Can C-reactive Protein Genetic Variants Identify Patients with Higher and Lower Cardiovascular Risk?
Received Date: Feb 19, 2018 / Accepted Date: Apr 16, 2018 / Published Date: Apr 23, 2018
Recent pre-clinical and clinical studies have revealed the C-reactive protein gene (CRP) is related to the degree of acute rise in plasma C-reactive protein (CRP) levels. Moreover, single nucleotide polymorphisms (SNPs) in the CRP gene could associate with increased risk of cancer, atherosclerosis, diabetes mellitus, bowel disease, rheumatoid arthritis, psoriasis, obstructive pulmonary disease, periodontitis, nonalcoholic fatty liver disease and cardiovascular (CV) diseases. Less is known about the role of variabilities of circulating levels of CRP due to SNPs as an individual biological marker of CV risk and poor clinical outcomes due to CV reasons. The results of clinical trials and some meat-analysis are controversial in this issue. The short commentary is depicted the possible role of SNPs in CRP gene as a personified biological marker of CV risk.
Keywords: Cardiovascular risk; Biological markers; C-reactive protein; Single nucleotide polymorphisms; Prognosis; Prediction
There is a large body of evidence that there are the possible interactions among selected single nucleotide polymorphisms (SNPs) in genes associated with systemic inflammation reaction [1,2]. In this context, plasma levels of systemic inflammation biomarkers might be extremely variable depending on immune phenotypes of cells (CD8dim, GZB+, CD13+ and CD56+) that are involved into immunecompromised state and regulate producing of pro-inflammatory cytokines, such as C-reactive protein (CRP) . CRP blood level closely relates to CRP genetic variants (SNPs) and it could be a good candidate for personal biological marker of cardiovascular disease (CVD) because recent studies have yielded strong association of several CRP genetic variants with increased mortality risk in general population as well as in patients with established CVD (Table 1). Moreover, CRP SNPs suggest a possible role of the inflammatory system as link between CVD risk factors and poor prognosis [3,4].
|CRP SNP||Population||Relation to circulating plasma CRP level||Relation to the CVD||Reference|
|rs1205||Caucasian populations of healthy men and women||Positive relation||Increase of CVD susceptibility||4|
|rs1205||Caucasian populations of healthy men and women with risk factors of CVD||Lack of relation||Lack of association with CVD||15|
|rs1205||Caucasian populations of healthy men and women||Lack of relation||Lack of association with CVD||10|
|rs1205||Caucasian population of patients with established CVD||Positive relation||Predictor of CVD||11,16|
|rs1800947 CC genotype||patients with risk factors of CVD||Positive relation in smokers||Predictor of atherosclerosis, myocardial infarction and||12,16|
|triallelic SNP (C-->T-->A)||Caucasian patients with risk factors of CVD||Positive relation that explains 26% of the individual variability in CRP level||Predictor of CVD||13|
|rs3093059 (T>C)||Asian populations||Negative relation||A marker of lowered risk of myocardial infarction||14|
|rs1800947 (G>C) and rs2794521 (G>A)||Asian and Caucasian populations||Positive relation||Lack of association||14,15|
Table 1: The controversial results of CRP SNPs in prediction of CVD; CRP: C-Reactive Protein; CVD: Cardiovascular Disease; SNPs: Single Nucleotide Polymorphism.
CRP is predominantly secreted by the liver and adipose tissues in response to inflammatory stress and is predominantly regulated by interleukin [IL]-6 and some chemokine produced by wide spectrum of immune cells. Despite SNP CRP rs1205 polymorphism associated with circulating plasma CRP levels and CVD susceptibility in some populations, there is evidence that several mutant alleles of IL-1 gene and IL-6 gene may promote an elevated level of CRP regardless of SNPs’ presentation in CRP gene .
