A Genetic Association Study of Serum Acute-Phase C-Reactive Protein Levels in Rheumatoid Arthritis: Implications for Clinical Interpretation
Background:
The acute-phase increase in serum C-reactive protein (CRP) is used to diagnose and monitor infectious and inflammatory diseases. Little is known about the influence of genetics on acute-phase CRP, particularly in patients with chronic inflammation.
Methods and Findings:
We studied two independent sets of patients with chronic inflammation due to rheumatoid arthritis (total 695 patients). A tagSNP approach captured common variation at the CRP locus and the relationship between genotype and serum CRP was explored by linear modelling. Erythrocyte sedimentation rate (ESR) was incorporated as an independent marker of inflammation to adjust for the varying levels of inflammatory disease activity between patients. Common genetic variants at the CRP locus were associated with acute-phase serum CRP (for the most associated haplotype: p = 0.002, p<0.0005, p<0.0005 in patient sets 1, 2, and the combined sets, respectively), translating into an approximately 3.5-fold change in expected serum CRP concentrations between carriers of two common CRP haplotypes. For example, when ESR = 50 mm/h the expected geometric mean CRP (95% confidence interval) concentration was 43.1 mg/l (32.1–50.0) for haplotype 1 and 14.2 mg/l (9.5–23.2) for haplotype 4.
Conclusions:
Our findings raise questions about the interpretation of acute-phase serum CRP. In particular, failure to take into account the potential for genetic effects may result in the inappropriate reassurance or suboptimal treatment of patients simply because they carry low-CRP–associated genetic variants. CRP is increasingly being incorporated into clinical algorithms to compare disease activity between patients and to predict future clinical events: our findings impact on the use of these algorithms. For example, where access to effective, but expensive, biological therapies in rheumatoid arthritis is rationed on the basis of a DAS28-CRP clinical activity score, then two patients with identical underlying disease severity could be given, or denied, treatment on the basis of CRP genotype alone. The accuracy and utility of these algorithms might be improved by using a genetically adjusted CRP measurement.
: Please see later in the article for the Editors' Summary
Vyšlo v časopise:
A Genetic Association Study of Serum Acute-Phase C-Reactive Protein Levels in Rheumatoid Arthritis: Implications for Clinical Interpretation. PLoS Med 7(9): e32767. doi:10.1371/journal.pmed.1000341
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pmed.1000341
Souhrn
Background:
The acute-phase increase in serum C-reactive protein (CRP) is used to diagnose and monitor infectious and inflammatory diseases. Little is known about the influence of genetics on acute-phase CRP, particularly in patients with chronic inflammation.
Methods and Findings:
We studied two independent sets of patients with chronic inflammation due to rheumatoid arthritis (total 695 patients). A tagSNP approach captured common variation at the CRP locus and the relationship between genotype and serum CRP was explored by linear modelling. Erythrocyte sedimentation rate (ESR) was incorporated as an independent marker of inflammation to adjust for the varying levels of inflammatory disease activity between patients. Common genetic variants at the CRP locus were associated with acute-phase serum CRP (for the most associated haplotype: p = 0.002, p<0.0005, p<0.0005 in patient sets 1, 2, and the combined sets, respectively), translating into an approximately 3.5-fold change in expected serum CRP concentrations between carriers of two common CRP haplotypes. For example, when ESR = 50 mm/h the expected geometric mean CRP (95% confidence interval) concentration was 43.1 mg/l (32.1–50.0) for haplotype 1 and 14.2 mg/l (9.5–23.2) for haplotype 4.
Conclusions:
Our findings raise questions about the interpretation of acute-phase serum CRP. In particular, failure to take into account the potential for genetic effects may result in the inappropriate reassurance or suboptimal treatment of patients simply because they carry low-CRP–associated genetic variants. CRP is increasingly being incorporated into clinical algorithms to compare disease activity between patients and to predict future clinical events: our findings impact on the use of these algorithms. For example, where access to effective, but expensive, biological therapies in rheumatoid arthritis is rationed on the basis of a DAS28-CRP clinical activity score, then two patients with identical underlying disease severity could be given, or denied, treatment on the basis of CRP genotype alone. The accuracy and utility of these algorithms might be improved by using a genetically adjusted CRP measurement.
