease (CVD) comprises coronary artery disease the major cause of death, disability, and financial burden in most
(CAD), stroke, congestive heart failure, carotid artery disease, and developed countries (Chandrashekara, 2014; Kelly et al., 2017).
peripheral artery disease (Nikpay et al., 2015). This disease is a Several clinical studies have identified a high correlation between
common manifestation of atherosclerosis, which has now been C‐reactive protein (CRP) levels and the severity of CAD in both
established as a chronic inflammatory disorder (Kelly, Scanlan, men and women (Chandrashekara, 2014; Idicula, Brogger, Naess,
McNally, Prichard, & Dodd, 2017; Nakou, Liberopoulos, Milionis, & Waje‐Andreassen, & Thomassen, 2009; Williams et al., 2008). The
Elisaf, 2008). CVD and the acute coronary syndrome (ACS) may be sera of patients with acute Streptococcus pneumonia infection formed

Abbreviations: ACS, acute coronary syndrome; AHA, American Heart Association; BMI, high body mass index; CDC, Centers for Disease Control and Prevention; CI, confidence interval; CRP,
C‐reactive protein; CVD, cardiovascular disease; FHS, Framingham heart study; HDL, high‐density lipoprotein; HR, hazard ratio; hs‐CRP, high‐sensitivity CRP; IMT, intima media thickness;
JUPITER, intervention trial evaluating rosuvastatin; LDL, low‐density lipoprotein; LDL‐C, low‐density lipoprotein cholesterol; LVH, left ventricular hypertrophy; NHANES III, National Health
and Nutrition Examination Survey; NOMAS, Northern Manhattan study; PAI‐1, plasminogen activator inhibitor‐1; PCI, percutaneous coronary intervention; PEACE, prevention of events with
angiotensin‐converting enzyme inhibition; PROVE IT‐TIMI 22, pravastatin or atorvastatin evaluation and infection therapy‐thrombolysis in myocardial infarction 22; RAH, resistant for arterial
hypertension; SNPs, single‐nucleotide polymorphisms; TNF‐a, tumor necrosis factor‐α.

*Avan and Tavakoly Sany contributed equally to this study.

8508 | © 2018 Wiley Periodicals, Inc. wileyonlinelibrary.com/journal/jcp J Cell Physiol. 2018;233:8508–8525.

AVAN ET AL. | 8509

a precipitin with an extract from the streptococcal bacterium. The attach to low‐density lipoprotein (LDL), and has been identified
extract was later confirmed as Fraction C and, as a result of its within the plaque, where it has been proposed to participate in the
reactivity with the C polysaccharide, the “substance” in the sera was inflammatory atherogenic processes (Deban et al., 2009; Everett
named CRP (M. Kaur, 2017; Mirhafez et al., 2016). A decade later, et al., 2006).
Oswald Avery and his research team described CRP as an “acute‐ This biomarker has several interesting features. It is an acute‐
phase reactant” that was increased in the sera of patients suffering phase protein that has been found to be a marker for infection,
from the inflammation and myocarditis associated with rheumatic increased in response to injury, systemic inflammation, and other
fever (Krams & Bäck, 2017). In 1950, other studies indicated that inflammatory stimuli (Alzalzalah, 2017; Burke et al., 2002; Chandra-
CRP concentrations consistently increased after myocardial necrosis shekara, 2014). The availability of hs‐CRP assays has supported CRP
and coronary ischemia (Krams & Bäck, 2017; Ridker, Rifai et al., as a strong biomarker in clinical practice because of its long half‐life,
1998). Despite these early findings, it was not until the 1990s that stability, ease of assay, and reproducible results (M. Kaur, 2017;
interest in the relationship between CRP and CVD was revitalized. In Shrivastava, Singh, Raizada, & Singh, 2015). CRP is predominantly
the mid‐1990s, immunoassays for CRP (high‐sensitivity [hs]‐CRP), synthesized in the liver in response to proinflammatory cytokines,
with greater sensitivity than those previously used routinely, especially interleukin IL‐1, IL‐6, and IL‐17, and tumor necrosis factor
revealed that high serum CRP concentrations predict future CVD (TNF)‐α (Chandrashekara, 2014; Shrivastava et al., 2015). It is also
(M. Kaur, 2017; Ridker, Buring, Shih, Matias, & Hennekens, 1998; produced by mature adipocytes and leukocytes a result of
Ridker, Rifai et al., 1998). inflammatory stimulation by lipopolysaccharide and TNF‐α (Bastard
CRP has been shown in several prospective, nested case– et al., 2006; Tsatsanis et al., 2005). CRP has the ability to enhance the
control studies to be associated with an increased risk of production of chemoattractant and adhesion molecules in endothelial
myocardial infarction (Christiansen, 2017; Ridker et al., 2000; cells (ECs), including monocyte chemoattractant protein 1 (MCP‐1)
Ridker, Rifai et al., 1998), stroke (Everett, Kurth, Buring, & Ridker, and soluble intracellular adhesion molecule‐1 (Lawson & Wolf, 2009;
2006; Idicula et al., 2009; Ridker, Buring et al., 1998), sudden Lespérance, Frasure‐Smith, Théroux, & Irwin, 2004; Ren, Khera, de
death from cardiac causes, and peripheral arterial disease Lemos, Ayers, & Rohatgi, 2017). Studies have shown that nonhepatic
(Chandrashekara, 2014; Nakou et al., 2008; Tavakoly Sany et al., cells (e.g., atherosclerotic plaques, neurons, monocytes, lymphocytes,
2015). Although the results of these studies are consistent, there and Kupffer cells) can produce CRP in very limited amounts
are limitations inherent in the design of nested case–control (Chandrashekara, 2014). Similarly, CRP is synthesized by epithelial
studies that make it difficult to assess the relative merit of CRP as cells of both renal epithelium (Jabs et al., 2005) and the respiratory
a risk marker. In particular, population‐based cut‐off points for tract (Huang, Chen, Wu, Wei, & Guo, 2013; Jabs et al., 2005) under
CRP remain uncertain, and reliable data describing receiver‐ certain circumstances. Coronary artery smooth muscle cells also
operating‐characteristic curves for CRP were not available appear to produce CRP upon stimulation by inflammatory cytokines
(Alzalzalah, 2017; Koenig, Khuseyinova, Baumert, & Mei- (Calabró, Willerson, & Yeh, 2003). Some studies have demonstrated
singer, 2008). that CRP is also produced at the site of the vessel wall and vulnerable
This review summarizes some of the latest data, which have plaque injured by percutaneous coronary intervention (PCI) to
examined the association of CRP variation with the risk of CVD activate oligodeoxynucleotide‐binding protein (Mac‐1) and restenosis
events to refute or support the role of CRP in CVD as a marker or a (Inoue et al., 2005; Meuwissen et al., 2006). These findings suggested
causal factor. We also discuss the impact of CRP genetic polymorph- that CRP levels may reach the maximum concentration in the plasma,
isms on plasma CRP levels and associations with the risk of CVD reacting to different inflammatory stimuli during infection or tissue
events. This review also summarizes current studies that have necrosis and decrease after the removal of inflammatory stimulus
examined the effect of several independent factors on plasma during an 18 hr half‐life (Jain, Gautam, & Naseem, 2011; Tonstad &
baseline CRP levels. Cowan, 2009).

