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{{Infobox gene}}
{{Infobox gene}}
'''C-reactive protein''' ('''CRP''') is an annular (ring-shaped), [[pentameric protein]] found in [[blood plasma]], whose levels rise in response to [[inflammation]]. It is an [[acute-phase protein]] of hepatic origin that increases following [[interleukin-6]] secretion by [[macrophage]]s and [[T cell]]s. Its physiological role is to bind to [[lysophosphatidylcholine]] expressed on the surface of dead or dying cells (and some types of bacteria) in order to activate the [[complement system]] via [[C1q]].<ref name="pmid10368284">{{cite journal | vauthors = Thompson D, Pepys MB, Wood SP | title = The physiological structure of human C-reactive protein and its complex with phosphocholine | journal = Structure | volume = 7 | issue = 2 | pages = 169–77 | date = Feb 1999 | pmid = 10368284 | doi = 10.1016/S0969-2126(99)80023-9 }}</ref>
'''C-reactive protein''' ('''CRP''') is an annular (ring-shaped), [[pentameric protein]] found in [[blood plasma]], whose levels rise in response to [[inflammation]]. It is an [[acute-phase protein]] of hepatic origin that increases following [[interleukin-6]] secretion by [[macrophage]]s and [[T cell]]s. Its physiological role is to bind to [[lysophosphatidylcholine]] expressed on the surface of dead or dying cells (and some types of bacteria) in order to activate the [[complement system]] via [[C1q]].<ref name="pmid10368284">{{cite journal | vauthors = Thompson D, Pepys MB, Wood SP | title = The physiological structure of human C-reactive protein and its complex with phosphocholine | journal = Structure | volume = 7 | issue = 2 | pages = 169–77 | date = February 1999 | pmid = 10368284 | doi = 10.1016/S0969-2126(99)80023-9 }}</ref>


CRP is synthesized by the [[liver]]<ref name="Pepys">{{cite journal | vauthors = Pepys MB, Hirschfield GM | title = C-reactive protein: a critical update | journal = The Journal of Clinical Investigation | volume = 111 | issue = 12 | pages = 1805–12 | date = Jun 2003 | pmid = 12813013 | pmc = 161431 | doi = 10.1172/JCI18921 }}</ref> in response to factors released by [[macrophage]]s and fat cells ([[adipocytes]]).<ref name="Lau">{{cite journal | vauthors = Lau DC, Dhillon B, Yan H, Szmitko PE, Verma S | title = Adipokines: molecular links between obesity and atheroslcerosis | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 288 | issue = 5 | pages = H2031–41 | date = May 2005 | pmid = 15653761 | doi = 10.1152/ajpheart.01058.2004 }}</ref> It is a member of the [[pentraxin]] family of proteins.<ref name=Pepys/> It is not related to [[C-peptide]] (insulin) or [[protein C]] (blood coagulation). C-reactive protein was the first [[pattern recognition receptor]] (PRR) to be identified.<!-- The page for CD14 (http://en.wikipedia.org/wiki/CD14) says that CD14 was the first PRR to be described. Which is it? --><ref name="pmid17828584">{{cite journal | vauthors = Mantovani A, Garlanda C, Doni A, Bottazzi B | title = Pentraxins in innate immunity: from C-reactive protein to the long pentraxin PTX3 | journal = Journal of Clinical Immunology | volume = 28 | issue = 1 | pages = 1–13 | date = Jan 2008 | pmid = 17828584 | doi = 10.1007/s10875-007-9126-7 }}</ref>
CRP is synthesized by the [[liver]]<ref name="Pepys">{{cite journal | vauthors = Pepys MB, Hirschfield GM | title = C-reactive protein: a critical update | journal = The Journal of Clinical Investigation | volume = 111 | issue = 12 | pages = 1805–12 | date = June 2003 | pmid = 12813013 | pmc = 161431 | doi = 10.1172/JCI18921 }}</ref> in response to factors released by [[macrophage]]s and fat cells ([[adipocytes]]).<ref name="Lau">{{cite journal | vauthors = Lau DC, Dhillon B, Yan H, Szmitko PE, Verma S | title = Adipokines: molecular links between obesity and atheroslcerosis | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 288 | issue = 5 | pages = H2031–41 | date = May 2005 | pmid = 15653761 | doi = 10.1152/ajpheart.01058.2004 }}</ref> It is a member of the [[pentraxin]] family of proteins.<ref name=Pepys/> It is not related to [[C-peptide]] (insulin) or [[protein C]] (blood coagulation). C-reactive protein was the first [[pattern recognition receptor]] (PRR) to be identified.<!-- The page for CD14 (http://en.wikipedia.org/wiki/CD14) says that CD14 was the first PRR to be described. Which is it? --><ref name="pmid17828584">{{cite journal | vauthors = Mantovani A, Garlanda C, Doni A, Bottazzi B | title = Pentraxins in innate immunity: from C-reactive protein to the long pentraxin PTX3 | journal = Journal of Clinical Immunology | volume = 28 | issue = 1 | pages = 1–13 | date = January 2008 | pmid = 17828584 | doi = 10.1007/s10875-007-9126-7 }}</ref>


== History and nomenclature ==
== History and nomenclature ==
Discovered by [[William S. Tillett|Tillett]] and Francis in 1930,<ref name="pmid19869788">{{cite journal | vauthors = Tillett WS, Francis T | title = Serological reactions in pneumonia with a nonprotein somatic fraction of pneumococcus | journal = The Journal of Experimental Medicine | volume = 52 | issue = 4 | pages = 561–71 | date = September 1930 | pmid = 19869788 | pmc = 2131884 | doi = 10.1084/jem.52.4.561 }}</ref> it was initially thought that CRP might be a pathogenic secretion since it was elevated in a variety of illnesses, including cancer.<ref name="Pepys"/> The later discovery of hepatic synthesis (made in the liver) demonstrated that it is a native protein.<ref name="isbn0-07-162591-7">{{cite book |vauthors=Kennelly PJ, Murray RF, Rodwell VW, Botham KM | title = Harper's illustrated biochemistry | publisher = McGraw-Hill Medical | location = | year = 2009 | pages = | isbn = 0-07-162591-7 }}</ref><ref name="isbn1-4160-0287-1">{{cite book |vauthors=Pincus MR, McPherson RA, Henry JB | title = Henry's clinical diagnosis and management by laboratory methods | publisher = Saunders Elsevier | location = | year = 2007 | pages = | isbn = 1-4160-0287-1 }}</ref><ref name="isbn1-4160-3285-1">{{cite book |vauthors=Ratey JJ, Noskin GA, Braun R, ((Hanley EN Jr)), McInnes IB, Ruddy S | title = Kelley's Textbook of Rheumatology: 2-Volume Set, Expert Consult: Online and Print (Textbook of Rheumatology (Kelley's)(2 Vol)) | publisher = Saunders | location = Philadelphia | year = 2008 | pages = | isbn = 1-4160-3285-1 }}</ref> Initially, CRP was measured using [[Quellung reaction]] which gave a positive or a negative reaction. More precise methods nowadays is using [[dynamic light scattering]] on antibodies specific to CRP.<ref name="Bray 2016">{{cite journal | vauthors = Bray C, Bell LN, Liang H, Haykal R, Kaiksow F, Mazza JJ, Yale SH | title = Erythrocyte Sedimentation Rate and C-reactive Protein Measurements and Their Relevance in Clinical Medicine | journal = Wisconsin Medical Journal (WMJ) | volume = 115 | issue = 6 | pages = 317–21 | date = December 2016 | pmid = 29094869 | url = http://www.wisconsinmedicalsociety.org/_WMS/publications/wmj/pdf/115/6/317.pdf }}</ref>


CRP was so named because it was first identified as a substance in the serum of patients with acute inflammation that reacted with the somatic 'C' carbohydrate antigen of the capsule of  
CRP was so named because it was first identified as a substance in the serum of patients with acute inflammation that reacted with the antibody against the somatic [[bacterial capsule|capsular]] polysaccharide (C-polysaccharide) of [[pneumococcus]].<ref>{{cite book | vauthors = Ananthanarayan R, Paniker CJ | name-list-format = vanc | title = Ananthanarayan and Paniker's Textbook of Microbiology | date = 1978 | publisher = Orient Longman | location = Himayatnagar, Hyderabad | isbn = 9788125028086 | page = 218 | edition = 7th  | url = https://books.google.com/books?id=MXMazr0LRDsC&pg=PA218 }}</ref><ref>{{cite book | vauthors = Levine M | chapter = Chapter 13: Chronic Periodontitis |title=Topics in Dental Biochemistry |publisher=Springer | location = Berlin, Heidelberg | date = 2011 |isbn=978-3-540-88115-5 | quote = C-reactive protein (CRP) was originally identified as binding to the phosphocholine attachment site of capsular polysaccharide (C-polysaccharide) from Streptococcus pneumoniae. }}</ref>
[[pneumococcus]].<ref>{{cite book | last1 = Ananthanarayan | first1 = R | last2 = Paniker | first2 = CJK | name-list-format = vanc | title = Ananthanarayan and Paniker's Textbook of Microbiology | date = 1978 | publisher =Orient Longman | location = Himayatnagar, Hyderabad | isbn = 9788125028086 | page = 218 | edition = 7th  | url = https://books.google.com/books?id=MXMazr0LRDsC&pg=PA218&lpg=PA218&dq=carbohydrate+antigen+of+pneumococcus+crp&source=bl&ots=0uLhfx5AnY&sig=pTNqpT9_bRlMMjOLQ3rnlys3oJo&hl=en&sa=X&ved=0CEkQ6AEwBWoVChMIkOLq3YP7yAIVRqOUCh0qzAB2#v=onepage&q=carbohydrate%20antigen%20of%20pneumococcus%20crp&f=false }}</ref>
 