: Please see later in the article for the Editors' Summary
Zdroje
1. CarlsonCS
AldredSF
LeePK
TracyRP
SchwartzSM
2005 Polymorphisms within the C-reactive protein (CRP) promoter region are associated with plasma CRP levels. Am J Hum Genet 77 64 77
2. MillerDT
ZeeRY
SukDJ
KozlowskiP
ChasmanDI
2005 Association of common CRP gene variants with CRP levels and cardiovascular events. Ann Hum Genet 69 623 638
3. CrawfordDC
SandersCL
QinX
SmithJD
ShephardC
2006 Genetic variation is associated with C-reactive protein levels in the Third National Health and Nutrition Examination Survey. Circulation 114 2458 2465
4. KathiresanS
LarsonMG
VasanRS
GuoCY
GonaP
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
5. LangeLA
CarlsonCS
HindorffLA
LangeEM
WalstonJ
2006 Association of polymorphisms in the CRP gene with circulating C-reactive protein levels and cardiovascular events. JAMA 296 2703 2711
6. DaneshJ
WheelerJG
HirschfieldGM
EdaS
EiriksdottirG
2004 C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med 350 1387 1397
7. DaneshJ
PepysMB
2009 C-reactive protein and coronary disease: is there a causal link? Circulation 120 2036 2039
8. PepysMB
HirschfieldGM
2003 C-reactive protein: a critical update. J Clin Invest 111 1805 1812
9. D'AiutoF
CasasJP
ShahT
HumphriesSE
HingoraniAD
2005 C-reactive protein (+1444C>T) polymorphism influences CRP response following a moderate inflammatory stimulus. Atherosclerosis 179 413 417
10. MotoyamaS
MiuraM
HinaiY
MaruyamaK
UsamiS
2009 C-reactive protein 1059G>C genetic polymorphism influences serum C-reactive protein levels after esophagectomy in patients with thoracic esophageal cancer. J Am Coll Surg 209 477 483
11. PerryTE
MuehlschlegelJD
LiuKY
FoxAA
CollardCD
2009 C-Reactive protein gene variants are associated with postoperative C-reactive protein levels after coronary artery bypass surgery. BMC Med Genet 10 38
12. SukDJ
ChasmanDI
CannonCP
MillerDT
ZeeRY
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
13. BrullDJ
SerranoN
ZitoF
JonesL
MontgomeryHE
2003 Human CRP gene polymorphism influences CRP levels: implications for the prediction and pathogenesis of coronary heart disease. Arterioscler Thromb Vasc Biol 23 2063 2069
14. RopesMW
RossmeislE
BauerW
1939 The relationship between the erythrocyte sedimentation rate and the plasma proteins. J Clin Invest 18 791 798
15. ZlonisM
1993 The mystique of the erythrocyte sedimentation rate. A reappraisal of one of the oldest laboratory tests still in use. Clin Lab Med 13 787 800
16. AnderssonR
MalmvallBE
BengtssonBA
1986 Acute phase reactants in the initial phase of giant cell arteritis. Acta Med Scand 220 365 367
17. Osei-BimpongA
MeekJH
LewisSM
2007 ESR or CRP? A comparison of their clinical utility. Hematology 12 353 357
18. SteerS
LadB
GrumleyJA
KingsleyGH
FisherSA
2005 Association of R602W in a protein tyrosine phosphatase gene with a high risk of rheumatoid arthritis in a British population: evidence for an early onset/disease severity effect. Arthritis Rheum 52 358 360
19. ArnettFC
EdworthySM
BlochDA
McShaneDJ
FriesJF
1988 The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31 315 324
20. RhodesB
MeekJ
WhittakerJC
VyseTJ
2008 Quantification of the genetic component of basal C-reactive protein expression in SLE nuclear families. Ann Hum Genet 72 611 620
21. BarrettJC
FryB
MallerJ
DalyMJ
2005 Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21 263 265
22. StephensM
DonnellyP
2003 A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 73 1162 1169
23. PepysMB
HirschfieldGM
TennentGA
GallimoreJR
KahanMC