2 | CRP C HA RA CTERISTIC A ND 3 | S E R U M CR P C O N C E N T R A T IO N S A N D
PRODUCTION T H E I R U SE I N D I S E A S E S T RA T I F I C A T IO N

CRP belongs to the pentraxin family of calcium‐dependent ligand‐ Surprisingly, in view of the range of the CRP response, speed, and
binding plasma proteins, composed of five identical nonglycosylated sensitivity, subjects in the general clinical studies tend to have
polypeptide subunits that has cyclic pentameric symmetry with a stable CRP levels, apart from occasional spikes, presumably
central core (Alzalzalah, 2017; Chandrashekara, 2014; Deban, related to systemic inflammation (Table 1; Schnell‐Inderst et al.,
Bottazzi, Garlanda, de la Torre, & Mantovani, 2009). Calcium atoms 2009; Shah et al., 2008). A large number of studies have shown
stabilize the integrity of the native pentamer and the structure of the that the median concentration of plasma CRP is 0.8 mg/L, the 90th
protomer (Deban et al., 2009; Magen et al., 2008). These atoms are centile is 3.0 mg/L, and the 99th centile is 10 mg/L in healthy
also essential for all physiological ligand binding by CRP. CRP may young adults (Mega et al., 2006; Pepys & Hirschfield, 2003). In the
T A B L E 1 Classification of serum CRP level based on recent clinical studies
8510
|

Study CRP classification (mg/L) Results

Coronary artery disease (CAD)
31 prospective cohorts Low risk: <1; moderate risk: 1–3; high risk: >3 Consistent association with CVD and CAD risk
(Shah et al., 2008) – CRP does not perform better than the Framingham risk equation
– Limited information to predict the risk of CAD events
German Institute of Medical hs‐CRP ranged from 0.7 to 2.47 – Independent association between hs‐CRP and CVD events that fell within the range of 0.7–2.47.
Documentation and Information – For patients with medium CVD risk 5%–20% in 10 years), hs‐CRP seems most likely to be
(DIMDI) (Schnell‐Inderst clinically relevant to support the decision as to whether or not additional statin therapy should
et al., 2009) be initiated for primary prevention
– Additional estimation of hs‐CRP level increases the incremental predictive value of the risk
prediction
253 ACS patients (Badran, Group 1: <45 years old,6.1 ± 1.2; Group 2: 45–65 – Young patients had different biochemical profiles and clinical, angiographic characteristics
Elnoamany, Khalil, & Eldin, 2013) years, 8.4 ± 2.9; Group 3: ≥65 years,11.5 ± 3.2 – Hs‐CRP was positively correlated to the severity of CAD only in the older group
– Hs‐CRP peak levels did not correlate with angiographic observation in the young patients
Heart and soul study Hospitalized: >3; baseline: ≤3 – In stable CAD, elevated CRP levels predict hospitalization independent of baseline heart failure,
(Williams et al., 2008) heart failure, CHD severity, subsequent MI events, and medication use
PROVE IT (Mega et al., 2006) hs‐CRP levels < 2 mg/L – Patients with hs‐CRP levels lower than 2 mg/L had fewer recurrent events
PEACE (Williams et al., 2008) hs‐CRP > 1 mg/L – hs CRP higher than 1 mg/L could be considered a significant predictor for adverse CVD events
1,444 patients in Brigham and Low: <1; moderate: 1–3; high: >3; mortality: >10 – In patients with ongoing ischemia, a preoperative CRP concentration more than 10 mg/L
Women's Hospital, Boston predicts mortality and morbidity after cardiac surgery
(Nakou et al., 2008) – These preoperative CRP concentrations ≤3 are associated with increased long‐term mortality
(5‐years) and extended hospital length of stay
– Patients without ongoing ischemia undergoing coronary artery bypass grafting
– In stable patients, prediction of mortality is unclear in lower values
Framingham heart study (Wilson Low: <1.00; moderate 1–2.99; high: ≥3.00 – CRP level in plasma could be used most effectively to estimate the risk for initial CVD events in
et al., 2008) The mean CRP is 2.28 for women and 2.67 for men patients with an intermediate risk of CVD events
– Offering moderate improvement in reclassification of risk
The women’s health study (Ridker, Mean (SD; mg/dl) Noncases: 2.8 (5.7); CAD cases: – No association between cardiovascular disease and Lp‐PLA2, although CRP was significantly
Buring et al., 1998) 3.3 (3.5) associated with disease incidence
Hypertension
Barzilai Medical Center Resistant for arterial hypertension (RAH): 6.9 ± 5.8; – RAH is associated with higher blood levels of complement C3 and CRP
(Magen et al., 2008) controlled (CAH): 4.2 ± 4.8

767 hypertensives patients Case group ≥ 2.54; control group = 0.4 – In Mongolian patients, increased CRP concentration was associated with hypertension, insulin
(Xu et al., 2008) resistance, and cigarette smoking
Others (Cottone et al., 2006; Y.S. – – In rural adults >50 years, hs‐CRP variation is not a risk factor for hypertension
Lee, Ryu, Park, Kang, & – TNF‐α and CRP are increased in endothelial activation and oxidative stress
Kim, 2005)
(Continues)
AVAN
ET AL.
TABLE 1 (Continued)
Study CRP classification (mg/L) Results
AVAN

Atherosclerosis
302 autopsies of men and women Acute rupture 3.2 hs‐CRP level; plaque erosion 2.9; CRP level significantly increased in patients with and without acute coronary thrombosis and
ET AL.

–
(Burke et al., 2002) stable plaque 2.5; controls 1.4 with severe CVD
– It correlates with numbers of thin‐cap atheroma and immune histochemical staining intensity
– hs‐CRP levels were most closely associated with independent risk factors, namely, smoking, BMI,
and age
(Nakou et al., 2008) Low: <1 hs‐CRP; average: 1–3; high: >3; >10 active – Strong predictive association between future atherothrombotic events (stroke, peripheral
inflammatory process arterial disease, and coronary events) and elevated hs‐CRP concentration in plasma
– hs‐CRP is identified as an independent predictor of diabetes
– hs‐CRP concentration in plasma serum may predict health outcome after myocardial infraction
Ischemic stroke
Bergen stroke study Geometric average value: – CRP level is associated with long‐term mortality and stroke severity when determined at least
(Idicula et al., 2009) Men 3.1 24 hr after onset
Women 3.7 – CRP levels is considered an independent predictor of long‐term mortality after ischemic stroke
– A crude association was observed between poor short‐term functional outcomes and elevated
CRP levels, which is likely a secondary symptom for stroke severity
– This association between elevated CRP levels and short‐term functional outcomes was not
significant after adjusting for confounding variables, such as stroke severity
– Elevated CRP levels were not associated with CVD events
Women’s health initiative Median value (mg/dl) Case group: 3.6; control – Multiple‐biomarker panels could be useful to stratify an individual's risk of stroke
observational study (R.C. Kaplan group: 2.6 – The importance of CRP for middle‐aged populations may be higher than that in older adults
et al., 2008)
Northern Manhattan study Median value for hs‐CRP: Prestroke 2.2; – Acutely hs‐CRP concentration increases, and Lp‐PLA2 mass and activity levels reduce after MI
(NOMAS; Elkind, Leon, Moon, poststroke 6.5; and stroke.
Paik, & Sacco, 2009) median 2.5 pre‐MI to 13.5 post‐MI – These variations show that estimations performed soon after MI and stroke may be less reliable
for long‐term risk stratification, and are not reflective of prestroke levels
Northern Manhattan study hs‐CRP > 3 mg/L: all‐cause mortality and risk of MI – Modestly associated with mortality and myocardial infarction
(NOMAS; Elkind et al., 2009) – Population characteristics may affect the value of hs‐CRP, such as age and other risk factors
15,632 initially healthy women hs‐CRP median control: 1.48; incident ischemic stroke: – hs‐CRP was a more potent biomarker of future ischemic stroke than CAD, whereas Lipid levels
who were followed for a 10‐year 2.85; incident CAD: 3.14 were associated more closely with CAD than stroke
period (Everett et al., 2006) – hs‐CRP is associated more closely with ischemic stroke than CAD
– Concomitant evaluation of hs‐CRP levels and lipid levels may improve risk assessment for CAD
and stroke
Other cardiovascular diseases (CVD)
287 incipient in lupus nephritis Without LVH: 3.93 (1.48–9.48); with LVH: 8.03 – CRP levels were independently associated with left ventricular mass index (LVMI), suggesting
patients in American College of (3.22–30.95) that estimation of hs‐CRP variation may provide practical clinical data to investigate (Lubrano &
Rheumatology (Shi et al., 2010) Balzan, 2015) left ventricular hypertrophy (LVH) in patient with lupus nephritis
(Continues)
|
8511
8512 | AVAN ET AL.