Discovered by [[William S. Tillett|Tillett]] and Francis in 1930,<ref name="pmid19869788">{{cite journal | vauthors = Tillett WS, Francis T | title = Serological reactions in pneumonia with a nonprotein somatic fraction of pneumococcus | journal = The Journal of Experimental Medicine | volume = 52 | issue = 4 | pages = 561–71 | date = Sep 1930 | pmid = 19869788 | pmc = 2131884 | doi = 10.1084/jem.52.4.561 }}</ref> it was initially thought that CRP might be a pathogenic secretion since it was elevated in a variety of illnesses, including cancer.<ref name="Pepys"/> The later discovery of hepatic synthesis demonstrated that it is a native protein.<ref name="isbn0-07-162591-7">{{cite book |vauthors=Kennelly PJ, Murray RF, Rodwell VW, Botham KM | title = Harper's illustrated biochemistry | publisher = McGraw-Hill Medical | location = | year = 2009 | pages = | isbn = 0-07-162591-7 }}</ref><ref name="isbn1-4160-0287-1">{{cite book |vauthors=Pincus MR, McPherson RA, Henry JB | title = Henry's clinical diagnosis and management by laboratory methods | publisher = Saunders Elsevier | location = | year = 2007 | pages = | isbn = 1-4160-0287-1 }}</ref><ref name="isbn1-4160-3285-1">{{cite book |vauthors=Ratey JJ, Noskin GA, Braun R, ((Hanley EN Jr)), McInnes IB, Ruddy S | title = Kelley's Textbook of Rheumatology: 2-Volume Set, Expert Consult: Online and Print (Textbook of Rheumatology (Kelley's)(2 Vol)) | publisher = Saunders | location = Philadelphia | year = 2008 | pages = | isbn = 1-4160-3285-1 }}</ref>


== Genetics and structure ==
== Genetics and structure ==


The ''CRP'' gene is located on [[chromosome]] 1 (1q23.2<ref>https://www.ncbi.nlm.nih.gov/gene/1401</ref>). It is a member of the small [[pentraxins]] family. It has 224 amino acids,<ref>[https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=protein&val=30224 NCBI Entrez Protein #CAA39671]</ref> has a monomer molecular mass of 25,106 [[Dalton (unit)|Da]], and has an annular pentameric discoid shape.
The ''CRP'' gene is located on [[chromosome]] 1 (1q23.2<ref>{{cite web | title = CRP C-reactive protein [Homo sapiens] | url = https://www.ncbi.nlm.nih.gov/gene/1401 | work = Entrez Gene | publisher = National Center for Biotechnology Information (NCBI), U.S. National Library of Medicine }}</ref>). It is a member of the small [[pentraxins]] family. The monomer has 224 amino acids,<ref>{{cite web | url = https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=protein&val=30224 | work = NCBI Entrez Protein | title = #CAA39671 }}</ref> and molecular mass of 25,106 [[Dalton (unit)|Da]].  In serum, it assembles into stable pentameric structure with a discoid shape.


== Function ==
== Function ==


CRP binds to the [[phosphocholine]] expressed on the surface of dead or dying cells and some bacteria. This activates the [[complement system]], promoting [[phagocytosis]] by macrophages, which clears necrotic and apoptotic cells and bacteria.
CRP binds to the [[phosphocholine]] expressed on the surface of dead or dying cells and some bacteria. This activates the [[complement system]], promoting [[phagocytosis]] by macrophages, which clears necrotic and apoptotic cells and bacteria.<ref name="Bray 2016"/>


This [[acute phase response]] occurs as a result of a rise in the concentration of [[Interleukin-6|IL-6]], which is produced by [[macrophage]]s<ref name=Pepys/> as well as [[adipocyte]]s<ref name="Lau"/> in response to a wide range of acute and chronic inflammatory conditions such as bacterial, viral, or fungal infections; rheumatic and other inflammatory diseases; malignancy; and tissue injury and necrosis. These conditions cause release of [[interleukin-6]] and other cytokines that trigger the synthesis of CRP and fibrinogen by the liver.
This so-called [[acute phase response]] occurs as a result of a rise in the concentration of [[Interleukin-6|IL-6]], which is produced by [[macrophage]]s<ref name=Pepys/> as well as [[adipocyte]]s<ref name="Lau"/> in response to a wide range of acute and chronic inflammatory conditions such as bacterial, viral, or fungal infections; rheumatic and other inflammatory diseases; malignancy; and tissue injury and necrosis. These conditions cause release of [[interleukin-6]] and other cytokines that trigger the synthesis of CRP and fibrinogen by the liver.


CRP binds to [[phosphocholine]] on micro-organisms. It is thought to assist in [[Complement system|complement]] binding to foreign and damaged cells and enhances phagocytosis by macrophages ([[opsonin|opsonin-mediated phagocytosis]]), which express a receptor for CRP. It plays a role in [[innate immunity]] as an early defense system against infections.
CRP binds to phosphocholine on micro-organisms. It is thought to assist in [[Complement system|complement]] binding to foreign and damaged cells and enhances phagocytosis by macrophages ([[opsonin|opsonin-mediated phagocytosis]]), which express a receptor for CRP. It plays a role in [[innate immunity]] as an early defense system against infections.<ref name="Bray 2016"/>


CRP rises within two hours of the onset of inflammation, up to a 50,000-fold, and peaks at 48 hours. Its half-life of 18 hours is constant, and therefore its level is determined by the rate of production and hence the severity of the precipitating cause. CRP is thus a marker for inflammation that can be used to screen for inflammation.
== Serum levels ==
 
In healthy adults, the normal concentrations of CRP varies between 0.8 mg/L to 3.0 mg/L. However, some healthy adults show elevated CRP at 10 mg/L. When there is a stimulus, the CRP level can rise 10,000-fold from less than 50 μg/l to more than 500 mg/L. Such levels can rise to 5 mg/L by 6 hours and peaks at 48 hours. The plasma half-life of CRP is 19 hours. Such half-life is constant in all medical conditions. Therefore, the only factor that affects the level of CRP in blood is its rate of production. The rate of CRP production increases with inflammation, infection, trauma, necrosis, malignancy, and allergic reaction. The CRP level also increases with age, possibly due to increasing subclinical condition. There is also no seasonal variations of CRP levels. [[Gene polymorphism]] of [[interleukin-1 family]], [[interleukin 6]], and polymorphic GT repeat of the CRP gene do affects the usual CRP levels when a person does not have any medical illnesses.<ref name=Pepys/> Other inflammatory mediators that can cause a rise in CRP are [[TGF beta 1]], and [[tumor necrosis factor alpha]]. In acute inflammation, CRP can raise as much as 50 to 100 mg/dL within 4 to 6 hours in mild to moderate inflammation or insult such as skin infection, cystitis, or bronchitis. It can double every 8 hours and reaches its peak at 36 to 50 hours following injury or inflammation. CRP between 100 to 500 mg/dL is considered as bacterial inflammation. CRP concentrations between 2 to 10 mg/dL are considered as metabolic inflammation (metabolic pathways that causes [[arteriosclerosis]] and [[type II diabetes mellitus]]). Once inflammation subsides, CRP level falls quickly because of its relatively short half-life.<ref name="Bray 2016"/>


== Clinical significance ==
== Clinical significance ==
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A high-sensitivity CRP (hs-CRP) test measures low levels of CRP using laser [[nephelometry]]. The test gives results in 25 minutes with a sensitivity down to 0.04&nbsp;mg/L.
A high-sensitivity CRP (hs-CRP) test measures low levels of CRP using laser [[nephelometry]]. The test gives results in 25 minutes with a sensitivity down to 0.04&nbsp;mg/L.


