A genetic risk score composed of rheumatoid arthritis risk alleles, HLA-DRB1 haplotypes, and response to TNFi therapy - results from a Swedish cohort study.

Xia Jiang,Sebastien Viatte,Johan Askling,Leonid Padyukov,Lars Alfredsson,Thomas Frisell,Saedis Saevarsdottir

doi:10.1186/s13075-016-1174-z

Abstract

BackgroundTo prevent debilitating and irreversible joint damage, rheumatoid arthritis (RA) is often treated with tumor necrosis factor inhibitor (TNFi), but many patients do not respond to this costly therapy. Few predictors for response are known, and it has been proposed that genetic factors which influence the development of RA may also influence disease severity and response to therapy. Several previous studies have attempted to confirm this but results remain inconclusive. We expand on previous studies by including more RA risk alleles, and maximize power by combining them into a genetic risk score.MethodWe linked genotyped RA patients from the Epidemiological Investigation of Rheumatoid Arthritis study to the Swedish Rheumatology Quality Register, identifying patients who started a TNFi as their first biological disease-modifying anti-rheumatic drug, with a return visit within 2–8 months after treatment start (N = 867). We calculated risk scores from 76 established RA risk SNPs, and four HLA-DRB1 amino acid positions, and tested whether risk scores or individual genetic risk factors could predict the European League Against Rheumatism (EULAR) response.ResultsWe found no association between any of the risk scores or HLA-DRB1 haplotypes and EULAR response, neither overall nor stratified by anti-citrullinated protein/peptide antibody (ACPA) status. When evaluating each of the 76 SNPs, we found that the number of SNPs presenting significant associations was not higher than expected by chance (5/76 SNPs had p < 0.05 in ACPA-positive RA, 4/76 in ACPA-negative RA).ConclusionOverall, known RA risk SNPs do not predict response to TNFi, either individually or when combined into a risk score. This does not support the hypothesis that genes influencing RA onset would also influence its prognosis and treatment response.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1174-z) contains supplementary material, which is available to authorized users.

Highlights

To prevent debilitating and irreversible joint damage, rheumatoid arthritis (RA) is often treated with tumor necrosis factor inhibitor (TNFi), but many patients do not respond to this costly therapy
When evaluating each of the 76 SNPs, we found that the number of SNPs presenting significant associations was not higher than expected by chance (5/76 SNPs had p < 0.05 in anti-citrullinated protein/peptide antibody (ACPA)-positive RA, 4/76 in ACPA-negative RA)
At the start of TNFi treatment, we identified comparable clinical presentations between the two subsets, except for a lower erythrocyte sedimentation rate (ESR) (24.2 vs 29.0, p = 0.0068) and a slightly higher tender joint count (TJC) (8.9 vs 7.5, p = 0.0074) among ACPA-negative patients

Summary

Introduction

To prevent debilitating and irreversible joint damage, rheumatoid arthritis (RA) is often treated with tumor necrosis factor inhibitor (TNFi), but many patients do not respond to this costly therapy. Before the advent of GWASs, studies of treatment response commonly focused on individual candidate markers This remains a viable strategy for conserving power by reducing the number of simultaneous tests, if good candidates can be found. Several investigations with limited samples (less than 130 subjects) have been conducted for the –308G > A polymorphism in the TNF gene [10,11,12,13,14,15,16,17,18], and found that the GG genotype is associated with a better response to TNFi treatment [11, 16,17,18] This finding, was neither supported by a following study with a larger sample [19] nor replicated in subsequent genome-wide interrogations [4,5,6,7, 9]

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