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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 in...

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Autores principales: Rhodes, Benjamin, Merriman, Marilyn E., Harrison, Andrew, Nissen, Michael J., Smith, Malcolm, Stamp, Lisa, Steer, Sophia, Merriman, Tony R., Vyse, Timothy J.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2943443/
https://www.ncbi.nlm.nih.gov/pubmed/20877716
http://dx.doi.org/10.1371/journal.pmed.1000341
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author Rhodes, Benjamin
Merriman, Marilyn E.
Harrison, Andrew
Nissen, Michael J.
Smith, Malcolm
Stamp, Lisa
Steer, Sophia
Merriman, Tony R.
Vyse, Timothy J.
author_facet Rhodes, Benjamin
Merriman, Marilyn E.
Harrison, Andrew
Nissen, Michael J.
Smith, Malcolm
Stamp, Lisa
Steer, Sophia
Merriman, Tony R.
Vyse, Timothy J.
author_sort Rhodes, Benjamin
collection PubMed
description 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
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spelling pubmed-29434432010-09-28 A Genetic Association Study of Serum Acute-Phase C-Reactive Protein Levels in Rheumatoid Arthritis: Implications for Clinical Interpretation Rhodes, Benjamin Merriman, Marilyn E. Harrison, Andrew Nissen, Michael J. Smith, Malcolm Stamp, Lisa Steer, Sophia Merriman, Tony R. Vyse, Timothy J. PLoS Med Research Article 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 Public Library of Science 2010-09-21 /pmc/articles/PMC2943443/ /pubmed/20877716 http://dx.doi.org/10.1371/journal.pmed.1000341 Text en Rhodes et al. http://creativecommons.org/licenses/by/4.0/ 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 properly credited.
spellingShingle Research Article
Rhodes, Benjamin
Merriman, Marilyn E.
Harrison, Andrew
Nissen, Michael J.
Smith, Malcolm
Stamp, Lisa
Steer, Sophia
Merriman, Tony R.
Vyse, Timothy J.
A Genetic Association Study of Serum Acute-Phase C-Reactive Protein Levels in Rheumatoid Arthritis: Implications for Clinical Interpretation
title A Genetic Association Study of Serum Acute-Phase C-Reactive Protein Levels in Rheumatoid Arthritis: Implications for Clinical Interpretation
title_full A Genetic Association Study of Serum Acute-Phase C-Reactive Protein Levels in Rheumatoid Arthritis: Implications for Clinical Interpretation
title_fullStr A Genetic Association Study of Serum Acute-Phase C-Reactive Protein Levels in Rheumatoid Arthritis: Implications for Clinical Interpretation
title_full_unstemmed A Genetic Association Study of Serum Acute-Phase C-Reactive Protein Levels in Rheumatoid Arthritis: Implications for Clinical Interpretation
title_short A Genetic Association Study of Serum Acute-Phase C-Reactive Protein Levels in Rheumatoid Arthritis: Implications for Clinical Interpretation
title_sort genetic association study of serum acute-phase c-reactive protein levels in rheumatoid arthritis: implications for clinical interpretation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2943443/
https://www.ncbi.nlm.nih.gov/pubmed/20877716
http://dx.doi.org/10.1371/journal.pmed.1000341
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