The risk of developing cardiovascular disease is quantified as follows:<ref>{{cite web|title=Normal results|url=http://www.nlm.nih.gov/medlineplus/ency/article/003356.htm|website=C-reactive protein|publisher=MedlinePlus|accessdate=23 April 2015}}</ref>
The risk of developing cardiovascular disease is quantified as follows:<ref>{{cite web|title=Normal results|url=https://www.nlm.nih.gov/medlineplus/ency/article/003356.htm|website=C-reactive protein|publisher=MedlinePlus|access-date=23 April 2015}}</ref>


* low: hs-CRP level under 1.0&nbsp;mg/L
* low: hs-CRP level under 1.0&nbsp;mg/L
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* high: above 3.0&nbsp;mg/L
* high: above 3.0&nbsp;mg/L


Normal concentration in healthy human serum is between 5 and 10&nbsp;mg/L, increasing with [[aging]].<ref>Thomas, Lothar, ''Labor und Diagnose''. TH-Books, Frankfurt, 2008, p. 1010</ref> Higher levels are found in late [[Pregnancy|pregnant]] women, mild [[inflammation]] and [[viral infection]]s (10–40&nbsp;mg/L), active inflammation, bacterial infection (40–200&nbsp;mg/L), severe [[bacterial infections]] and [[burn]]s (>200&nbsp;mg/L).<ref>{{cite journal | author = Dr. Keng Sheng Chew | title = What's new in Emergencies Trauma and Shock? C-reactive protein as a potential clinical biomarker for influenza infection...|url = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3391832/| journal = Emergencies, Trauma, and Shock | volume = 5 | issue = 2 | pages = 115-117| date = Apr-Jun 2012 |doi = 10.4103/0974-2700.96477}}</ref>
Normal levels increase with [[aging]].<ref>Thomas, Lothar, ''Labor und Diagnose''. TH-Books, Frankfurt, 2008, p. 1010</ref> Higher levels are found in late [[Pregnancy|pregnant]] women, mild [[inflammation]] and [[viral infection]]s (10–40&nbsp;mg/L), active inflammation, bacterial infection (40–200&nbsp;mg/L), severe [[bacterial infections]] and [[burn]]s (>200&nbsp;mg/L).<ref name="pmid22787338">{{cite journal | vauthors = Chew KS | title = What's new in Emergencies Trauma and Shock? C-reactive protein as a potential clinical biomarker for influenza infection: More questions than answers | journal = Journal of Emergencies, Trauma, and Shock | volume = 5 | issue = 2 | pages = 115–7 | date = April 2012 | pmid = 22787338 | pmc = 3391832 | doi = 10.4103/0974-2700.96477 }}</ref>


CRP is a more sensitive and accurate reflection of the acute phase response than the ESR<ref name="pmid23689052"/> ([[Erythrocyte sedimentation rate|Erythrocyte Sedimentation Rate]]). ESR may be normal while CRP is elevated. CRP returns to normal more quickly than ESR in response to therapy.
CRP is a more sensitive and accurate reflection of the acute phase response than the ESR<ref name="pmid23689052"/> ([[Erythrocyte sedimentation rate|Erythrocyte Sedimentation Rate]]). ESR may be normal while CRP is elevated. CRP returns to normal more quickly than ESR in response to therapy.
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The utility of CRP in differentiating inflammatory diseases (including [[inflammatory bowel disease]], [[intestinal lymphoma]], [[intestinal tuberculosis]], and [[Behçet's disease|Behcet's syndrome]]) has been investigated and compared to other inflammatory biomarkers, such as ESR and WBC.<ref name="pmid23689052"/>
The utility of CRP in differentiating inflammatory diseases (including [[inflammatory bowel disease]], [[intestinal lymphoma]], [[intestinal tuberculosis]], and [[Behçet's disease|Behcet's syndrome]]) has been investigated and compared to other inflammatory biomarkers, such as ESR and WBC.<ref name="pmid23689052"/>


=== Cancer ===
=== Cardiovascular disease ===


The role of inflammation in cancer is not well understood. Some organs of the body show greater risk of cancer when they are chronically inflamed.<ref>{{cite journal | vauthors = Lu H, Ouyang W, Huang C | title = Inflammation, a key event in cancer development | journal = Molecular Cancer Research | volume = 4 | issue = 4 | pages = 221–33 | date = Apr 2006 | pmid = 16603636 | doi = 10.1158/1541-7786.MCR-05-0261 }}</ref> While there is an association between increased levels of C-reactive protein and risk of developing cancer, there is no association between genetic polymorphisms influencing circulating levels of CRP and cancer risk.<ref name="pmid22035340">{{cite journal | vauthors = Allin KH, Nordestgaard BG | title = Elevated C-reactive protein in the diagnosis, prognosis, and cause of cancer | journal = Critical Reviews in Clinical Laboratory Sciences | volume = 48 | issue = 4 | pages = 155–70 | year = 2011 | pmid = 22035340 | doi = 10.3109/10408363.2011.599831 }}</ref>
Recent research suggests that patients with elevated basal levels of CRP are at an increased risk of [[diabetes]],<ref name="pmid11466099">{{cite journal | vauthors = Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM | title = C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus | journal = Jama | volume = 286 | issue = 3 | pages = 327–34 | date = July 2001 | pmid = 11466099 | doi = 10.1001/jama.286.3.327 }}</ref><ref name="pmid17327459">{{cite journal | vauthors = Dehghan A, Kardys I, de Maat MP, Uitterlinden AG, Sijbrands EJ, Bootsma AH, Stijnen T, Hofman A, Schram MT, Witteman JC | display-authors = 6 | title = Genetic variation, C-reactive protein levels, and incidence of diabetes | journal = Diabetes | volume = 56 | issue = 3 | pages = 872–8 | date = March 2007 | pmid = 17327459 | doi = 10.2337/db06-0922 }}</ref> [[hypertension]] and [[cardiovascular disease]]. A study of over 700 nurses showed that those in the highest [[quartile]] of [[trans fat]] consumption had blood levels of CRP that were 73% higher than those in the lowest quartile.<ref name="pmid15735094">{{cite journal | vauthors = Lopez-Garcia E, Schulze MB, Meigs JB, Manson JE, Rifai N, Stampfer MJ, Willett WC, Hu FB | display-authors = 6 | title = Consumption of trans fatty acids is related to plasma biomarkers of inflammation and endothelial dysfunction | journal = The Journal of Nutrition | volume = 135 | issue = 3 | pages = 562–6 | date = March 2005 | pmid = 15735094 | doi = 10.1093/jn/135.3.562 }}</ref> Although one group of researchers indicated that CRP may be only a moderate risk factor for cardiovascular disease,<ref name="pmid15070788">{{cite journal | vauthors = Danesh J, Wheeler JG, Hirschfield GM, Eda S, Eiriksdottir G, Rumley A, Lowe GD, Pepys MB, Gudnason V | display-authors = 6 | title = C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease | journal = The New England Journal of Medicine | volume = 350 | issue = 14 | pages = 1387–97 | date = April 2004 | pmid = 15070788 | doi = 10.1056/NEJMoa032804 }}</ref> this study (known as the Reykjavik Study) was found to have some problems for this type of analysis related to the characteristics of the population studied, and there was an extremely long follow-up time, which may have attenuated the association between CRP and future outcomes.<ref>Koenig, Wolfgang (2006). [http://www.crphealth.com/conf/hcp/5,59/doctor.wolfgang.koenig.c-reactive.protein.%96.a.critical.cardiovascular.risk.html "C-reactive protein - a critical cardiovascular risk marker"]. CRPhealth.com.</ref> Others have shown that CRP can exacerbate [[ischemic]] [[necrosis]] in a [[complement (biology)|complement]]-dependent fashion and that CRP inhibition can be a safe and effective therapy for [[Myocardial infarction|myocardial]] and [[Cerebral infarction|cerebral]] [[infarct]]s; so far, this has been demonstrated in animal models only.<ref name="pmid16642000">{{cite journal | vauthors = Pepys MB, Hirschfield GM, Tennent GA, Gallimore JR, Kahan MC, Bellotti V, Hawkins PN, Myers RM, Smith MD, Polara A, Cobb AJ, Ley SV, Aquilina JA, Robinson CV, Sharif I, Gray GA, Sabin CA, Jenvey MC, Kolstoe SE, Thompson D, Wood SP | display-authors = 6 | title = Targeting C-reactive protein for the treatment of cardiovascular disease | journal = Nature | volume = 440 | issue = 7088 | pages = 1217–21 | date = April 2006 | pmid = 16642000 | doi = 10.1038/nature04672 }}</ref>


