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

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Abstract

ABSTRACT: INTRODUCTION: In many European countries, restrictions exist around the prescription of anti-tumour necrosis factor (anti-TNF) treatments for rheumatoid arthritis (RA). Eligibility and response to treatment is assessed 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 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 following anti-TNF treatment. METHODS: DNA samples from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS) were genotyped for rs1205, rs1800947 and rs3091244 using either TaqMan(R) or the Sequenom(R) 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 baseline CRP, baseline DAS28-CRP and change in DAS28-CRP were evaluated using linear regression in STATA v.10. RESULTS: 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 following treatment with an anti-TNF over 6 months (P=0.302). 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 and response to anti-TNF treatment, without adjusting for CRP genotype.

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