C-reactive Protein CRP

C-reactive protein is an acute phase reactant that is stimulated by IL-6, produced in the liver and subsequently secreted into the bloodstream in response to any type of viral or bacterial inflammation, coronary artery disease, rheumatoid arthritis, many cancers.

It has been estimated, by the comparison of monozygotic and dizygotic twins, that there is a 52% heritable risk, with results of genetic testing of CRP being suggestive of t identification of an individual’s CRP SNPs may well  be a practical and useful clinical approach for prediction of cardiovascular event risk. (1)

  • C-reactive protein (CRP) encoded by CRP gene is a reflection of systemic inflammation
  • CRP-level-associated polymorphism rs1205 within the CRP gene is associated with 2-hour glucose level: The SAPPHIRe study
  • Evidence shows that certain subtle variations in the CRP gene sequence, mostly single nucleotide polymorphisms, predictably and strongly influence the blood level of CRP
  • Association of Polymorphisms in the CRP Gene With Circulating C-Reactive Protein Levels and Cardiovascular Events
  • Genetic polymorphisms in C-reactive protein increase cancer susceptibility
  • SNP studies also show that the content of inflammatory markers (IL-6, CRP, and α2-microglobulin) would be influenced by the interaction between polymorphisms within metabolic pathways
  • CRP polymorphisms and DNA methylation of the AIM2 gene influence associations between trauma exposure, PTSD, and C-reactive protein
  • The presence of a mucosal cytokine response was first observed in UTI. Interleukin (IL)-6 is secreted by uroepithelial cells and acts as an endogenous pyrogen, activates hepatocyte CRP production and stimulates mucosal B cells to produce IgA antibodies
  • CRP polymorphisms and chronic kidney disease in the third national health and nutrition examination survey
  • Results are very suggestive that heritability of lung function is at least partly controlled by the CRP gene. Applying a Mendelian randomisation approach, the study supports a causal association between low-grade general inflammation and airway diseases
  • High Sensitive C – Reactive Protein as a Marker for Inflammation in Irritable Bowel Syndrome

A cross-sectional study consisting of 945 siblings from 330 families collected by the Stanford Asian Pacific Program in Hypertension and Insulin Resistance (SAPPHIRe) investigated associations between CRP polymorphisms, circulating CRP, diabetes, and glucose levels

Circulating CRP is significantly associated with diabetes and glucose levels, and amongst genes associated with those findings, the CRP gene has exhibited the strongest effect.  CRP is a general marker of systemic inflammation, and is associated with increased risks of mortality in diseases including diabetes, hypertension, coronary heart disease, and stroke. (2) Findings from a 2017  cross-sectional study consisting of 945 siblings from 330 families collected by the Stanford Asian Pacific Program in Hypertension and Insulin Resistance (SAPPHIRe) concluded a positive correlation between CRP gene and glucose intolerance, with fasting and two hour glucose levels being major clinical measurements in the onset of Diabetes Type II.  (3) Although, collectively, lifestyle factors, cigarette smoking, dietary habits influence risk factors for cardio-vascular events and diabetes, Shen et al. for example, showed that several CRP SNPs are associated with serum CRP levels in patients with metabolic syndrome. (4)

C-Reactive Protein Gene Polymorphisms, C-Reactive Protein Blood Levels, and Cardiovascular Disease Risk

CRP has been shown to be a powerful and specific predictor of cardiovascular event risk in otherwise healthy populations.  (5)

Recent studies have shown that the interindividual variations in CRP levels not only reflect environmental cues but are also a consequence of the genetic variation in the CRP gene itself.  Studies demonstrate that CRP activates monocytes, endothelial cells, vascular smooth muscle cells, which in turn lowers nitric oxide levels and increases angiotensin II signalling and plasminogen activator inhibitor-1 and endothelin-1 activity revealing the proatherogenic, prothrombotic, and pro endothelial contribution of CRP.  Evidence shows the presence of CRP in vascular lesions and local production of the protein therein. 

CRP is known to promote arterial thrombosis, accelerates atherosclerosis, induces endothelial dysfunction, and exacerbates vascular injury response. 

During an acute response, Interleukin 6 (IL-6) stimulates production of CRP, with a resultant rise of 1,000 fold within 24 hours.

One of the first associations of CRP gene variants, and CRP serum levels was reported with SLE – Systemic Lupus Erythematosus,   and strongly linked with SLE risk.  (6)

C-reactive protein (CRP) is an inflammation protein that may play a role in the pathogenesis of cardiovascular disease (CVD).