In a 2004 [[prospective cohort study]] on colon cancer risk associated with CRP levels, people with [[colon cancer]] had higher average CRP concentrations than people without colon cancer.<ref name="pmid14762037">{{cite journal | vauthors = Erlinger TP, Platz EA, Rifai N, Helzlsouer KJ | title = C-reactive protein and the risk of incident colorectal cancer | journal = JAMA | volume = 291 | issue = 5 | pages = 585–90 | date = Feb 2004 | pmid = 14762037 | doi = 10.1001/jama.291.5.585 | url = http://jama.ama-assn.org/content/291/5/585.full.pdf }}</ref> It can be noted that the average CRP levels in both groups were well within the range of CRP levels usually found in healthy people. However, these findings may suggest that low inflammation level can be associated with a lower risk of colon cancer, concurring with previous studies that indicate [[Non-steroidal anti-inflammatory drug|anti-inflammatory drugs]] could lower colon cancer risk.<ref name="pmid12621133">{{cite journal | vauthors = Baron JA, Cole BF, Sandler RS, Haile RW, Ahnen D, Bresalier R, McKeown-Eyssen G, Summers RW, Rothstein R, Burke CA, Snover DC, Church TR, Allen JI, Beach M, Beck GJ, Bond JH, Byers T, Greenberg ER, Mandel JS, Marcon N, Mott LA, Pearson L, Saibil F, van Stolk RU | title = A randomized trial of aspirin to prevent colorectal adenomas | journal = The New England Journal of Medicine | volume = 348 | issue = 10 | pages = 891–9 | date = Mar 2003 | pmid = 12621133 | doi = 10.1056/NEJMoa021735 }}</ref>
It has been hypothesized that patients with high CRP levels might benefit from use of [[statins]]. This is based on the [[JUPITER trial]] that found that elevated CRP levels without hyperlipidemia benefited. Statins were selected because they have been proven to reduce levels of CRP.<ref name=Pepys/><ref name="pmid18997196">{{cite journal | vauthors = Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ | display-authors = 6 | title = Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein | journal = The New England Journal of Medicine | volume = 359 | issue = 21 | pages = 2195–207 | date = November 2008 | pmid = 18997196 | doi = 10.1056/NEJMoa0807646 }}</ref> Studies comparing effect of various statins in hs-CRP revealed similar effects of different statins.<ref name="pmid22025854">{{cite journal | vauthors = Sindhu S, Singh HK, Salman MT, Fatima J, Verma VK | title = Effects of atorvastatin and rosuvastatin on high-sensitivity C-reactive protein and lipid profile in obese type 2 diabetes mellitus patients | journal = Journal of Pharmacology & Pharmacotherapeutics | volume = 2 | issue = 4 | pages = 261–5 | date = October 2011 | pmid = 22025854 | pmc = 3198521 | doi = 10.4103/0976-500X.85954 }}</ref><ref name="pmid11306519">{{cite journal | vauthors = Jialal I, Stein D, Balis D, Grundy SM, Adams-Huet B, Devaraj S | title = Effect of hydroxymethyl glutaryl coenzyme a reductase inhibitor therapy on high sensitive C-reactive protein levels | journal = Circulation | volume = 103 | issue = 15 | pages = 1933–5 | date = April 2001 | pmid = 11306519 | doi = 10.1161/01.CIR.103.15.1933 }}</ref> A subsequent trial however failed to find that CRP was useful for determining statin benefit.<ref name="pmid21277016">{{cite journal | vauthors = ((Heart Protection Study Collaborative Group)), Emberson J, Bennett D, Link E, Parish S, Danesh J, Armitage J, Collins R | title = C-reactive protein concentration and the vascular benefits of statin therapy: an analysis of 20,536 patients in the Heart Protection Study | journal = Lancet | volume = 377 | issue = 9764 | pages = 469–76 | date = February 2011 | pmid = 21277016 | pmc = 3042687 | doi = 10.1016/S0140-6736(10)62174-5 }}</ref>


=== Cardiovascular disease ===
In a meta-analysis of 20 studies involving 1,466 patients with [[coronary artery disease]], CRP levels were found to be reduced after exercise interventions. Among those studies, higher CRP concentrations or poorer lipid profiles before beginning exercise were associated with greater reductions in CRP.<ref name="pmid22520533">{{cite journal | vauthors = Swardfager W, Herrmann N, Cornish S, Mazereeuw G, Marzolini S, Sham L, Lanctôt KL | title = Exercise intervention and inflammatory markers in coronary artery disease: a meta-analysis | journal = American Heart Journal | volume = 163 | issue = 4 | pages = 666–76.e1-3 | date = April 2012 | pmid = 22520533 | doi = 10.1016/j.ahj.2011.12.017 }}</ref>


Recent research suggests that patients with elevated basal levels of CRP are at an increased risk of [[diabetes]],<ref name="pmid11466099">{{cite journal | vauthors = Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM | title = C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus | journal = JAMA | volume = 286 | issue = 3 | pages = 327–34 | date = Jul 2001 | pmid = 11466099 | doi = 10.1001/jama.286.3.327 }}</ref><ref name="pmid17327459">{{cite journal | vauthors = Dehghan A, Kardys I, de Maat MP, Uitterlinden AG, Sijbrands EJ, Bootsma AH, Stijnen T, Hofman A, Schram MT, Witteman JC | title = Genetic variation, C-reactive protein levels, and incidence of diabetes | journal = Diabetes | volume = 56 | issue = 3 | pages = 872–8 | date = Mar 2007 | pmid = 17327459 | doi = 10.2337/db06-0922 }}</ref> [[hypertension]] and [[cardiovascular disease]]. A study of over 700 nurses showed that those in the highest [[quartile]] of [[trans fat]] consumption had blood levels of CRP that were 73% higher than those in the lowest quartile.<ref name="pmid15735094">{{cite journal | vauthors = Lopez-Garcia E, Schulze MB, Meigs JB, Manson JE, Rifai N, Stampfer MJ, Willett WC, Hu FB | title = Consumption of trans fatty acids is related to plasma biomarkers of inflammation and endothelial dysfunction | journal = The Journal of Nutrition | volume = 135 | issue = 3 | pages = 562–6 | date = Mar 2005 | pmid = 15735094 | doi =  }}</ref> Although one group of researchers indicated that CRP may be only a moderate risk factor for cardiovascular disease,<ref name="pmid15070788">{{cite journal | vauthors = Danesh J, Wheeler JG, Hirschfield GM, Eda S, Eiriksdottir G, Rumley A, Lowe GD, Pepys MB, Gudnason V | title = C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease | journal = The New England Journal of Medicine | volume = 350 | issue = 14 | pages = 1387–97 | date = Apr 2004 | pmid = 15070788 | doi = 10.1056/NEJMoa032804 }}</ref> this study (known as the Reykjavik Study) was found to have some problems for this type of analysis related to the characteristics of the population studied, and there was an extremely long follow-up time, which may have attenuated the association between CRP and future outcomes.<ref>Koenig, Wolfgang (2006). [http://www.crphealth.com/conf/hcp/5,59/doctor.wolfgang.koenig.c-reactive.protein.%96.a.critical.cardiovascular.risk.html "C-reactive protein - a critical cardiovascular risk marker"]. CRPhealth.com.</ref> Others have shown that CRP can exacerbate [[ischemic]] [[necrosis]] in a [[complement (biology)|complement]]-dependent fashion and that CRP inhibition can be a safe and effective therapy for [[Myocardial infarction|myocardial]] and [[Cerebral infarction|cerebral]] [[infarct]]s; so far, this has been demonstrated in animal models only.<ref name="pmid16642000">{{cite journal | vauthors = Pepys MB, Hirschfield GM, Tennent GA, Gallimore JR, Kahan MC, Bellotti V, Hawkins PN, Myers RM, Smith MD, Polara A, Cobb AJ, Ley SV, Aquilina JA, Robinson CV, Sharif I, Gray GA, Sabin CA, Jenvey MC, Kolstoe SE, Thompson D, Wood SP | title = Targeting C-reactive protein for the treatment of cardiovascular disease | journal = Nature | volume = 440 | issue = 7088 | pages = 1217–21 | date = Apr 2006 | pmid = 16642000 | doi = 10.1038/nature04672 }}</ref>
To clarify whether CRP is a bystander or active participant in atherogenesis, a 2008 study compared people with various genetic CRP variants. Those with a high CRP due to genetic variation had no increased risk of cardiovascular disease compared to those with a normal or low CRP.<ref name="pmid18971492">{{cite journal | vauthors = Zacho J, Tybjaerg-Hansen A, Jensen JS, Grande P, Sillesen H, Nordestgaard BG | title = Genetically elevated C-reactive protein and ischemic vascular disease | journal = The New England Journal of Medicine | volume = 359 | issue = 18 | pages = 1897–908 | date = October 2008 | pmid = 18971492 | doi = 10.1056/NEJMoa0707402 }}</ref> A study published in 2011 shows that CRP is associated with lipid responses to low-fat and high-polyunsaturated fat diets.<ref name="pmid19297430">{{cite journal | vauthors = St-Onge MP, Zhang S, Darnell B, Allison DB | title = Baseline serum C-reactive protein is associated with lipid responses to low-fat and high-polyunsaturated fat diets | journal = The Journal of Nutrition | volume = 139 | issue = 4 | pages = 680–3 | date = April 2009 | pmid = 19297430 | pmc = 2666362 | doi = 10.3945/jn.108.098251 }}</ref>