Note: CAH, congenital adrenal hyperplasia; CHD, coronary heart disease; CRP, C‐reactive protein; Lp‐PLA2, lipoprotein-associated phospholipase A2; MI, myocardial infarction; PEACE, prevention of events
acute‐phase stimulus (e.g., acute inflammation) within 6 hr, plasma

Self‐reported experiences of everyday discrimination are associated with higher CRP levels in

High CRP levels were associated with a significantly increased risk for both for all‐cause and
CRP levels increase from 50 µg/L to more than 500 mg/L within 48
hr, that is, 10,000‐fold 26 (Pepys & Hirschfield, 2003; Shrivastava
et al., 2015; Wilson et al., 2008). Importantly, acute‐phase CRP
values show no relationship to fasting state or diurnal patterns and
have a long half‐life. Subsequently, the plasma CRP levels return to
Additional measurement needed to evaluate the CRP variations over time

with angiotensin‐converting enzyme inhibition; PROVE IT, pravastatin or atorvastatin evaluation and infection therapy; SD, standard deviation; TNF‐α, TNF‐α tumor necrosis factor
very low reference values with the same speed (Shrivastava et al.,
2015). In plasma, the half‐life of CRP is around 19 hr and is
constant under various conditions in sick and healthy people. Thus,
hs‐CRP levels play an important direct role in atherothrombosis

the speed of production of CRP directly reflects the intensity of

pathological process and it is the only factor that can be used to
estimate CRP levels (Pepys & Hirschfield, 2003; Shrivastava
et al., 2015).
The hs‐CRP assay refers to a laboratory method that measures
the concentration of CRP in serum at low levels (Cottone et al., 2006;
Magen et al., 2008). Assays for hs‐CRP identified automated and
commercial CRP immunoassay systems with higher sensitivity than
before, which is a new development in clinical practice (R.C. Kaplan
older African‐American adults.

et al., 2008; Y.S. Lee et al., 2005).

The classification of serum hs‐CRP concentrations is as follows:
CVD‐related mortality

<1 mg/L are defined as low‐grade inflammation, which is a slight

increase in the baseline concentration of CRP; levels between
1 and 3 mg/L are moderately increased; and individuals with CRP
levels higher 3 mg/L and LDL cholesterol below 130 mg/dl are
Results

defined as being at high risk for future cardiovascular events

(Elkind et al., 2009; Ridker & Silvertown, 2008). Values above
–

–
–

10 mg/L are considered clinically active inflammatory states, such

as major trauma, chronic inflammatory diseases, and severe
hsCRP, low risk: <1; moderate risk: 1–3; high risk: >3

infection (Nakou et al., 2008; Shrivastava et al., 2015). These

classifications help to explain why those with arthritis, periodontal
disease, and other systemic inflammatory disorders all have a
Geometric average value (SD) 0.84 (5.52)

higher vascular risk.

4 | C L I N I C A L U S E O F CR P
CRP classification (mg/L)

In recent years, attention has been focused on the clinical utility of

Low: 0.3; high: ≥0.3

serum CRP because of the following reasons (Figure 1):

– A large prospective study documented that elevated CRP is

emerging as a clinical marker for many noncommunicable
diseases (i.e., ischemic stroke, CAD, hypertension, insulin
resistance, peripheral artery disease, and metabolic syndrome)
because it is very stable in plasma or serum with very marginal
296 older African‐American adults
(Lewis, Aiello, Leurgans, Kelly, &

Examination Survey (NHANES)

fluctuations, it has assay characteristics that are useful for

National Health and Nutrition

clinical use and more cost effective.

III (Simanek et al., 2011)

– It can be easily standardized, and measured with high

(Continued)

sensitivity to yield the same results in frozen, stored, or fresh

Silvertown, 2008)
PEACE (Ridker &

plasma, reflecting the stability of the protein (Brindle, Fujita,

Barnes, 2010)

Shofer, & O'Connor, 2010; Shrivastava et al., 2015). In addition,

TABLE 1

clinical trials and epidemiological studies have found that there

Study

is no significant difference and diurnal variation in the

distribution curve between women and men, and its
AVAN ET AL. | 8513

– Based on the considerable evidence of an expert panel

assembled by the American Heart Association (AHA) termed
CRP and the Centers for Disease Control and Prevention
(CDC), serum CRP levels were considered useful nonspecific
biochemical biomarkers of inflammation (Shrivastava et al.,
2015; Tully et al., 2015), which contributes significantly to (a)
screening of organic disease (Menees, Powell, Kurlander,
Goel, & Chey, 2015; Tibble, Sigthorsson, Foster, Forgacs, &
Bjarnason, 2002), (b) monitoring of the response to treat-
ment of infection and inflammation (Menees et al., 2015;
F I G U R E 1 Representation of CRP‐mediated effects on
Simanek et al., 2011), and (c) detection of inter current
atherosclerosis and CHD. CRP, C‐reactive protein; CVD,
infection (Tan et al., ).
cardiovascular disease; LDL, low density lipoprotein,
PAI, plasminogen activator inhibitor [Color figure can be viewed at
wileyonlinelibrary.com]
5 | T H E R O L E O F CR P I N C V D