A prospective, population-based Cardiovascular Health Study, 4 tag single-nucleotide polymorphisms (SNPs)  over 3941 European American along with  5 tag SNPs (addition of 790A/T) were genotyped in 700 black (African American) participants, aged 65 years or older, all of whom were without myocardial infarction (MI) or stroke before study entry. Median follow-up was 13 years (1989-2003) deduced that variations in the CRP gene are associated with plasma CRP concentration along with CVD risk in older adults. (7)

Genetic polymorphisms in the CRP gene are associated with an increased overall risk of cancer. Subgroup analyses by ethnicity and cancer type also showed an significant association in Caucasians and colorectal cancer

Elevated levels of C-reactive protein (CRP) partially induced by polymorphisms in the CRP gene have been associated with human cancer in a meta-analysis over 8 case controlled studies.  Genetic polymorphisms in the CRP gene were positively associated with an increased overall risk of cancer, along with sub-group analyses by ethnicity and cancer type revealing a significant association in Caucasians with colorectal cancer.  (8)

Altogether, such immune-related gene-diet interactions might affect anthropometric parameters, metabolic profile, and cardiovascular measurements and thereby alter individual susceptibility to metabolic (obesity, diabetes, and non-alcoholic fatty liver diseases), autoimmune (Crohn’s disease), and cardiovascular disorders (atherosclerosis)

Chronic inflammatory diseases occur as a consequence imbalance between effector and regulatory mechanisms of immune system. Several factors such as genetic polymorphisms, environmental factors, and dietary components correlate with the imbalance of immune homeostasis, which may lead to inflammatory and autoimmune diseases.

 Exposure to low doses of carcinogens may happen continuously during a lifetime. Furthermore, the body’s response to carcinogens and chemo protective agents depends upon several factors such as genetic polymorphisms and epigenetic modification.

Single nucleotide polymorphism (SNP) studies have established the interaction between polymorphisms within the genes related to immune and inflammatory responses (CRP, IL-1, TNFα, IL-6, LTA4, and SCD-1) and diet composition (vitamin D status, botanical formulation, fat intake, and fatty acid supplementation).

Immune-related, gene-diet interactions might affect anthropometric parameters, metabolic profile, and cardiovascular measurements and thereby alter individual susceptibility to metabolic (obesity, diabetes, and non-alcoholic fatty liver diseases), autoimmune (Crohn’s disease), and cardiovascular disorders (atherosclerosis).

Sometimes, there is a common sense link between nutrition and health – for example, eating too much correlates to obesity. Other times, the link is surprising – for example, when lean people get diabetes. Generally, both links need to incorporate the full range of genetic, environmental, and epigenetic factors. The epigenetic regulation of the link between nutrition and health starts from the preconception and gestation period and lasts throughout life. (9)

This study examined genetic factors that influence CRP levels in patients with PTSD which was positively correlated with plasma CRP levels. The relationship between PTSD and CRP was mediated by DNA methylation, while CRP SNPs moderated the association between PTSD and CRP levels.

Findings from recent genetic and blood-biomarker studies provide converging evidence for the role of inflammatory processes in the pathophysiology of PTSD.

One of the most extensively validated and widely studied markers of peripheral inflammation is C-Reactive Protein, (CRP), a protein found in blood that responds to inflammatory stimuli by triggering cellular reactions that lead to their clearance. CRP is a highly sensitive inflammatory reactant produced primarily in the liver that increases dramatically in response to relevant stimuli.

Recent studies have found CRP in stroke lesions and brain tissue from patients with various neurodegenerative diseases. Several larger and more recent studies have reported positive associations between CRP and PTSD.

Additionally, some studies have found associations between elevated CRP and childhood adversity or adulthood traumatic events, suggesting that trauma exposure itself may initiate a pro-inflammatory state.

Genome-wide association (GWAS) studies featuring numbers > 10,000 have shown individual CRP polymorphisms to explain substantial individual differences in blood CRP levels.

Study findings provide important new insights in to the genetic and epigenetic mechanisms of the association between traumatic stress and peripheral inflammation and identify DNA methylation, CRP gene variation, and CRP levels as potentially useful targets for future PTSD biomarker research. (10)

Elevated CRP and bacteriuria accompanies acute pyelonephritis and cytokines may be quantified in the urine. IL-6 and IL-8 are produced by infected cells in the urinary tract and elevated levels accompany symptomatic infections.  CRP is stimulated by IL-6 that is produced by macrophages and fat cells. (11)

Chronic kidney disease (CKD) represents a major public health problem worldwide. Even in its early stages, CKD is associated with poor outcomes and premature death mainly due to cardiovascular causes.

Familial aggregation of CKD and end stage renal disease (ESRD) has been reported in populations throughout the world for all types of nephropathy, underscoring the importance of genetic factors.

CRP gene polymorphisms are associated with serum C-reactive protein concentrations and may play a role in chronic kidney disease (CKD) progression. A recently reported study found an association between the gene variant rs2808630 and CKD progression in African Americans with hypertensive kidney disease.

These results supported a previous study demonstrating an association between CRP gene variant rs2808630 and CKD progression in a longitudinal cohort of African American with hypertensive kidney disease. (12)

Systemic inflammation, genetic susceptibility and lung function

Local inflammation in airway diseases is well recognised, but less is known about the association between low-grade systemic inflammatory processes and lung function. The present study was performed to assess the association between inflammatory markers and lung function, taking into account polymorphisms in genes coding for inflammatory markers.

CRP and IL-6 peripheral levels were found to be associated with lung function.

Results were very suggestive that heritability of lung function is at least partly controlled by the CRP gene.