It has been hypothesized that patients with high CRP levels might benefit from use of [[statins]]. This is based on the [[JUPITER trial]] that found that elevated CRP levels without hyperlipidemia benefited. Statins were selected because they have been proven to reduce levels of CRP.<ref name=Pepys/><ref name="pmid18997196">{{cite journal | vauthors = Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ | title = Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein | journal = The New England Journal of Medicine | volume = 359 | issue = 21 | pages = 2195–207 | date = Nov 2008 | pmid = 18997196 | doi = 10.1056/NEJMoa0807646 }}</ref> Studies comparing effect of various statins in hs-CRP revealed similar effects of different statins.<ref name="pmid22025854">{{cite journal | vauthors = Sindhu S, Singh HK, Salman MT, Fatima J, Verma VK | title = Effects of atorvastatin and rosuvastatin on high-sensitivity C-reactive protein and lipid profile in obese type 2 diabetes mellitus patients | journal = Journal of Pharmacology & Pharmacotherapeutics | volume = 2 | issue = 4 | pages = 261–5 | date = Oct 2011 | pmid = 22025854 | pmc = 3198521 | doi = 10.4103/0976-500X.85954 }}</ref><ref name="pmid11306519">{{cite journal | vauthors = Jialal I, Stein D, Balis D, Grundy SM, Adams-Huet B, Devaraj S | title = Effect of hydroxymethyl glutaryl coenzyme a reductase inhibitor therapy on high sensitive C-reactive protein levels | journal = Circulation | volume = 103 | issue = 15 | pages = 1933–5 | date = Apr 2001 | pmid = 11306519 | doi = 10.1161/01.CIR.103.15.1933 }}</ref> A subsequent trial however failed to find that CRP was useful for determining statin benefit.<ref name="pmid21277016">{{cite journal | vauthors = ((Heart Protection Study Collaborative Group)), Emberson J, Bennett D, Link E, Parish S, Danesh J, Armitage J, Collins R | title = C-reactive protein concentration and the vascular benefits of statin therapy: an analysis of 20,536 patients in the Heart Protection Study | journal = Lancet | volume = 377 | issue = 9764 | pages = 469–76 | date = Feb 2011 | pmid = 21277016 | pmc = 3042687 | doi = 10.1016/S0140-6736(10)62174-5 }}</ref>
=== Coronary heart disease risk ===


In a meta-analysis of 20 studies involving 1,466 patients with [[coronary artery disease]], CRP levels were found to be reduced after exercise interventions. Among those studies, higher CRP concentrations or poorer lipid profiles before beginning exercise were associated with greater reductions in CRP.<ref name="pmid22520533">{{cite journal | vauthors = Swardfager W, Herrmann N, Cornish S, Mazereeuw G, Marzolini S, Sham L, Lanctôt KL | title = Exercise intervention and inflammatory markers in coronary artery disease: a meta-analysis | journal = American Heart Journal | volume = 163 | issue = 4 | pages = 666–76.e1–3 | date = Apr 2012 | pmid = 22520533 | doi = 10.1016/j.ahj.2011.12.017 }}</ref>
Arterial damage results from [[macrophage|white blood cell]] invasion and [[inflammation]] within the wall. CRP is a general marker for inflammation and infection, so it can be used as a very rough proxy for heart disease risk. Since many things can cause elevated CRP, this is not a very [[Sensitivity and specificity|specific]] prognostic indicator.<ref name="Lloyd-Jones">{{cite journal | vauthors = Lloyd-Jones DM, Liu K, Tian L, Greenland P | title = Narrative review: Assessment of C-reactive protein in risk prediction for cardiovascular disease | journal = Annals of Internal Medicine | volume = 145 | issue = 1 | pages = 35–42 | date = July 2006 | pmid = 16818927 | doi = 10.7326/0003-4819-145-1-200607040-00129 | url = http://annals.org/cgi/content/full/0000605-200607040-00129v1 | access-date = 2008-05-01 | archive-url = https://web.archive.org/web/20080417140838/http://www.annals.org/cgi/content/full/0000605-200607040-00129v1# | archive-date = 2008-04-17 | dead-url = yes | df =  }}</ref><ref>{{cite journal | vauthors = Bower JK, Lazo M, Juraschek SP, Selvin E | title = Within-person variability in high-sensitivity C-reactive protein | journal = Archives of Internal Medicine | volume = 172 | issue = 19 | pages = 1519–21 | date = October 2012 | pmid = 22945505 | pmc = 3613132 | doi = 10.1001/archinternmed.2012.3712 }}</ref> Nevertheless, a level above 2.4&nbsp;mg/L has been associated with a doubled risk of a coronary event compared to levels below 1&nbsp;mg/L;<ref name=Pepys/> however, the study group in this case consisted of patients who had been diagnosed with unstable angina pectoris; whether elevated CRP has any predictive value of acute coronary events in the general population of all age ranges remains unclear. Currently, C-reactive protein is not recommended as a cardiovascular disease screening test for average-risk adults without symptoms.<ref name=Cecil>{{cite book |last1=Goldman |first1=Lee | name-list-format = vanc |title=Goldman's Cecil Medicine |publisher=Elsevier Saunders |location=Philadelphia |isbn=1437727883 |year=2011 |pages=54 |edition=24th }}</ref>


To clarify whether CRP is a bystander or active participant in atherogenesis, a 2008 study compared people with various genetic CRP variants. Those with a high CRP due to genetic variation had no increased risk of cardiovascular disease compared to those with a normal or low CRP.<ref name="pmid18971492">{{cite journal | vauthors = Zacho J, Tybjaerg-Hansen A, Jensen JS, Grande P, Sillesen H, Nordestgaard BG | title = Genetically elevated C-reactive protein and ischemic vascular disease | journal = The New England Journal of Medicine | volume = 359 | issue = 18 | pages = 1897–908 | date = Oct 2008 | pmid = 18971492 | doi = 10.1056/NEJMoa0707402 }}</ref> A study published in 2011 shows that CRP is associated with lipid responses to low-fat and high-polyunsaturated fat diets.<ref name="pmid19297430">{{cite journal | vauthors = St-Onge MP, Zhang S, Darnell B, Allison DB | title = Baseline serum C-reactive protein is associated with lipid responses to low-fat and high-polyunsaturated fat diets | journal = The Journal of Nutrition | volume = 139 | issue = 4 | pages = 680–3 | date = Apr 2009 | pmid = 19297430 | pmc = 2666362 | doi = 10.3945/jn.108.098251 }}</ref>
The [[American Heart Association]] and U.S. [[Centers for Disease Control and Prevention]] have defined risk groups as follows:<ref>{{cite web |url=http://labtestsonline.org/understanding/analytes/hscrp/tab/test |title=hs-CRP |access-date=June 3, 2013}}</ref>
* Low Risk: less than 1.0&nbsp;mg/L
* Average risk: 1.0 to 3.0&nbsp;mg/L
* High risk: above 3.0&nbsp;mg/L
But hs-CRP is not to be used alone and should be combined with elevated levels of cholesterol, LDL-C, [[triglycerides]], and glucose level. Smoking, hypertension and diabetes also increase the risk level of cardiovascular disease.