Numerous clinical studies have revealed that SNPs in the CRP gene have associated with increased risk of cancer, atherosclerosis, diabetes mellitus, bowel disease, rheumatoid arthritis, psoriasis, obstructive pulmonary disease, periodontitis, nonalcoholic fatty liver disease and CVD [5-9]. However, CRP genotype mediated rather CRP levels at acute phase of inflammation than at constitutional levels beyond antigen stimulation that is one of intriguing fact explaining controversial results of numerous pre-clinical and clinical studies depicted this issue . On the other hand, in healthy men and women the polymorphisms of CRP were found in mild-to-moderate association with the basal CRP levels. Whether SNPs in CRP genes are powerful individual predictor of CV disease and poor clinical outcomes in patients with established CV is not fully clear .
Current evidence confirmed that CV risk factors may correspond to CRP levels and thereby directly affect local inflammation especially in the plaques, sub-intima of vascular walls, kidney and adipose tissues. The average CRP level in plasma was significantly higher in the smokers, with the highest level found among those with the CRP rs1800947 CC genotype . In Framingham Heart Study twelve clinical covariates (body mass index, diabetes mellitus, obesity, hypertension, heart failure, etc.) explained 26% of the individual variability in CRP level in the participants . Moreover, triallelic SNP in CRP gene (C-->T-->A), located in the promoter sequence, explained 1.4% of total serum CRP variation, and haplotypes harboring the minor T and A alleles of the SNP were close associated with higher CRP level . In meta-analysis performed by Zhu et al.  CRP rs3093059 (T>C) polymorphism was found as a marker of lowered risk of myocardial infarction, especially among Asian populations. However, similar associations were not observed in CRP rs1800947 (G>C) and rs2794521 (G>A) polymorphisms (all p>0.05) among both Asian and Caucasian populations . González-Giraldo et al.  in meta-analysis of clinical trials did not find significant associations between SNPs in CRP gene reported as CRP-rs1800947 (5 studies) and CRP-rs1205 (3 studies) and a risk of ischemic stroke. In contrast, Kolz et al.  reported found two polymorphisms within the C-reactive protein (CRP ) gene rs1800947 and rs1205, of which the minor alleles were strongly associated with lower levels of C-reactive protein and increased survival after myocardial infarction. It has suggested that increased plasma levels of CRP were associated with higher rates of acute and/or recurrent coronary atherothrombotic events, while this was not found in stable coronary artery disease . However, CRP has been reported in number of studies to be a risk factor for CV disease and to have prognostic impact in patients with coronary artery disease, although a genetic variation in CRP and risk of CV disease were related modestly. Probably, there is need to reassess the role of CRP variability as a biological marker in general population and discover novel indicators of the individual CV risk [18-20]. Future large clinical studies are required to identify additional genetic risk factors for CV disease in different populations.
In conclusion, inconsistent results in determination of the predictive role of SNPs in CRP gene as a biological marker of CV disease and CV events require more investigations. Probably, ethnic and race particularities are main factors contributing to higher individual variability in CRP concentrations in different population. Finally, it is concerned that SNPs in CRP gene are promising biomarkers for CV risk stratifications.
- Markt SC, Rider JR, Penney KL, Schumacher FR, Epstein MM, et al. (2014) Genetic variation across C-reactive protein and risk of prostate cancer. Prostate 74: 1034-1042.
- Hage FG, Szalai AJ (2009) The role of C-reactive protein polymorphisms in inflammation and cardiovascular risk. Curr Atheroscler Rep 11: 124-130.
- Berezin AE (2016) Prognostication in different heart failure phenotypes: the role of circulating biomarkers. Journal of Circ Biomark 5: 1-8.
- Dehghan A, Dupuis J, Barbalic M, Bis JC, Eiriksdottir G, et al. (2011) Meta-analysis of genome-wide association studies in >80,000 subjects identifies multiple loci for C-reactive protein levels. Circulation 123: 731-738.
