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Correlation of C-reactive protein haplotypes with serum C-reactive protein level and response to anti-tumor necrosis factor therapy in UK rheumatoid arthritis patients: results from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate cohort

Darren Plant1, Ibrahim Ibrahim1, Mark Lunt1, Stephen Eyre1, Edward Flynn1, Kimme L Hyrich1, Ann W Morgan23, Anthony G Wilson4, John D Isaacs5, BRAGGGSS6 and Anne Barton17*

Author affiliations

1 Arthritis Research UK Epidemiology Unit, Manchester Academy of Health Science, University of Manchester, Oxford Road, Manchester, M13 9PT, UK

2 NIHR Leeds Musculoskeletal Biomedical Research Unit, Chapel Allerton Hospital, The Leeds Teaching Hospitals NHS Trust, Chapeltown Road, Leeds, LS7 4SA, UK

3 Leeds Institute of Molecular Medicine, Wellcome Trust Brenner Building, St. James's University Hospital, The Leeds Teaching Hospitals NHS Trust, Beckett Street, Leeds, LS9 7TF, UK

4 Department of Infection and Immunity, University of Sheffield Medical School, Beech Hill Road, Sheffield, S10 2RX, UK

5 Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University and Newcastle upon Tyne NHS Foundation Trust, Framlington Place, Newcastle-upon-Tyne, NE2 4HH, UK

6 Member details at end of article

7 NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Grafton Street, Manchester, M13 9WL, UK

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Citation and License

Arthritis Research & Therapy 2012, 14:R214  doi:10.1186/ar4052

Published: 7 October 2012



In many European countries, restrictions exist around the prescription of anti-tumor necrosis factor (anti-TNF) treatments for rheumatoid arthritis (RA). Eligibility and response to treatment is assessed by using the disease activity score 28 (DAS28) algorithm, which incorporates one of two inflammatory markers, erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP). Although DAS28-CRP provides a more reliable measure of disease activity, functional variants exist within the CRP gene that affect basal CRP production.

Therefore, we aimed to determine the relation between functional genetic variants at the CRP gene locus and levels of serum CRP in RA patients, and whether these variants, alone or in combination, are correlated with DAS28-CRP and change in DAS28-CRP after anti-TNF treatment.


DNA samples from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS) were genotyped for rs1205, rs1800947, and rs3091244 by using either TaqMan or the Sequenom MassARRAY iPLEX system.

Estimated haplotypes were constructed for each sample by using the expectation maximization algorithm implemented in the haplo.stats package within the R statistical program.

CRP values were log transformed, and the association between single nucleotide polymorphisms (SNPs), haplotypes of SNPs and baseline CRP, baseline DAS28-CRP, and change in DAS28-CRP were evaluated by using linear regression in STATA v.10.


Baseline CRP measurements were available for 599 samples with 442 also having data 6 months after treatment with an anti-TNF. For these 442 samples, the study had > 80% power to detect a clinically meaningful difference of 0.6 DAS28 Units for an allele frequency of 5%. Estimated haplotype frequencies corresponded with previous frequencies reported in the literature. Overall, no significant association was observed between any of the markers investigated and baseline CRP levels. Further, CRP haplotypes did not correlate with baseline CRP (P = 0.593), baseline DAS28-CRP (P = 0.540), or change in DAS28-CRP after treatment with an anti-TNF over a 6-month period (P = 0.302).


Although CRP genotype may influence baseline CRP levels, in patients with very active disease, no such association was found. This suggests that genetic variation at the CRP locus does not influence DAS28-CRP, which may continue to be used in determining eligibility for and response to anti-TNF treatment, without adjusting for CRP genotype.