=== Fibrosis and inflammation ===
=== Fibrosis and inflammation ===


[[Scleroderma]], [[polymyositis]], and [[dermatomyositis]] elicit little or no CRP response. CRP levels also tend not to be elevated in [[Systemic lupus erythematosus|SLE]] unless [[serositis]] or [[synovitis]] is present. Elevations of CRP in the absence of clinically significant inflammation can occur in [[Kidney failure|renal failure]]. CRP level is an independent risk factor for atherosclerotic disease. Patients with high CRP concentrations are more likely to develop [[stroke]], [[myocardial infarction]], and severe [[Peripheral artery disease|peripheral vascular disease]].<ref name="Risk">{{cite journal | vauthors = Clearfield MB | title = C-reactive protein: a new risk assessment tool for cardiovascular disease | journal = The Journal of the American Osteopathic Association | volume = 105 | issue = 9 | pages = 409–16 | date = Sep 2005 | pmid = 16239491 | url = http://www.jaoa.org/content/105/9/409.full }}</ref> Elevated level of CRP can also be observed in [[inflammatory bowel disease]] (IBD), including [[Crohn's disease]] and [[ulcerative colitis]].<ref name="pmid23689052">{{cite journal | vauthors = Liu S, Ren J, Xia Q, Wu X, Han G, Ren H, Yan D, Wang G, Gu G, Li J | title = Preliminary case-control study to evaluate diagnostic values of C-reactive protein and erythrocyte sedimentation rate in differentiating active Crohn's disease from intestinal lymphoma, intestinal tuberculosis and Behcet's syndrome | journal = The American Journal of the Medical Sciences | volume = 346 | issue = 6 | pages = 467–72 | date = Dec 2013 | pmid = 23689052 | doi = 10.1097/MAJ.0b013e3182959a18 }}{{Unreliable medical source|date=August 2013|sure=y}}</ref>
[[Scleroderma]], [[polymyositis]], and [[dermatomyositis]] elicit little or no CRP response. CRP levels also tend not to be elevated in [[Systemic lupus erythematosus|SLE]] unless [[serositis]] or [[synovitis]] is present. Elevations of CRP in the absence of clinically significant inflammation can occur in [[Kidney failure|renal failure]]. CRP level is an independent risk factor for atherosclerotic disease. Patients with high CRP concentrations are more likely to develop [[stroke]], [[myocardial infarction]], and severe [[Peripheral artery disease|peripheral vascular disease]].<ref name="Risk">{{cite journal | vauthors = Clearfield MB | title = C-reactive protein: a new risk assessment tool for cardiovascular disease | journal = The Journal of the American Osteopathic Association | volume = 105 | issue = 9 | pages = 409–16 | date = September 2005 | pmid = 16239491 | url = http://www.jaoa.org/content/105/9/409.full | access-date = 2013-02-10 | archive-url = https://web.archive.org/web/20120110071000/http://www.jaoa.org/content/105/9/409.full# | archive-date = 2012-01-10 | dead-url = yes | df =  }}</ref> Elevated level of CRP can also be observed in [[inflammatory bowel disease]] (IBD), including [[Crohn's disease]] and [[ulcerative colitis]].<ref name="pmid23689052">{{cite journal | vauthors = Liu S, Ren J, Xia Q, Wu X, Han G, Ren H, Yan D, Wang G, Gu G, Li J | title = Preliminary case-control study to evaluate diagnostic values of C-reactive protein and erythrocyte sedimentation rate in differentiating active Crohn's disease from intestinal lymphoma, intestinal tuberculosis and Behcet's syndrome | journal = The American Journal of the Medical Sciences | volume = 346 | issue = 6 | pages = 467–72 | date = December 2013 | pmid = 23689052 | doi = 10.1097/MAJ.0b013e3182959a18 }}{{Unreliable medical source|date=August 2013|sure=y}}</ref>


High levels of CRP has been associated to point mutation '''Cys130Arg''' in '''''APOE''''' gene, coding for [[apolipoprotein E]], establishing a link between [[lipid]] values and inflammatory markers modulation.<ref>{{cite journal|author=Sidore, C. |display-authors=etal |title=Genome sequencing elucidates Sardinian genetic architecture and augments association analyses for lipid and blood inflammatory markers |year=2015 |journal=Nature Genetics |volume=47 |pages=1272–1281 |doi=10.1038/ng.3368 |pmid=26366554 |pmc=4627508}}</ref>
High levels of CRP has been associated to point mutation '''Cys130Arg''' in '''''APOE''''' gene, coding for [[apolipoprotein E]], establishing a link between [[lipid]] values and inflammatory markers modulation.<ref>{{cite journal | vauthors = Sidore C, Busonero F, Maschio A, Porcu E, Naitza S, Zoledziewska M, Mulas A, Pistis G, Steri M, Danjou F, Kwong A, Ortega Del Vecchyo VD, Chiang CW, Bragg-Gresham J, Pitzalis M, Nagaraja R, Tarrier B, Brennan C, Uzzau S, Fuchsberger C, Atzeni R, Reinier F, Berutti R, Huang J, Timpson NJ, Toniolo D, Gasparini P, Malerba G, Dedoussis G, Zeggini E, Soranzo N, Jones C, Lyons R, Angius A, Kang HM, Novembre J, Sanna S, Schlessinger D, Cucca F, Abecasis GR | display-authors = 6 | title = Genome sequencing elucidates Sardinian genetic architecture and augments association analyses for lipid and blood inflammatory markers | journal = Nature Genetics | volume = 47 | issue = 11 | pages = 1272–1281 | date = November 2015 | pmid = 26366554 | pmc = 4627508 | doi = 10.1038/ng.3368 }}</ref>


=== Obstructive sleep apnea ===
=== Cancer ===


C-reactive protein (CRP), a marker of systemic inflammation, is also increased in [[obstructive sleep apnea]] (OSA). CRP and interleukin-6 (IL-6) levels were significantly higher in patients with OSA compared to obese control subjects.<ref name="pmid23533751">{{cite journal | vauthors = Latina JM, Estes NA, Garlitski AC | title = The Relationship between Obstructive Sleep Apnea and Atrial Fibrillation: A Complex Interplay | journal = Pulmonary Medicine | volume = 2013 | issue = | pages = 621736 | year = 2013 | pmid = 23533751 | pmc = 3600315 | doi = 10.1155/2013/621736 }}</ref> Patients with OSA have higher plasma CRP concentrations that increased corresponding to the severity of their apnea-hypopnea index score.  Treatment of OSA with CPAP (continuous positive airway pressure) significantly alleviated the effect of OSA on CRP and IL-6 levels.<ref name="pmid23533751"/>
The role of inflammation in cancer is not well understood. Some organs of the body show greater risk of cancer when they are chronically inflamed.<ref>{{cite journal | vauthors = Lu H, Ouyang W, Huang C | title = Inflammation, a key event in cancer development | journal = Molecular Cancer Research | volume = 4 | issue = 4 | pages = 221–33 | date = April 2006 | pmid = 16603636 | doi = 10.1158/1541-7786.MCR-05-0261 }}</ref> While there is an association between increased levels of C-reactive protein and risk of developing cancer, there is no association between genetic polymorphisms influencing circulating levels of CRP and cancer risk.<ref name="pmid22035340">{{cite journal | vauthors = Allin KH, Nordestgaard BG | title = Elevated C-reactive protein in the diagnosis, prognosis, and cause of cancer | journal = Critical Reviews in Clinical Laboratory Sciences | volume = 48 | issue = 4 | pages = 155–70 | year = 2011 | pmid = 22035340 | doi = 10.3109/10408363.2011.599831 }}</ref>


=== Coronary heart disease risk ===
In a 2004 [[prospective cohort study]] on colon cancer risk associated with CRP levels, people with [[colon cancer]] had higher average CRP concentrations than people without colon cancer.<ref name="pmid14762037">{{cite journal | vauthors = Erlinger TP, Platz EA, Rifai N, Helzlsouer KJ | title = C-reactive protein and the risk of incident colorectal cancer | journal = Jama | volume = 291 | issue = 5 | pages = 585–90 | date = February 2004 | pmid = 14762037 | doi = 10.1001/jama.291.5.585 | url = http://jama.ama-assn.org/content/291/5/585.full.pdf }}</ref> It can be noted that the average CRP levels in both groups were well within the range of CRP levels usually found in healthy people. However, these findings may suggest that low inflammation level can be associated with a lower risk of colon cancer, concurring with previous studies that indicate [[Non-steroidal anti-inflammatory drug|anti-inflammatory drugs]] could lower colon cancer risk.<ref name="pmid12621133">{{cite journal | vauthors = Baron JA, Cole BF, Sandler RS, Haile RW, Ahnen D, Bresalier R, McKeown-Eyssen G, Summers RW, Rothstein R, Burke CA, Snover DC, Church TR, Allen JI, Beach M, Beck GJ, Bond JH, Byers T, Greenberg ER, Mandel JS, Marcon N, Mott LA, Pearson L, Saibil F, van Stolk RU | display-authors = 6 | title = A randomized trial of aspirin to prevent colorectal adenomas | journal = The New England Journal of Medicine | volume = 348 | issue = 10 | pages = 891–9 | date = March 2003 | pmid = 12621133 | doi = 10.1056/NEJMoa021735 }}</ref>


Arterial damage results from [[macrophage|white blood cell]] invasion and [[inflammation]] within the wall. CRP is a general marker for inflammation and infection, so it can be used as a very rough proxy for heart disease risk. Since many things can cause elevated CRP, this is not a very [[Sensitivity and specificity|specific]] prognostic indicator.<ref name="Lloyd-Jones">{{cite journal | vauthors = Lloyd-Jones DM, Liu K, Tian L, Greenland P | title = Narrative review: Assessment of C-reactive protein in risk prediction for cardiovascular disease | journal = Annals of Internal Medicine | volume = 145 | issue = 1 | pages = 35–42 | date = Jul 2006 | pmid = 16818927 | doi = 10.7326/0003-4819-145-1-200607040-00129 | url = http://annals.org/cgi/content/full/0000605-200607040-00129v1 }}</ref><ref>{{Cite journal|last=Bower|first=JK|last2=Lazo|first2=M|last3=Juraschek|first3=SP|last4=Selvin|first4=E|date=2012|year=|title=Within-person variability in high-sensitivity C-reactive protein|journal=Archives of Internal Medicine|volume=172|issue=19|pages=1519–1521|doi=10.1001/archinternmed.2012.3712|issn=1538-3679|pmc=3613132|pmid=22945505|via=}}</ref> Nevertheless, a level above 2.4&nbsp;mg/L has been associated with a doubled risk of a coronary event compared to levels below 1&nbsp;mg/L;<ref name=Pepys/> however, the study group in this case consisted of patients who had been diagnosed with unstable angina pectoris; whether elevated CRP has any predictive value of acute coronary events in the general population of all age ranges remains unclear. Currently, C-reactive protein is not recommended as a cardiovascular disease screening test for average-risk adults without symptoms.<ref name=Cecil>{{cite book|last1=Goldman|first1=Lee|title=Goldman's Cecil Medicine|publisher=Elsevier Saunders|location=Philadelphia|isbn=1437727883|year=2011|pages=54|edition=24th}}</ref>
=== Obstructive sleep apnea ===