- Nimptsch K, Aleksandrova K, Boeing H, Janke J, Lee YA, et al. (2015) Association of CRP genetic variants with blood concentrations of C-reactive protein and colorectal cancer risk. Int J Cancer 136: 1181-1192.
- Danik JS, Ridker PM (2007) Genetic determinants of C-reactive protein. Curr Atheroscler Rep 9: 195-203.
- Henderson P, Kennedy NA, Van Limbergen JE, Cameron FL, Satsangi J, et al. (2015) Serum C-reactive protein and CRP genotype in pediatric inflammatory bowel disease: influence on phenotype, natural history, and response to therapy. Inflamm Bowel Dis 21: 596-605.
- Papaoikonomou S, Tousoulis D, Tentolouris N, Papageorgiou N, Miliou A, et al. (2015) Genetic variant of the C-reactive Protein gene and prevalence of peripheral arterial disease in patients with type 2 diabetes mellitus. J. Diabetes Metab 6: 529-534.
- Nasibullin TR, Yagafarova LF, Yagafarov IR, Timasheva YR, Erdman VV, et al. (2016) Combinations of polymorphic markers of chemokine genes, Their receptors and acute phase protein genes as potential predictors of coronary heart diseases. Acta Naturae 8: 111-116.
- Nath AP, Ritchie SC, Byars SG, Fearnley LG, Havulinna AS, et al. (2017) An interaction map of circulating metabolites, immune gene networks, and their genetic regulation. Genome Biol 18: 146.
- Omland T, White HD (2017) State of the Art: Blood Biomarkers for Risk Stratification in Patients with Stable Ischemic Heart Disease. Clin Chem 63: 165-176.
- Luetragoon T, Rutqvist LE, Tangvarasittichai O, Andersson BÅ, Löfgren S, et al. (2017) Interaction among smoking status, single nucleotide polymorphisms and markers of systemic inflammation in healthy individuals. Immunology.
- Kathiresan S, Larson MG, Vasan RS, Guo CY, Gona P, et al. (2006) Contribution of clinical correlates and 13 C-reactive protein gene polymorphisms to interindividual variability in serum C-reactive protein level. Circulation 113: 1415-1423.
- Zhu Y, Liu T, He H, Sun Y, Zhuo F (2013) C-Reactive protein gene polymorphisms and myocardial infarction risk: A meta-analysis and metaregression. Genet Test Mol Biomarkers 17: 873-880.
- González-Giraldo Y, Barreto GE, Fava C, Forero DA (2016) Ischemic stroke and six genetic variants in CRP, EPHX2, FGA, and NOTCH3 Genes: A meta-analysis. J Stroke Cerebrovasc Dis 25: 2284-2289.
- Kolz M, Koenig W, Müller M, Andreani M, Greven S, et al. (2008) DNA variants, plasma levels and variability of C-reactive protein in myocardial infarction survivors: results from the AIRGENE study. Eur Heart J 29: 1250-1258.
- Suk DJ, Chasman DI, Cannon CP, Miller DT, Zee RY, et al. (2006) Influence of genetic variation in the C-reactive protein gene on the inflammatory response during and after acute coronary ischemia. Ann Hum Genet 70: 705-716.
- Berezin A, Kremzer A, Martovitskaya Y, Samura T, Berezina T (2016) The novel biomarker risk prediction score in patients with chronic heart failure. Clin Hypertens 22: 3.
- Berezin AE (2016) Diabetes mellitus related biomarker: The predictive role of growth-differentiation factor-15. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 10: S154-S157.
- Berezin AE (2017) Up-to-date clinical approaches of biomarkers’ use in heart failure. Biomed Res Ther 4: 1341-1370.
Citation: Berezin A (2018) Can C-reactive Protein Genetic Variants Identify Patients with Higher and Lower Cardiovascular Risk? J Clin Exp Cardiolog 9: 580. DOI: 10.4172/2155-9880.1000580
Copyright: © 2018 Berezin A. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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