serum concentrations are independent of ethnicity and age Elevated levels of hs‐CRP in plasma correlate with an increased risk
(Shrivastava et al., 2015; Xu et al., 2008). of cardiovascular events (Menees et al., 2015). In agreement with this
– A large number of in vivo and vitro studies have found that observation, the Canadian Cardiovascular Society, the National
serum CRP is a strong independent predictor of future CVD Academy of Clinical Biochemistry Laboratory Medicine, and the
risk and events (Alzalzalah, 2017; Gupta, Gupta, Gupta, AHA (CDC/AHA) suggested that CRP plays a pivotal role in many
Arora, & Gupta, 2013). The attention focused on CRP reflects aspects of CVD as described briefly below based on major clinical
a strong correlation between elevated plasma levels of CRP studies:
and the risk of future atherothrombotic events (Chandrashe-
kara, 2014; Wilson et al., 2008), including stroke (Elkind et al., 5.1 | Women’s health study
2009; Idicula et al., 2009), coronary events (Christiansen, 2017; The prospective data among apparently healthy middle‐aged
Shah et al., 2008; Shrivastava et al., 2015), and peripheral women showed that women with the highest baseline serum
arterial disease (Gupta et al., 2013; Inoue et al., 2005). CRP levels had a seven fold increase in the risk of stroke or
– Current knowledge suggests that serum hs‐CRP could be myocardial infraction (95% confidence interval [CI] 2.7–19.9;
useful to estimate the risk of plaque rupture (De Rosa et al., relative risk [RR] = 7.3; p = 0.0001) and a five fold increase in the
2017; Hong et al., 2011) and the vulnerability of the risk of any CVD events (95% CI 2.3–10.1; RR = 4.8; p = 0.0001;
atheromatous lesion (Libby, 2006; Zhong et al., 2015). In Ansell, 2005; Peng, Dong, & Wang, 2016). These studies noted
contrast, none of the other systemic markers of inflammation, that serum CRP is a strong independent risk factor to predict the
such as upstream cytokine mediators, sensitive acute‐phase risk of CVD than models limited to usual factors since CRP is able
proteins, negative acute‐phase proteins, or cruder multifactor- to predict CVD events even among women with no readily
ial measures, have such robust and desirable characteristics apparent markers for CVD (Filiberto et al., 2013; Peng et al.,
(Marks & Neill, 2007; Shrivastava et al., 2015). 2016; Ridker, Buring et al., 1998).
– Recent studies have shown that plasma CRP concentrations It is also of interest that the risks of CVD associated with CRP
predict the risk of the metabolic syndrome because compo- levels were lower for men than women (Ebong et al., 2016;
nents of the metabolic syndrome (i.e., central obesity, hyper- Shrivastava et al., 2015). This results reflect the effect modification
tension, low plasma concentrations of high‐density lipoprotein by sex. Although this appears to be the main result for previous
(HDL), increased plasma triglyceride concentrations, and studies, this could be due to differences in the methods of blood
increased concentrations of blood glucose) correlate with collection and CRP assay techniques, which were different from
increased plasma CRP concentrations (Hoogeveen et al., those in previous studies (Ebong et al., 2016).
2014; Shrivastava et al., 2015; Tully et al., 2015). A prospective population‐based study of apparently healthy
– Current studies suggested that exercise, weight loss, smoking postmenopausal women (n = 366) showed that hs‐CRP was
cessation, diet, and diabetes control also reduce serum CRP associated to LDL cholesterol (LDL‐C) (Nakou et al., 2008) and
levels (Church et al., 2010). Therefore, CRP levels could be concentrations might be a moderator of the contribution of hs-CRP
used as an inflammation fitness score to assess improvement of to CVD events (Kamath, Xavier, Sigamani, & Pais, 2015). The
CVD. Some medicines are associated with a reduction in serum Multi‐Ethnic Study of Atherosclerosis from 2000 to 2012 showed
CRP levels. These include statins, aspirin, thiazolidinediones, that Loge hs‐CRP was associated with cardiovascular risk in patients
thienopyridines, and angiotensin (AT)‐converting enzyme in- who had mean LDL‐C concentrations equal to 130 mg/dl or higher
hibitors (Ridker, Rifai et al., 1998; Shrivastava et al., 2015). (95% CI: 1.05, 1.60; hazard ratio [HR] = 1.29), but not in those with
8514 | AVAN ET AL.

LDL‐C concentrations less than 130 mg/dl (CI: 0.74, 1.05; HR = 0.88, and other confounders (Christiansen, 2017; Syvänen, Korhonen,
95%; p for interaction = 0.003; Blaha et al., 2011; Meysamie Jaatinen, Vahlberg, & Aarnio, 2011).
et al., 2017). Recent studies reported that elevated hs‐CRP level is an
A case–control study of postmenopausal women has indicated independent predictor of heart failure and long‐term mortality
that serum hs‐CRP is the strongest predictor of cardiovascular risk (Christiansen, 2017; Zhang et al., 2017). Also, they introduced hs‐
compared with homocysteine and other inflammatory markers, and CRP as a prognostic marker in patients with heart failure (Kamath
baseline lipid levels (Liu et al., 2014; Morrow & Ridker, 2000). Also, et al., 2015; Zhang et al., 2017). Recently, higher mortality was
hs‐CRP was the strongest predictor of cardiovascular risk even in found in patients with hs‐CRP levels >3 mg/L (Shah et al., 2008).
women with LDL cholesterol <130 mg/L (Kamath et al., 2015) and Similarity, the prevention of events with angiotensin‐converting
added prognostic information to the Framingham score (Kamath enzyme inhibition trial revealed that a higher serum hs‐CRP
et al., 2015; Ridker, 2007). concentration, even >1 mg/L, was associated with a higher risk of
It is noteworthy that a prospective study based on serum hs‐CRP myocardial infarction, stroke, and cardiovascular death in patients
demonstrated that women with metabolic syndrome were at greater with stable CAD (hs‐CRP 1–3 mg/L: adjusted HR = 1.39; 95% CI
risk for cardiovascular events (Devaraj, Singh, & Jialal, 2009). Several 1.06–1.81; p = 0.016; hs‐CRP >3 mg/L: adjusted HR = 1.52; 95% CI
epidemiological studies have concluded that obesity with metabolic 1.15–2.02; p = 0.003; Nakou et al., 2008; Shah et al., 2008). Data
syndrome seems to be associated with higher levels of CRP and from the Rotterdam Study based on a prospective population in
probably increase CVD risk (Tully et al., 2015). From these findings, women and men (>55 years old) showed a strong association
serum hs‐CRP was shown to be the most significant predictor of the between the incidence of heart failure and serum hs‐CRP levels in
risk of cardiovascular events in future (J. Kaur, 2014; Naik, Balaji, men with the HR = 3.73 (95% CI 2.40–5.78) (Kardys et al., 2006;
Ganjayi, & Reddy, 2015). Lewis et al., 2010). Similarly, a prospective population‐based study
Recent clinical studies examined the effects of hormone‐ demonstrated an association between cardiovascular mortality and
replacement therapy (HRT) on markers of cardiovascular risk in elevated hs‐CRP levels (>3 mg/L) in a large group of middle‐aged
postmenopausal women (Gooren, Wierckx, & Giltay, 2014). The men (n = 3,620; Kamath et al., 2015; Shrivastava et al., 2015).
estrogen replacement use increased hs‐CRP by 38% at 3 years Recent research suggests that the Reynolds Risk Score for men,
(p = 0.002) and 40% (p = 0.01) at 1 year (Gooren et al., 2014; which includes hs‐CRP, has significantly better ability to predict the
Ouyang, Michos, & Karas, 2006). Also, an HRT‐induced increase overall cardiovascular risk than traditional models (Kamath
was observed in the median concentration of hs‐CRP (54%) after et al., 2015).
12 months of treatment with tibolone (Bowden et al., 2006). Data from the carotid atherosclerosis progression study
Moreover, significant changes in hs‐CRP were associated with oral revealed a significant association between serum hs‐CRP levels
HRT after 3 months, whereas the hs‐CRP concentration remained and baseline carotid intima media thickness (IMT) in all carotid
unchanged after 3 and 12 months of treatment with transdermal segments (Blaha et al., 2011; Burke et al., 2002). However, this
HRT (Chocano‐Bedoya et al., 2014; Ouyang et al., 2006; Taşçı et al., association was no longer significant after controlling for cardio-
2014). This result may indicate that HRT may be promote CVD vascular risk factors, sex, and age (Kamath et al., 2015; M. Kaplan
(Gooren et al., 2014). However, a recent meta‐analysis concluded et al., 2014 ). Also, serum hs‐CRP was not related to individual IMT
that HRT decreases the risk of CVD events in young postmeno- progression. Also, the Cardiovascular Health Study has shown an
pausal women, whereas it increases, and then decreases risk over insignificant association between any CRP gene polymorphism and
time in older women (Noyce, 2017). carotid artery wall IMT (Lorenz, Karbstein, Markus, & Sitzer, 2007;
Zhang et al., 2017). Recent studies revealed that increased hs‐CRP
levels in patients with acute ischemic stroke are significantly
5.2 | Coronary artery diseases
associated with an increased risk of recurrent stroke or other
A recent study showed that serum CRP evaluation was useful for cardiovascular events (Kamath et al., 2015; Naik et al., 2015).
patients at intermediate risk of CAD compared with other Moreover, the proatherogenic actions of CRP were supported by
markers since CRP could predict the risk of CAD in first its detection in atherosclerotic plaque and its binding to very‐LDL
cardiovascular events from 10% to nearly 20% within a period and LDL (De Rosa et al., 2017; Shrivastava et al., 2015).
of 10 years (Lubrano & Balzan, 2015; Shi et al., 2010). Similarly, Inflammatory mechanisms play a pivotal role in all stages of
there is growing evidence that elevation of serum hs‐CRP levels atherosclerosis (Lubrano & Balzan, 2015; Shrivastava et al., 2015).
predicts a poor cardiovascular prognosis and clinical outcomes in CRP could be involved in all stages by directly influencing the
ACS and may be used to identify high‐risk patients for more atherosclerotic process, such as apoptosis, complement activation,
aggressive management with statins and antiplatelet agents (Kelly monocyte recruitment, vascular cell activation, thrombosis, and
et al., 2017; Nakou et al., 2008). Furthermore, higher serum hs‐ lipid accumulation (De Rosa et al., 2017; M. Kaplan et al., 2014).
CRP concentrations were positively correlated with peripheral CRP is present in the atherosclerotic lesion specifically in the
arterial disease independent of body mass index (BMI), waist vascular intima, where it colocalizes with lipoproteins, monocyte‐
circumference, smoking, serum total cholesterol, blood pressure, derived macrophages, and monocytes (M. Kaplan et al., 2014;
AVAN ET AL. | 8515