The [[American Heart Association]] and U.S. [[Centers for Disease Control and Prevention]] have defined risk groups as follows:<ref>{{cite web |url=http://labtestsonline.org/understanding/analytes/hscrp/tab/test |title=hs-CRP |accessdate=June 3, 2013}}</ref>
C-reactive protein (CRP), a marker of systemic inflammation, is also increased in [[obstructive sleep apnea]] (OSA).  CRP and interleukin-6 (IL-6) levels were significantly higher in patients with OSA compared to obese control subjects.<ref name="pmid23533751">{{cite journal | vauthors = Latina JM, Estes NA, Garlitski AC | title = The Relationship between Obstructive Sleep Apnea and Atrial Fibrillation: A Complex Interplay | journal = Pulmonary Medicine | volume = 2013 | issue =  | pages = 621736 | year = 2013 | pmid = 23533751 | pmc = 3600315 | doi = 10.1155/2013/621736 }}</ref> Patients with OSA have higher plasma CRP concentrations that increased corresponding to the severity of their apnea-hypopnea index score. Treatment of OSA with CPAP (continuous positive airway pressure) significantly alleviated the effect of OSA on CRP and IL-6 levels.<ref name="pmid23533751"/>
* Low Risk: less than 1.0&nbsp;mg/L
* Average risk: 1.0 to 3.0&nbsp;mg/L
* High risk: above 3.0&nbsp;mg/L
But hs-CRP is not to be used alone and should be combined with elevated levels of cholesterol, LDL-C, [[triglycerides]], and glucose level. Smoking, hypertension and diabetes also increase the risk level of cardiovascular disease.


=== Rheumatoid arthritis ===
=== Rheumatoid arthritis ===


It has previously been speculated that single-nucleotide polymorphisms in the CRP gene may affect clinical decision-making based on CRP in rheumatoid arthritis, e.g. DAS28 (Disease Activity Score 28 joints). A recent study showed that CRP genotype and haplotype were only marginally associated with serum CRP levels and without any association to the DAS28 score.<ref name="pmid25359432">{{cite journal | vauthors = Ammitzbøll CG, Steffensen R, Bøgsted M, Hørslev-Petersen K, Hetland ML, Junker P, Johansen JS, Pødenphant J, Østergaard M, Ellingsen T, Stengaard-Pedersen K | title = CRP genotype and haplotype associations with serum C-reactive protein level and DAS28 in untreated early rheumatoid arthritis patients | journal = Arthritis Research & Therapy | volume = 16 | issue = 5 | pages = 475 | year = 2014 | pmid = 25359432 | pmc = 4247621 | doi = 10.1186/s13075-014-0475-3 }}</ref> Thus, that DAS28, which is the core parameter for inflammatory activity in RA, can be used for clinical decision-making without adjustment for CRP gene variants.
It has previously been speculated that single-nucleotide polymorphisms in the CRP gene may affect clinical decision-making based on CRP in rheumatoid arthritis, e.g. DAS28 (Disease Activity Score 28 joints). A recent study showed that CRP genotype and haplotype were only marginally associated with serum CRP levels and without any association to the DAS28 score.<ref name="pmid25359432">{{cite journal | vauthors = Ammitzbøll CG, Steffensen R, Bøgsted M, Hørslev-Petersen K, Hetland ML, Junker P, Johansen JS, Pødenphant J, Østergaard M, Ellingsen T, Stengaard-Pedersen K | display-authors = 6 | title = CRP genotype and haplotype associations with serum C-reactive protein level and DAS28 in untreated early rheumatoid arthritis patients | journal = Arthritis Research & Therapy | volume = 16 | issue = 5 | pages = 475 | date = October 2014 | pmid = 25359432 | pmc = 4247621 | doi = 10.1186/s13075-014-0475-3 }}</ref> Thus, that DAS28, which is the core parameter for inflammatory activity in RA, can be used for clinical decision-making without adjustment for CRP gene variants.


== See also ==
== See also ==

Revision as of 07:23, 2 January 2019

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C-reactive protein (CRP) is an annular (ring-shaped), pentameric protein found in blood plasma, whose levels rise in response to inflammation. It is an acute-phase protein of hepatic origin that increases following interleukin-6 secretion by macrophages and T cells. Its physiological role is to bind to lysophosphatidylcholine expressed on the surface of dead or dying cells (and some types of bacteria) in order to activate the complement system via C1q.[1]

CRP is synthesized by the liver[2] in response to factors released by macrophages and fat cells (adipocytes).[3] It is a member of the pentraxin family of proteins.[2] It is not related to C-peptide (insulin) or protein C (blood coagulation). C-reactive protein was the first pattern recognition receptor (PRR) to be identified.[4]

History and nomenclature

Discovered by Tillett and Francis in 1930,[5] it was initially thought that CRP might be a pathogenic secretion since it was elevated in a variety of illnesses, including cancer.[2] The later discovery of hepatic synthesis (made in the liver) demonstrated that it is a native protein.[6][7][8] Initially, CRP was measured using Quellung reaction which gave a positive or a negative reaction. More precise methods nowadays is using dynamic light scattering on antibodies specific to CRP.[9]

CRP was so named because it was first identified as a substance in the serum of patients with acute inflammation that reacted with the antibody against the somatic capsular polysaccharide (C-polysaccharide) of pneumococcus.[10][11]

Genetics and structure

The CRP gene is located on chromosome 1 (1q23.2[12]). It is a member of the small pentraxins family. The monomer has 224 amino acids,[13] and molecular mass of 25,106 Da. In serum, it assembles into stable pentameric structure with a discoid shape.

Function

CRP binds to the phosphocholine expressed on the surface of dead or dying cells and some bacteria. This activates the complement system, promoting phagocytosis by macrophages, which clears necrotic and apoptotic cells and bacteria.[9]

This so-called acute phase response occurs as a result of a rise in the concentration of IL-6, which is produced by macrophages[2] as well as adipocytes[3] in response to a wide range of acute and chronic inflammatory conditions such as bacterial, viral, or fungal infections; rheumatic and other inflammatory diseases; malignancy; and tissue injury and necrosis. These conditions cause release of interleukin-6 and other cytokines that trigger the synthesis of CRP and fibrinogen by the liver.

CRP binds to phosphocholine on micro-organisms. It is thought to assist in complement binding to foreign and damaged cells and enhances phagocytosis by macrophages (opsonin-mediated phagocytosis), which express a receptor for CRP. It plays a role in innate immunity as an early defense system against infections.[9]

Serum levels

In healthy adults, the normal concentrations of CRP varies between 0.8 mg/L to 3.0 mg/L. However, some healthy adults show elevated CRP at 10 mg/L. When there is a stimulus, the CRP level can rise 10,000-fold from less than 50 μg/l to more than 500 mg/L. Such levels can rise to 5 mg/L by 6 hours and peaks at 48 hours. The plasma half-life of CRP is 19 hours. Such half-life is constant in all medical conditions. Therefore, the only factor that affects the level of CRP in blood is its rate of production. The rate of CRP production increases with inflammation, infection, trauma, necrosis, malignancy, and allergic reaction. The CRP level also increases with age, possibly due to increasing subclinical condition. There is also no seasonal variations of CRP levels. Gene polymorphism of interleukin-1 family, interleukin 6, and polymorphic GT repeat of the CRP gene do affects the usual CRP levels when a person does not have any medical illnesses.[2] Other inflammatory mediators that can cause a rise in CRP are TGF beta 1, and tumor necrosis factor alpha. In acute inflammation, CRP can raise as much as 50 to 100 mg/dL within 4 to 6 hours in mild to moderate inflammation or insult such as skin infection, cystitis, or bronchitis. It can double every 8 hours and reaches its peak at 36 to 50 hours following injury or inflammation. CRP between 100 to 500 mg/dL is considered as bacterial inflammation. CRP concentrations between 2 to 10 mg/dL are considered as metabolic inflammation (metabolic pathways that causes arteriosclerosis and type II diabetes mellitus). Once inflammation subsides, CRP level falls quickly because of its relatively short half-life.[9]

Clinical significance

Diagnostic use

CRP is used mainly as a marker of inflammation. Apart from liver failure, there are few known factors that interfere with CRP production.[2] Interferon alpha inhibits CRP production from liver cells which may explain the relatively low levels of CRP found during viral infections compared to bacterial infections [14]

Measuring and charting CRP values can prove useful in determining disease progress or the effectiveness of treatments. ELISA, immunoturbidimetry, nephelometry, rapid immunodiffusion, and visual agglutination are all methods used to measure CRP.

