Background/Purpose:  There are no biomarkers that predict response to anti-TNF therapy in rheumatoid arthritis (RA).  Here, we conduct a genome-wide association study (GWAS) to identify genetic variants that influence response to anti-TNF therapy.

Methods: GWAS data were aggregated on 2,743 RA patients as part of an international collaboration. Clinical data and Disease Activity Score (DAS28) were available for RA patients treated with three anti-TNF medications: etanercept (N=773), infliximab (N=894) or adalimumab (N=1,071). GWAS data were quality controlled by genotype batch, and all data were imputed to 2.5M SNPs using IMPUTE with HapMap2 CEU. Change in DAS28 (delta-DAS) was used as the primary phenotype in linear regression association tests of all samples combined and subset by anti-TNF drug.  We adjusted for baseline DAS28 and three ancestry-derived principal component eigenvectors. Expression quantitative trait locus (eQTL) data for the CD84 locus were available for peripheral blood mononuclear cells (PBMCs, N=228). Replication samples from the Portuguese Reuma.pt registry (n=405), and the Japanese IORRA and Kyoto University Hospital registries (n=374), were genotyped using Sequenom and/or TaqMan and analyzed as in our GWAS.

Results: While no single SNP was genome-wide significant for association with delta-DAS in an analysis of all samples combined, a SNP at the 1q23/CD84 locus was highly significant in the etanercept subset of patients (rs6427528, P=7×10^-8).  This same SNP was not associated with delta-DAS in the infliximab or adalimumab subsets (P>0.05). The allele associated with a better response, which is in the 3’ UTR of an immune-related gene CD84, is also associated with higher CD84 gene expression in PBMCs (P<10^-12). In a subset of RA patients with gene expression data, CD84 gene expression correlates with baseline DAS (n=210, P=0.02), and demonstrates a non-signficant trend toward predicting response to etanercept therapy.  In a small replication study, the SNP was not associated with response to etanercept therapy among European (n=139, P=0.4) or Japanese (n=151, P=0.8) RA patients.

Conclusion: GWAS in etanercept-treated RA patients revealed a highly suggestive association with the CD84 locus.  Further, CD84 gene expression is under genetic control and influenced by disease activity.   These findings provide support that CD84 genotypes and/or expression may serve as a useful biomarker for response to etanercept treatment in RA, although larger replication studies are required.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/genome-wide-association-study-and-gene-expression-analysis-identifies-cd84-as-a-predictor-of-response-to-etanercept-therapy-in-rheumatoid-arthritis/