Nakou et al., 2008). CRP may play a role in many aspects of CVD Moreover, these results showed that all‐cause mortality was
and atherogenesis as explained briefly below: decreased by statins therapy (odds ratio 0.86; 95% CI 0.79–0.94),
as were coronary heart disease events (RR = 0.73; 95% CI 0.67–
• CRP increases macrophages' ability to make foam cells and 0.80), revascularization rates (RR = 0.62; 95% CI 0.54–0.72), and
enhances LDL uptake into macrophages (Meuwissen et al., 2006). stroke rates (RR = 0.78; 95% CI 0.68–0.89) (Nakou et al., 2008).
Also, CRP binds the phosphocholine of oxidized LDL (Shrivastava Available evidence demonstrated that statins therapy is likely to
et al., 2015). be a cost‐effective approach to improve quality of life in people
• CRP directly facilitates and amplifies innate immunity by activation with CVD risk (Nakou et al., 2008; Pagidipati et al., 2017).
of the classical pathway of the complement system; this action has Data from the cholesterol and recurrent events trial have
already been associated with the progression and initiation of CVD shown that serum hs‐CRP levels may reflect infarct size and
(Galkina & Ley, 2009). predict outcome after myocardial infarction. In randomized‐
• CRP has important antiatherogenic effects, such as expression of controlled trials, patients with acute myocardial infarction were
endothelial NO synthase (Gradinaru, Borsa, Ionescu, & Prada, assigned to placebo or pravastatin (40 mg/day); those with
2015). These effects include decreased vasoconstriction, smooth elevated hs‐CRP levels at baseline exhibited an increased risk of
muscle cell proliferation, and platelet aggregation (Gradinaru et al., recurrent coronary events (RR = 1.77; p = 0.02; Kamath et al.,
2015; Shrivastava et al., 2015). 2015; Ong et al., 2015).
• Activation of macrophages leads to secretion of a powerful A prespecified analysis of the reversal of atherosclerosis with
procoagulant and tissue factor, which increase dissemination of aggressive lipid lowering and the pravastatin or atorvastatin
intravascular coagulation and thrombosis in the inflammation evaluation and infection therapy‐thrombolysis in myocardial
process (Shrivastava et al., 2015). infarction 22 (PROVE IT‐TIMI 22) studies demonstrated that
• CRP can lead to the attraction of monocytes to the site of injury by lowering LDL‐C levels and lowering hs‐CRP levels in patients with
upregulation of the expression of adhesion molecules in ECs CVD by intensive statin therapy (randomized to atorvastatin
(Pfützner, Schöndorf, Hanefeld, & Forst, 2010). 80 mg/day vs. pravastatin 40 mg/day) attenuated the risk of
• CRP indirectly affects specific response of the immune system, cardiovascular events and atherosclerotic lesion progression
during atherogenesis, by increasing of IL‐12 from macrophages, (Nissen et al., 2005; Pagidipati et al., 2017). Specifically, PROVE
with the subsequent induction of interferon gamma production IT revealed that the patients at the highest risk were those in
and CD4+ T (mature T‐helper cells) lymphocyte differentiation whom both hs‐CRP (≥2 mg/L) and LDL‐C (≥70 mg/dl) concentra-
(Calabro, Golia, & Yeh, 2012). tions were elevated despite statin therapy (Kostapanos & Elisaf,
• CRP increases the expression and activity of plasminogen activator 2011). Patients whose hs‐CRP concentration remained elevated
inhibitor‐1 (PAI‐1); through this action, PAI‐1 regulates fibrinolysis. (≥2 mg/L) but LDL‐C was reduced to <70 (A.V. Khera et al., 2015)
High levels of PAI‐1 decrease fibrinolysis and thus lead to had the same recurrent event rates as those whose LDL was
atherogenesis (Cesari, Pahor, & Incalzi, 2010). ≥70 mg/dl but hs‐CRP levels were lowered to <2 mg/L. Patients
with both low LDL cholesterol and hs‐CRP concentrations had the
lowest risk (Nakou et al., 2008; Ridker, Rifai et al., 1998).
5.3 | Statin therapy
Data from the myocardial ischemia reduction with aggressive
An Intervention Trial Evaluating Rosuvastatin (JUPITER) study cholesterol lowering studies have shown that the use of atorvastatin
showed that statin therapy (from 20 mg/day to 80 mg/day) is treatment with a high dose (80 mg/day) during 24–96 hr for
effective in the primary prevention of CVD events among patients non‐Q‐wave myocardial infarction or unstable angina was associated
with elevated hs‐CRP levels (>2 mg/L) and below average concentra- with a greater reduction in hs‐CRP and ultimately ischemic events
tions of LDL cholesterol levels (<130 mg/dl; Nakou et al., 2008; after 16 weeks in comparison with placebo (B.‐K. Lee et al., 2016;
Wong, 2009). In these clinical trials, unequivocal evidence of a Schwartz et al., 2001; Wong, 2009). Data from recent studies have
reduction in cardiovascular mortality and morbidity was observed showned a significant reduction in hs‐CRP levels after statin
among patients who received rosuvastatin compared with those who treatment, which were inversely correlated with the rate of disease
received placebo. Also, the rates of CVD events RR were significantly progression in patients with CAD (Pagidipati et al., 2017;
increased in relation to the elevated hs‐CRP levels at baseline Wong, 2009).
(Kavsak et al., 2007; Yusuf et al., 2016). Rosuvastatin reduced hs‐CRP to a greater extent compared with
Data from randomized‐controlled trials have shown that statin placebo, but rosuvastatin did not decrease the incidences of nonfatal
therapy reduces hs‐CRP levels significantly from baseline until stroke, nonfatal myocardial infractions, and cardiovascular deaths
24 weeks (Kavsak et al., 2007; A.V. Khera et al., 2015; Nakou et al., (Kjekshus et al., 2007; Nakou et al., 2008; Pagidipati et al., 2017).
2008). In all trials, LDL cholesterol and total cholesterol were However, in the same trials, rosuvastatin significantly decreased the
independently reduced, but the change in hs‐CRP levels was rate of cardiovascular hospitalizations and it did not decrease the
unrelated to LDL‐C (Albert, Danielson, Rifai, Ridker, & PRINCE primary outcome (Kjekshus et al., 2007; Nakou et al., 2008). These
Investigators, 2001; Taylor et al., 2013; van Wissen et al., 2002). results may indicate no direct association between reduction of
8516 | AVAN ET AL.