File:Blood values sorted by mass and molar concentration.png
Reference ranges for blood tests, showing C-reactive protein in brown-yellow in center.

A high-sensitivity CRP (hs-CRP) test measures low levels of CRP using laser nephelometry. The test gives results in 25 minutes with a sensitivity down to 0.04 mg/L.

The risk of developing cardiovascular disease is quantified as follows:[15]

  • low: hs-CRP level under 1.0 mg/L
  • average: between 1.0 and 3.0 mg/L
  • high: above 3.0 mg/L

Normal levels increase with aging.[16] Higher levels are found in late pregnant women, mild inflammation and viral infections (10–40 mg/L), active inflammation, bacterial infection (40–200 mg/L), severe bacterial infections and burns (>200 mg/L).[17]

CRP is a more sensitive and accurate reflection of the acute phase response than the ESR[18] (Erythrocyte Sedimentation Rate). ESR may be normal while CRP is elevated. CRP returns to normal more quickly than ESR in response to therapy.

The utility of CRP in differentiating inflammatory diseases (including inflammatory bowel disease, intestinal lymphoma, intestinal tuberculosis, and Behcet's syndrome) has been investigated and compared to other inflammatory biomarkers, such as ESR and WBC.[18]

Cardiovascular disease

Recent research suggests that patients with elevated basal levels of CRP are at an increased risk of diabetes,[19][20] hypertension and cardiovascular disease. A study of over 700 nurses showed that those in the highest quartile of trans fat consumption had blood levels of CRP that were 73% higher than those in the lowest quartile.[21] Although one group of researchers indicated that CRP may be only a moderate risk factor for cardiovascular disease,[22] this study (known as the Reykjavik Study) was found to have some problems for this type of analysis related to the characteristics of the population studied, and there was an extremely long follow-up time, which may have attenuated the association between CRP and future outcomes.[23] Others have shown that CRP can exacerbate ischemic necrosis in a complement-dependent fashion and that CRP inhibition can be a safe and effective therapy for myocardial and cerebral infarcts; so far, this has been demonstrated in animal models only.[24]

It has been hypothesized that patients with high CRP levels might benefit from use of statins. This is based on the JUPITER trial that found that elevated CRP levels without hyperlipidemia benefited. Statins were selected because they have been proven to reduce levels of CRP.[2][25] Studies comparing effect of various statins in hs-CRP revealed similar effects of different statins.[26][27] A subsequent trial however failed to find that CRP was useful for determining statin benefit.[28]

In a meta-analysis of 20 studies involving 1,466 patients with coronary artery disease, CRP levels were found to be reduced after exercise interventions. Among those studies, higher CRP concentrations or poorer lipid profiles before beginning exercise were associated with greater reductions in CRP.[29]

To clarify whether CRP is a bystander or active participant in atherogenesis, a 2008 study compared people with various genetic CRP variants. Those with a high CRP due to genetic variation had no increased risk of cardiovascular disease compared to those with a normal or low CRP.[30] A study published in 2011 shows that CRP is associated with lipid responses to low-fat and high-polyunsaturated fat diets.[31]

Coronary heart disease risk

Arterial damage results from white blood cell invasion and inflammation within the wall. CRP is a general marker for inflammation and infection, so it can be used as a very rough proxy for heart disease risk. Since many things can cause elevated CRP, this is not a very specific prognostic indicator.[32][33] Nevertheless, a level above 2.4 mg/L has been associated with a doubled risk of a coronary event compared to levels below 1 mg/L;[2] however, the study group in this case consisted of patients who had been diagnosed with unstable angina pectoris; whether elevated CRP has any predictive value of acute coronary events in the general population of all age ranges remains unclear. Currently, C-reactive protein is not recommended as a cardiovascular disease screening test for average-risk adults without symptoms.[34]

The American Heart Association and U.S. Centers for Disease Control and Prevention have defined risk groups as follows:[35]

  • Low Risk: less than 1.0 mg/L
  • Average risk: 1.0 to 3.0 mg/L
  • High risk: above 3.0 mg/L

But hs-CRP is not to be used alone and should be combined with elevated levels of cholesterol, LDL-C, triglycerides, and glucose level. Smoking, hypertension and diabetes also increase the risk level of cardiovascular disease.

Fibrosis and inflammation

Scleroderma, polymyositis, and dermatomyositis elicit little or no CRP response. CRP levels also tend not to be elevated in SLE unless serositis or synovitis is present. Elevations of CRP in the absence of clinically significant inflammation can occur in renal failure. CRP level is an independent risk factor for atherosclerotic disease. Patients with high CRP concentrations are more likely to develop stroke, myocardial infarction, and severe peripheral vascular disease.[36] Elevated level of CRP can also be observed in inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis.[18]

High levels of CRP has been associated to point mutation Cys130Arg in APOE gene, coding for apolipoprotein E, establishing a link between lipid values and inflammatory markers modulation.[37]

Cancer

The role of inflammation in cancer is not well understood. Some organs of the body show greater risk of cancer when they are chronically inflamed.[38] While there is an association between increased levels of C-reactive protein and risk of developing cancer, there is no association between genetic polymorphisms influencing circulating levels of CRP and cancer risk.[39]

In a 2004 prospective cohort study on colon cancer risk associated with CRP levels, people with colon cancer had higher average CRP concentrations than people without colon cancer.[40] It can be noted that the average CRP levels in both groups were well within the range of CRP levels usually found in healthy people. However, these findings may suggest that low inflammation level can be associated with a lower risk of colon cancer, concurring with previous studies that indicate anti-inflammatory drugs could lower colon cancer risk.[41]

Obstructive sleep apnea

C-reactive protein (CRP), a marker of systemic inflammation, is also increased in obstructive sleep apnea (OSA). CRP and interleukin-6 (IL-6) levels were significantly higher in patients with OSA compared to obese control subjects.[42] Patients with OSA have higher plasma CRP concentrations that increased corresponding to the severity of their apnea-hypopnea index score. Treatment of OSA with CPAP (continuous positive airway pressure) significantly alleviated the effect of OSA on CRP and IL-6 levels.[42]

Rheumatoid arthritis

It has previously been speculated that single-nucleotide polymorphisms in the CRP gene may affect clinical decision-making based on CRP in rheumatoid arthritis, e.g. DAS28 (Disease Activity Score 28 joints). A recent study showed that CRP genotype and haplotype were only marginally associated with serum CRP levels and without any association to the DAS28 score.[43] Thus, that DAS28, which is the core parameter for inflammatory activity in RA, can be used for clinical decision-making without adjustment for CRP gene variants.

See also

Additional images

References

  1. ↑ Thompson D, Pepys MB, Wood SP (February 1999). "The physiological structure of human C-reactive protein and its complex with phosphocholine". Structure. 7 (2): 169–77. doi:10.1016/S0969-2126(99)80023-9. PMID 10368284.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 Pepys MB, Hirschfield GM (June 2003). "C-reactive protein: a critical update". The Journal of Clinical Investigation. 111 (12): 1805–12. doi:10.1172/JCI18921. PMC 161431. PMID 12813013.
  3. ↑ 3.0 3.1 Lau DC, Dhillon B, Yan H, Szmitko PE, Verma S (May 2005). "Adipokines: molecular links between obesity and atheroslcerosis". American Journal of Physiology. Heart and Circulatory Physiology. 288 (5): H2031–41. doi:10.1152/ajpheart.01058.2004. PMID 15653761.
  4. ↑ Mantovani A, Garlanda C, Doni A, Bottazzi B (January 2008). "Pentraxins in innate immunity: from C-reactive protein to the long pentraxin PTX3". Journal of Clinical Immunology. 28 (1): 1–13. doi:10.1007/s10875-007-9126-7. PMID 17828584.
  5. ↑ Tillett WS, Francis T (September 1930). "Serological reactions in pneumonia with a nonprotein somatic fraction of pneumococcus". The Journal of Experimental Medicine. 52 (4): 561–71. doi:10.1084/jem.52.4.561. PMC 2131884. PMID 19869788.
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  8. ↑ Ratey JJ, Noskin GA, Braun R, Hanley EN Jr, McInnes IB, Ruddy S (2008). Kelley's Textbook of Rheumatology: 2-Volume Set, Expert Consult: Online and Print (Textbook of Rheumatology (Kelley's)(2 Vol)). Philadelphia: Saunders. ISBN 1-4160-3285-1.
  9. ↑ 9.0 9.1 9.2 9.3 Bray C, Bell LN, Liang H, Haykal R, Kaiksow F, Mazza JJ, Yale SH (December 2016). "Erythrocyte Sedimentation Rate and C-reactive Protein Measurements and Their Relevance in Clinical Medicine" (PDF). Wisconsin Medical Journal (WMJ). 115 (6): 317–21. PMID 29094869.
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