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SAT0014 Correlation of CRP haplotypes with response to anti-TNF therapy in UK patients – results from the BRAGGSS cohort
  1. I. Ibrahim1,
  2. D. Plant1,
  3. K. Hyrich1,
  4. A. Morgan2,
  5. A. Wilson3,
  6. J. Isaacs4,
  7. A. Barton1
  1. 1Arthritis Research UK Epidemiology Unit, University of Manchester, Manchester
  2. 2NIHR-Leeds Musculoskeletal Biomedical Research Unit, University of Leeds, Leeds
  3. 3Section of Musculoskeletal Sciences, University of Sheffield, Sheffield
  4. 4Musculoskeletal Research Group, Newcastle University and Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, United Kingdom

Abstract

Background Anti-TNF medication is the most effective treatment method in patients with RA and reduces inflammation by blocking the TNF pathway. However, this treatment is expensive, costing ∼£10,000 per patient, per year. Hence in the UK, restrictions exist around the prescription of anti-TNF medication and both eligibility for, and response to therapy is assessed using the 28 joint disease activity score (DAS28). The DAS28 incorporates one of two markers of inflammation, ESR or CRP; indeed, it has been suggested that DAS28-CRP provides a more reliable measure of disease activity.

C - reactive protein (CRP), an acute phase inflammatory marker that rises rapidly in response to acute inflammation, is elevated in patients with RA and can be used to calculate the DAS28-CRP. However, functional variants exist within the CRP gene that affect basal CRP production, and thus basal levels in a population can vary.

We hypothesised that genetic variation at the CRP locus may influence the baseline DAS28-CRP and the change in DAS28-CRP in patients receiving anti-TNF treatment for RA.

Objectives To determine the relationship between functional genetic variants at the CRP gene locus and levels of serum CRP in RA patients and determine whether these variants, alone or in combination, are correlated with DAS28-CRP and change in DAS28-CRP.

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

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

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

Results Baseline serum CRP measurements were available for 599 samples. Follow-up CRP data, 6 months after treatment with an anti-TNF, were available for 442 samples. 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 seen between any of the markers investigated and baseline CRP levels. Further, CRP haplotypes did not correlate with baseline CRP (p=1.00), baseline DAS28 (p=1.00), or improvement in DAS28 over 6 months after commencing anti-TNF treatment (p=1.00).

Moreover, adjustment for ESR as an independent marker of inflammation did not have an effect on correlation of CRP haplotypes with baseline CRP, baseline DAS28 or change in DAS28.

Conclusions 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 anti-TNF drugs.

Finally, a lack of correlation could be reflective of a lack of power, particularly for some of the less frequent haplotypes observed. In the future, more powerful studies will be needed to confirm these preliminary results.

Disclosure of Interest None Declared

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