hs‐CRP by statin therapy and primary outcomes for patients with seven haplotype‐tagging SNPs were evaluated, including rs3091244,
heart failure (Kjekshus et al., 2007) rs309358, rs1800947, rs2808630, rs1417938, rs3093066, and
rs1205, and a strong association was found between CRP levels
and CRP haplotypes (Danila et al., 2015; Zhang et al., 2017). Also,
5.4 | Angiography
other large‐scale studies, including the National Health and Nutrition
PCI with stent implantation is a mainstay in the management of Examination Survey (NHANES III), the Framingham heart study
severe coronary artery atherosclerotic disease (Ahmed et al., 2016; (FHS), and the third National Health, reported strong associations
Mincu, Jánosi, Vinereanu, Rassaf, & Totzeck, 2017). Indeed, PCI between plasma CRP levels and CRP genotypes (Lawlor et al., 2008;
currently outperforms coronary artery bypass grafting, and the use Shen & Ordovas, 2009). Thus, it is seems that individuals carrying
of interventional procedures is projected to increase even more with certain CRP alleles associated with higher CRP expressions are at a
the adoption of new‐generation drug‐eluting stents (Badran et al., higher risk for CVD (Nimptsch et al., 2015; Schulz et al., 2016).
2013; Nazeminezhad et al., 2014; Wada et al., 2017). Several studies Although data from experimental models and in vitro observations
have examined the prognostic role of CRP levels after elective or confirm the impact of functional genetic variants of CRP, their value
emergent PCI with a positive prognostic impact (Almagor, Keren, & as predictors for further CVD events is unclear (Schulz et al., 2016;
Banai, 2003; Gach et al., 2007; Zairis et al., 2002). On the other hand, Zhu, Liu, He, Sun, & Zhuo, 2013).
other interventional studies failed to show a significant correlation On the basis of epidemiological observations, the association
between CRP levels and recurrent events or restenosis after elective between CRP functional genetic polymorphisms and CVD events
or emergent PCI (Almagor et al., 2003; Bafadhel, Kishk, & Yousef, might be affected by confounding and reverse causation, which may
2013; Youssef et al., 2012). Data from recent studies have shown a potentially bias the results of studies (Casas et al., 2006; Heikkilä,
significant reduction in hs‐CRP levels after statin treatment (Badran Ebrahim, & Lawlor, 2007). Recent developments in the genetic
et al., 2013; Ding, Hu, Wu, & Tomlinson, 2015), which were inversely dissection provide new options and treatment strategies to determine
correlated with the rate of disease progression in patients with CAD the impact of the CRP genotype on disease development by taking
(Almagor et al., 2003; Nakou et al., 2008; Wada et al., 2017). advantage of the “Mendelian randomization” (Casas et al., 2006;
There is evidence that hs‐CRP level is an independent predictor Interleukin‐6 Receptor Mendelian Randomisation Analysis Consor-
of the occurrence of restenosis after coronary artery stenting tium, 2012). This method was used to gain insight into the true nature
(Badran et al., 2013; Ding et al., 2015). Similarly, in patients with of associations between the CRP polymorphism and health outcomes
stable angina pectoris, elevated hs‐CRP concentration after PCI (Figure 2). In this respect, several large‐scale cohort studies have
could be a strong predictor for long‐term adverse cardiac events. evaluated the effect of CRP SNPs on CRP concentrations in patients
Moreover, there is evidence for a strong association between high with CVD disease (Casas et al., 2006; Danila et al., 2015; Interleukin‐6
preoperative hs‐CRP concentration and long‐term risk of cardiovas- Receptor Mendelian Randomisation Analysis Consortium, 2012).
cular events in patients who undergo coronary artery bypass grafting On the basis of in vitro observations, a CRP concentration
(Ansell, 2005; Badran et al., 2013; Ding et al., 2015; Wada ≥5 mg/L and CRP SNP rs1800947 were independent risk factors for
et al., 2017) CVD events in patients of Caucasian origin from Central Germany
(3‐years of follow‐up) (Chandrashekara, 2014). Similarity, in an Italian
population, the SNP rs1800947 of the CRP gene led to a higher risk
5.5 | Functional genetic variants of CRP
for CVD events after 2 years of follow‐up (Danila et al., 2015). In a
The cardiovascular health study showed that polymorphisms in the Russian population, CC genotype carriers of SNP rs1130864
CRP gene could be associated with CRP synthesis and CVD events experienced a higher CVD risk after 2 years of follow‐up (Barsova
(Shen & Ordovas, 2009). Twin and family studies revealed that the et al., 2015). Results from the from large cohort study of CVD risk in
genetic variation impact 40% of the variance in plasma CRP levels African American and European American young adults detected
(Chandrashekara, 2014; Schulz et al., 2016). Several tagging single‐ four tag SNPs that were genotyped in a white (European American)
nucleotide polymorphisms (SNPs) were described to be associated
with circulating CRP levels in plasma (Ancelin et al., 2015; Schulz
et al., 2016). Data from the study of three cohorts, including the
physicians’ health study, the pravastatin inflammation/CRP evalua-
tion trial, and women’s health study, have shown that a set of CRP
SNPs, including intron 1 SNP, rs1417938; two promoter SNPs,
rs3091244 and rs3093059; exon 2 SNP and rs1800947; and two
three prime untranslated region (3′‐UTR) SNPs, rs1205 and
rs1130864, were significantly associated with plasma CRP levels in
F I G U R E 2 Casual association of circulating CRP levels, CRP
all study cohorts (Shen & Ordovas, 2009; Vinayagamoorthy et al., genetic variants with CVD events. CRP, C‐reactive protein; CVD,
2014). This result in agreement with data from a large cohort study in cardiovascular disease [Color figure can be viewed at
African American and European American young adults. In this study, wileyonlinelibrary.com]
AVAN ET AL. | 8517