2006 Targeting C-reactive protein for the treatment of cardiovascular disease. Nature 440 1217 1221
24. RidkerPM
PareG
ParkerA
ZeeRY
DanikJS
2008 Loci related to metabolic-syndrome pathways including LEPR, HNF1A, IL6R, and GCKR associate with plasma C-reactive protein: the Women's Genome Health Study. Am J Hum Genet 82 1185 1192
25. VerzilliC
ShahT
CasasJP
ChapmanJ
SandhuM
2008 Bayesian meta-analysis of genetic association studies with different sets of markers. Am J Hum Genet 82 859 872
26. KushnerI
SamolsD
MagreyM
2010 A unifying biologic explanation for “high-sensitivity” C-reactive protein and “low-grade” inflammation. Arthritis Care Res (Hoboken) 62 442 446
27. FransenJ
WelsingPM
de KuijzerRM
van RielPL
2004 Disease activity scores using C-reactive protein: CRP may replace ESR in the assessment of RA disease activity. Ann Rheum Dis 62 Suppl 1 151
28. ArtzAS
WickremaA
DinnerS
GodleyLA
KocherginskyM
2008 Pretreatment C-reactive protein is a predictor for outcomes after reduced-intensity allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 14 1209 1216
29. BajwaEK
KhanUA
JanuzziJL
GongMN
ThompsonBT
2009 Plasma C-reactive protein levels are associated with improved outcome in ARDS. Chest 136 471 480
30. KimDK
OhSY
KwonHC
LeeS
KwonKA
2009 Clinical significances of preoperative serum interleukin-6 and C-reactive protein level in operable gastric cancer. BMC Cancer 9 155
31. KoikeY
MikiC
OkugawaY
YokoeT
ToiyamaY
2008 Preoperative C-reactive protein as a prognostic and therapeutic marker for colorectal cancer. J Surg Oncol 98 540 544
32. KompotiM
DrimisS
PapadakiA
KotsomytisK
PoulopoulouC
2008 Serum C-reactive protein at admission predicts in-hospital mortality in medical patients. Eur J Intern Med 19 261 265
33. MoonJM
ChunBJ
2009 Predicting the complicated neutropenic fever in the emergency department. Emerg Med J 26 802 806
34. PooleCD
ConwayP
ReynoldsA
CurrieCJ
2008 The association between C-reactive protein and the likelihood of progression to joint replacement in people with rheumatoid arthritis: a retrospective observational study. BMC Musculoskelet Disord 9 146
35. van der Helm-van MilA
leCS
vanDH
BreedveldFC
ToesRE
2007 A prediction rule for disease outcome in patients with recent-onset undifferentiated arthritis: how to guide individual treatment decisions. Arthritis Rheum 56 433 440
36. RhodesB
WongA
NavarraSV
VillaminC
VyseTJ
2008 Genetic determinants of basal C-reactive protein expression in Filipino systemic lupus erythematosus families. Genes Immun 9 153 160
37. RhodesB
MorrisDL
SubrahmanyanL
AubinC
de LeonCF
2008 Fine-mapping the genetic basis of CRP regulation in African Americans: a Bayesian approach. Hum Genet 123 633 642
Štítky
Interné lekárstvoČlánok vyšiel v časopise
PLOS Medicine
2010 Číslo 9
- Statinová intolerance
- Očkování proti virové hemoragické horečce Ebola experimentální vakcínou rVSVDG-ZEBOV-GP
- Co dělat při intoleranci statinů?
- Pleiotropní účinky statinů na kardiovaskulární systém
- DESATORO PRE PRAX: Aktuálne odporúčanie ESPEN pre nutričný manažment u pacientov s COVID-19
Najčítanejšie v tomto čísle
- Seventy-Five Trials and Eleven Systematic Reviews a Day: How Will We Ever Keep Up?
- A Genetic Association Study of Serum Acute-Phase C-Reactive Protein Levels in Rheumatoid Arthritis: Implications for Clinical Interpretation
- Persistence with Statins and Onset of Rheumatoid Arthritis: A Population-Based Cohort Study
- Effectiveness of Chest Physiotherapy in Infants Hospitalized with Acute Bronchiolitis: A Multicenter, Randomized, Controlled Trial