Among polymorphisms in CRP and IL-6 genes, only SNPs in the CRP gene showed an association with lung function measures. (13)

A total of 242 IBS patients and 244 Healthy Controls were studied. CRP levels in the IBS group were significantly higher. Levels were highest in IBS-D patients with greater disease severity. High sensitive -CRP levels mildly correlated with symptoms severity; this correlation was stronger for the IBS-D patients.  IBS was a significant independent predictor for higher high sensitive-CRP levels, whereas other pain and psychological co-morbidities were not.

Irritable bowel syndrome (IBS) is a common disorder with a global prevalence of 8-23% of the adult population and is slightly more prevalent in the industrialised world than in developing countries.

Although IBS is not considered an inflammatory disease, recent studies suggest a possible role for alterations in the intestinal immune function and low grade inflammation in its pathogenesis.

Additional support for a potential role for low-grade inflammation in IBS came from epidemiological observational studies showing that in 6-17% of IBS patients the onset of symptoms may relate to an acute episode of gastrointestinal infection.

The median high sensitive-CRP level was significantly higher in the IBS group compared with the Healthy Controls.

In the presence of pain and/or psychological (depression, anxiety and somatisation) syndromes, all strata, high sensitive-CRP levels were consistently higher in the IBS group compared with the Healthy Controls. For pain syndrome-defined strata, high sensitive -CRP was 36-46% higher in IBS patients, with similar differences being observed within psychological syndrome strata.

The study was able to demonstrate, for the first time, that high sensitive-CRP levels correlate with symptoms’ severity of IBS suggesting that IBS, and specifically IBS-D, may be associated with systemic inflammatory responses.

In conclusion, the result of this study supports the hypothesis that intestinal inflammation may play a role in the pathogenesis of symptoms in a subgroup of patients with IBS. The findings are suggestive that inflammatory responses in IBS may be identified in peripheral blood, specifically in IBS-D patients with severe symptoms. (14)

1.             Dhingra R, Gona P, Nam B-H, D’Agostino RB, Sr., Wilson PWF, Benjamin EJ, et al. C-reactive protein, inflammatory conditions, and cardiovascular disease risk. The American journal of medicine. 2007;120(12):1054-62.

2.             Dehghan A, Dupuis J Fau – Barbalic M, Barbalic M Fau – Bis JC, Bis Jc Fau – Eiriksdottir G, Eiriksdottir G Fau – Lu C, Lu C Fau – Pellikka N, et al. Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels. (1524-4539 (Electronic)).

3.             Sheu WH-H, Wang W-C, Wu K-D, He C-T, Hwu C-M, Quertermous T, et al. CRP-level-associated polymorphism rs1205 within the CRP gene is associated with 2-hour glucose level: The SAPPHIRe study. Scientific Reports. 2017;7(1):7987.

4.             Shen J, Ordovas JM. Impact of genetic and environmental factors on hsCRP concentrations and response to therapeutic agents. Clinical chemistry. 2009;55(2):256-64.

5.             Hage FG, Szalai AJ. C-reactive protein gene polymorphisms, C-reactive protein blood levels, and cardiovascular disease risk. (1558-3597 (Electronic)).

6.             Hage FG, Szalai AJ. The role of C-reactive protein polymorphisms in inflammation and cardiovascular risk. Current Atherosclerosis Reports. 2009;11(2):124-30.

7.             Lange LA, Carlson CS, Hindorff LA, Lange EM, Walston J, Durda JP, et al. Association of Polymorphisms in the CRP Gene With Circulating C-Reactive Protein Levels and Cardiovascular Events. JAMA. 2006;296(22):2703-11.

8.             Geng P, Sa R, Li J, Li H, Liu C, Liao Y, et al. Genetic polymorphisms in C-reactive protein increase cancer susceptibility. Scientific Reports. 2016;6(1):17161.

9.             Saghazadeh A, Mahmoudi M, Rezaei N. Nutrigenomic Immunity. In: Mahmoudi M, Rezaei N, editors. Nutrition and Immunity. Cham: Springer International Publishing; 2019.

10.          Miller MW, Maniates H, Wolf EJ, Logue MW, Schichman SA, Stone A, et al. CRP polymorphisms and DNA methylation of the AIM2 gene influence associations between trauma exposure, PTSD, and C-reactive protein. Brain, Behavior, and Immunity. 2018;67:194-202.

11.          RagnarsdC3ttir B-s, Svanborg C. Susceptibility to acute pyelonephritis or asymptomatic bacteriuria: Hostb. 2012.

12.          Hung AM, Ikizler TA, Griffin MR, Glenn K, Greevy RA, Grijalva CG, et al. CRP polymorphisms and chronic kidney disease in the third national health and nutrition examination survey. BMC Medical Genetics. 2011;12(1):65.

13.          Sunyer J, Pistelli R, Plana E, Andreani M, Baldari F, Kolz M, et al. Systemic inflammation, genetic susceptibility and lung function. European Respiratory Journal. 2008;32(1):92-7.

14.          Hod K, Ringel-Kulka T, Martin CF, Maharshak N, Ringel Y. High-sensitive C-Reactive Protein as a Marker for Inflammation in Irritable Bowel Syndrome. Journal of clinical gastroenterology. 2016;50(3):227-32.