population and a black (African American) population, aged 65 years moderate relationship between hs‐CRP and HDL‐C, thyroglobulin
or older (Casas et al., 2006; Zhang et al., 2017). The 790T and 1919T (TG), and BMI (Ishii et al., 2013). In a study carried out by Rana et al.
tag SNPs were associated with elevated hs‐CRP concentrations in (2007), changes in plasma CRP showed a positive association with
black and white participants, respectively. The 2667C allele was waist circumference and BMI in both men and women. Recent
associated with lower CRP concentrations in white participants, studies showed that obesity, a low‐grade inflammation state, results
whereas the 3872A allele was associated with lower CRP concentra- from the release of chemokines, cytokines, and hormone‐like factors
tions in both participants (Lange et al., 2006; Vinayagamoorthy et al., (Nehete, Magden, Nehete, Hanley, & Abee, 2014; Ramos‐Nino, 2013).
2014). The 1919T allele was significantly associated with an Enhanced adipose mass is linked to increases in inflammatory
increased risk of stroke and CVD mortality in the white population, molecules, such as CRP, IL‐6, TNF, resistin, migration inhibitory
whereas the 790T allele was associated with a four fold increased factor, serum amyloid A, and inducible nitric oxide synthase (Luo
risk of myocardial infarction in black participants. The 2667C and et al., 2016; Ramos‐Nino, 2013; Yang et al., 2017). Adipose tissue
3872A alleles were associated with a decreased risk of CVD produces approximately 25% of the total circulating IL‐6. In obese
mortality in older adults (Danila et al., 2015; Lange et al., 2006). individuals, adipose tissue is developed by increasing the number of
However, the results were controversial as other cohorts, including macrophages, which is the most important source of increase in the
the NHANES III and the FHS, showed no or little association between circulating inflammatory molecules in obesity (Bleau, Karelis, St‐
the CRP genotype and the risk of CVD events (Cupples et al., 2007; Pierre, & Lamontagne, 2015; Haneklaus & O'Neill, 2015).
McManus et al., 2013). Moreover, using the same approach, others
found that although CRP concentrations in plasma are associated
6.2 | Physical activity
with a common CRP polymorphism, there was no association with
the CVD events and genotype (Danila et al., 2015; Lange et al., 2006; Physical inactivity is highly associated with increased concentrations of
Mahmood, Levy, Vasan, & Wang, 2014; Tsao & Vasan, 2015). inflammatory markers and with CAD risk. Evidence has recently
Several factors influence the interpretation of these results, such indicated a relationship between a decrease in physical activity and
as the proportion of variability of CRP levels (CRP locus), RR of CVD an increased CAD risk in males (20%) and females (36%; Shen &
disease, small sample sizes, sex, age, and stages of disease (Elliott Ordovas, 2009). In some epidemiological studies, health evaluations of
et al., 2009; Osman, L’Allier, Elgharib, & Tardif, 2006). In summary, elderly men and women, athletes, and middle‐aged men have shown an
considerable evidence has shown a significant association between inverse relation between CRP and physical activities (Kasapis &
the baseline plasma CRP levels and CRP polymorphisms; however, Thompson, 2005; Loprinzi, 2015). Unfortunately, different statements
the genetic association with the risk of CVD outcomes is equivocal were reported about a lifestyle practices (e.g., exercise). In fact, the data
despite the fact that CRP levels are a strong independent predictor are usually classified in different ways without any standardized
of CVD (Elliott et al., 2009; Lange et al., 2006; Vinayagamoorthy methodology. For instance, the effect of physical activity level in one
et al., 2014). In this respect, further studies are needed to provide study may be categorized as moderate, but as light in a different study.
compelling evidence to evaluate the casual association of circulating Moreover, self‐reported physical activity differs from measured physical
CRP levels and CRP genetic variants with CVD events. fitness. On the other hand, the presence of subgroups in a broader class
also makes it difficult for investigators to interpret the data (Kasapis &
Thompson, 2005; Loprinzi, 2015). For example, physical activity can be
6 | CRP A ND L I FESTYLE RISK F ACT O RS classified into relaxing time and professional activity. Furthermore, even
the types of physical activity (e.g., resistance or flexibility training, and
Recent clinical evidence identified several lifestyle risk factors that aerobic exercise) differ from each other. On the other hand, the CRP
affect CRP levels in plasma as described briefly below: concentration was lower in physically active people than in those who
were physically inactive and among alcohol drinkers than nondrinkers
(Kasapis & Thompson, 2005; Plaisance & Grandjean, 2006).
6.1 | Overweight and obesity
High BMI is significantly correlated with high CRP levels in the
6.3 | Diabetes
plasma. Also, overweight and obese individuals have higher CRP
concentrations compared with normal‐weight or lean individuals One of the other remarkable features of hs‐CRP (especially in high
(Shen & Ordovas, 2009). Increased levels of hs‐CRP are linked to levels) is its strong and independent correlation with type II diabetes
BMI, insulin, homeostatic model assessment, and intact proinsulin (Asemi, Zare, Shakeri, Sabihi, & Esmaillzadeh, 2013; Schernthaner et al.,
(Onuma et al., 2016; Park, Park, & Yu, 2005). The relationship 2017). Increased levels of hs‐CRP are a significant predictor for the
between BMI and CRP was more powerful than the relationship future diagnosis of metabolic syndrome and type II diabetes and remain
between any other continual variable involving measured lipid risk effective even after considering smoking, family history of diabetes
factors and age with CRP (Houde et al., 2015; Ishii et al., 2013). This mellitus, BMI, and other factors (Gurven et al., 2016; Martín‐Timón,
correlation was stronger in women in comparison with men (Houde Sevillano‐Collantes, Segura‐Galindo, & del Cañizo‐Gómez, 2014).
et al., 2015). Otsuka et al. (2008) showed that there is a relatively Moreover, it has been indicated that there is an involvement of high
8518 | AVAN ET AL.

hs‐CRP with cardiovascular morbidity and mortality in people with concentrations, but African‐Americans, South Asians, and Hispanics
these diseases (Gurven et al., 2016; Martín‐Timón et al., 2014). showed the highest concentrations (Fonseca & Izar, 2016; Ford et al.,
In a diabetes study conducted in Mexico city, it was shown that 2003; Nazmi & Victora, 2007). The level of CRP in African‐Americans
baseline hs‐CRP is considerably correlated with the progression of the was higher than that in white individuals (median, 3.0 vs. 2.3 mg/L;
metabolic syndrome. It was also shown that the CRP concentration in p < 0.001), whereas white women, African American women, and black
women, smokers, and people with diabetes was higher than that in men, men, all had higher CRP levels in comparison with white men, and the
nonsmokers, and those without diabetes, respectively (Fonseca & Izar, highest levels were observed among black women. Furthermore, the
2016; Schernthaner et al., 2017). In addition to being an independent reviews showed that the range of hs‐CRP differs in various ethnicities
predictor (in its low‐level increases) of future cardiovascular events, and groups (Nazmi & Victora, 2007; Uchino et al., 2016).
CRP can predict diabetes incidence and hypertension risk (Bowden
et al., 2006; Gurven et al., 2016; Schernthaner et al., 2017).
6.7 | Diet
There are data demonstrating that diets are positively associated with
6.4 | Tobacco use
high saturated and trans‐fatty acids and biomarkers of inflammation,
Considerable clinical evidence has shown that smoking is associated such as CRP (Shen & Ordovas, 2009). Also, recent studies have shown
with increased levels of IL‐6, TNF‐α, and CRP. Based on a large that a high omega 6/omega 3 ratio accelerates cardiovascular and
population‐based study, there is an independent and strong dose– inflammatory diseases, and increased levels of omega 3 fatty acids
response relationship between cigarette smoking and CRP (Wendling exert inhibitory effects (Shivappa et al., 2014). Many interventions that
et al., 2016, 2017). In fact, cigarette smoking is associated with are known to decrease cardiovascular risk are linked to lower levels of
elevated values of CRP (Wendling et al., 2016). However, CRP has CRP; specifically, weight loss, physical activity, diet, and giving up
been reported to be significantly elevated 10–19 years after smoking smoking all result in declined vascular risk and reduced levels of CRP
cessation, which suggests a continuing low‐grade inflammatory (Kasapis & Thompson, 2005; Loprinzi, 2015).
response in former smokers (Tonstad & Cowan, 2009). Also, most
of the other (noninflammatory) smoking‐induced changes are
6.8 | Sex
reversible after giving up smoking. According to categorical variables,
elevated baseline CRP was related to the status of smoking as ex‐ Blacks and females had higher levels of CRP, and this correlation was
smokers and recent smokers had higher CRP compared with the greater in women in comparison with men. The level of CRP in black
nonsmokers (Tonstad & Cowan, 2009; Wendling et al., 2017). individuals was higher than that in white individuals (median, 3.0 vs.
2.3 mg/L; p < 0.001) and the CRP level of women was higher than that
in men (median, 3.3 vs. 1.8 mg/L; p < .001; Doran et al., 2013;
6.5 | Alcohol
A. Khera et al., 2005). The relationship between obesity, IL‐6, and
In recent years, an association between CRP concentrations with CRP was related more to the blood pressure in women; however, this
alcohol consumption has been proven. It has been shown that was not observed in smokers (A. Khera et al., 2005; Peng et al., 2016).
moderate consumption of alcohol is associated with reduced CRP In women with cardiovascular events, levels of CRP have been found
levels (Albert, Glynn, & Ridker, 2003; Imhof et al., 2001). In a study, to be higher compared with control subjects (Doran et al., 2013).
Albert et al. (2003) reported the median CRP values to be 2.60 mg/L
and 1.6 mg/L in those consuming less than one drink per month and
6.9 | Cancer development
those consuming 5–7 drinks per week, respectively. Furthermore, a
slight increase in CRP (1.8 mg/L) was observed in those consuming CVD and cancer are the two leading causes of chronic disease and
more than two drinks daily. On the other hand, the CRP concentra- death worldwide (Hashimoto, 2016; Heikkilä et al., 2009). These
tion was lower in physically active people than in those who were diseases have various possible delicate interactions and similarities,
physically inactive, and among alcohol drinkers than nondrinkers including similar risk factors, supporting a shared biology for which
(Albert et al., 2003; Shivappa et al., 2014). there is emerging evidence (Koene, Prizment, Anne Blaes, & Konety,
2017). The extensive overlap in disease prevention and risk factors
for cancer and CVD shows that both diseases have some common
6.6 | Racial/ethnic
basic molecular networks or pathways. In developed countries,
Socioeconomic and racial/ethnic factors strongly influence CVD environmental and lifestyle risk factors have been associated with
outcomes and risk factors. CRP level is associated with cardiovascular four most common malignancies (lung, colorectal, breast, and
risk, and knowledge about its distribution in the population may help prostate cancer; Koene et al., 2017; Nöthlings, Ford, Kröger, &
direct preventive efforts. In 2003, the AHA/CDC panel recommended Boeing, 2010). The World Health Organization reported that more
a significant need to study ethnic differences in CRP concentrations than 30% of incidences of CVD and cancer deaths could be
(Doran, Zhu, & Muennig, 2013; Nazmi & Victora, 2007). Based on prevented by following a healthy lifestyle, including a healthy diet,
population‐based studies, most white individuals had the lowest CRP no smoking, physical activity >3.5 hr weekly, and BMI < 3.5 (WHO,
AVAN ET AL. | 8519

2015). Furthermore, the results from the large number of epidemio- observation suggests that the CAD process is characterized by
logic studies demonstrate that controlling CVD risk factors can help increasing levels of biomarkers of inflammation. Many clinical studies
reduce the risk of incident cancer over time (Koene et al., 2017; have focused on CRP variations in the plasma to improve global
Nöthlings et al., 2010; Rasmussen‐Torvik et al., 2013). Thus, under- cardiovascular risk prediction.
standing the delicate interaction between cancer and CVD in These studies showed that CRP is not only an excellent
different populations may lead to earlier detection, better preven- biomarker or mediator of atherosclerosis and CVD but it also
tion, and a safer treatment strategy. independently and strongly predicts adverse cardiovascular events,
Chronic inflammation appears to be major a unifying biological including ischemic stroke, myocardial infarction, and sudden cardiac
mechanism in the pathogenesis and progression of both CVD and death, in individuals. The commercial availability of CRP can lead to
cancer, and occurs in common conditions, such as hyperglycemia, the development of high‐sensitivity screening for this marker as it is
obesity, diabetes, hypertriglyceridemia, and hypertension (Heikkilä reliable, reproducible, and simple, and can be applied as a clinical
et al., 2009; Koene et al., 2017), and this may, in part, demonstrate guide for the management, prognosis, and diagnosis of CVD.
why cancer and CVD share several risk factors. Recently, accumulating The reported impact of CRP gene polymorphisms on CVD events
evidence has reported that chronic inflammation is associated with the provides some support for strong epidemiological associations
severity and progression of many cancers, and may also play a causal between CRP and CVD events. However, these associations might
role in carcinogenesis and malignant transformation of cells (Nelson be affected by confounding or reverse causation. On the basis of the
et al., 2013). Considerable circumstantial and factual evidence has Mendelian randomization method, the confounding impacts of
shown that inflammation‐associated oxidative damage is linked to environmental exposure might be overcome since the associations
carcinogenesis by inactivating mutations in tumor‐suppressor genes and between specific gene polymorphisms and CVD events are not
modifying posttranslational in proteins involved in apoptotic control or commonly susceptible to confounding and reverse causation.
DNA repair (Heikkilä et al., 2009). Similarly, inflammatory enzymes, Lifestyle factors also affect the variation in CRP levels, and there
transcription factors, and cytokines promote the proliferation and is support for the notion that lifestyle factors may interact to define
growth of cancer cells, and inhibit apoptosis. In addition, the activation this complex trait. Therefore, further characterization of the
of inflammatory pathways could promote vascular permeability, interaction and influence of lifestyle factors and genetic variations
angiogenesis, and cell motility, therefore facilitating progression of on the CRP response to CVD events may have major implications for
many tumors (Koene et al., 2017; Zhu et al., 2013). the development of more therapeutic approaches and personalized
Therefore, recently, a large number of studies have focused on preventive to reduce CVD events.
circulating biomarkers of inflammation to predict tumor recurrence
and treatment response. They demonstrated that the presence of a
AC KNO WL EDG M EN TS
systemic inflammatory response, as evidenced by an elevated IL‐6
levels and an elevated CRP level, is associated with an increased risk This research was sponsored by Mashhad University of Medical
of prevalent cancer, including lung, breast, ovarian cancers, and Sciences. The author thanks the vice president of research at
possibly colorectal, but unrelated to prostate cancer risk (Hashimoto, Mashhad University of Medical Sciences.
2016; Heikkilä et al., 2009).
Several investigations have reported that these cancer cells
CON F LI CTS OF I NTERE ST
produce CRP, and it stimulates the differentiation and growth of
some malignant cells. Similarly, population‐based investigations have The authors contributed equally to this work. All authors have read
indicated that patients with cancer tend to have higher circulating and approved the final manuscript. The authors declare that they have
CRP concentrations than healthy individuals (Heikkilä et al., 2009). no competing interests. This work was supported by the Mashhad
However, it is still unclear whether circulating CRP concentrations University of Medical Sciences under Grant number (IR 910705).
play causal roles in malignancy because CRP is a nonspecific marker
of many diseases, and the biological processes involved in the
malignant development in different organs may be different (Heikkilä ORCI D

et al., 2009; Koene et al., 2017). Therefore, individual association Amir Avan http://orcid.org/0000-0002-4968-0962
studies need to examine the causal role of CRP as inflammation
biomarkers with different cancer types to provide robust biological
R E F E R E N CE S
evidence for a causal relationship.
Ahmed, M., Chowdhury, N. A., Rahman, A., Rahman, M., Amin, M. G.,
Jannat, S., & Mollah, R. I. (2016). Elevated plasma high sensitivity
7 | CONC LU SION S C‐reactive protein (hs‐CRP) level is a predictor of periprocedural
myocardial injury during percutaneous coronary intervention (PCI).
Bangladesh Heart Journal, 30(1), 5–12.
CVD is the leading cause of disability and death in humans, and is Albert, M. A., Danielson, E., Rifai, N., & Ridker, P. M. (2001). Effect of statin
increasing in incidence rapidly in the developing world. Recent therapy on C‐reactive protein levels: The pravastatin inflammation/
8520 | AVAN ET AL.

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