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Genome-wide association study and gene expression analysis identifies CD84 as a predictor of response to etanercept therapy in rheumatoid arthritis.

ABSTRACT: Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheumatoid arthritis (RA). It is unknown why some RA patients fail to respond adequately to anti-TNF therapy, which limits the development of clinical biomarkers to predict response or new drugs to target refractory cases. To understand the biological basis of response to anti-TNF therapy, we conducted a genome-wide association study (GWAS) meta-analysis of more than 2 million common variants in 2,706 RA patients from 13 different collections. Patients were treated with one of three anti-TNF medications: etanercept (n = 733), infliximab (n = 894), or adalimumab (n = 1,071). We identified a SNP (rs6427528) at the 1q23 locus that was associated with change in disease activity score (?DAS) in the etanercept subset of patients (P = 8 × 10(-8)), but not in the infliximab or adalimumab subsets (P>0.05). The SNP is predicted to disrupt transcription factor binding site motifs in the 3' UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1 × 10(-11) in 228 non-RA patients and P = 0.004 in 132 RA patients). Consistent with the genetic findings, higher CD84 gene expression correlated with lower cross-sectional DAS (P = 0.02, n = 210) and showed a non-significant trend for better ?DAS in a subset of RA patients with gene expression data (n = 31, etanercept-treated). A small, multi-ethnic replication showed a non-significant trend towards an association among etanercept-treated RA patients of Portuguese ancestry (n = 139, P = 0.4), but no association among patients of Japanese ancestry (n = 151, P = 0.8). Our study demonstrates that an allele associated with response to etanercept therapy is also associated with CD84 gene expression, and further that CD84 expression correlates with disease activity. These findings support a model in which CD84 genotypes and/or expression may serve as a useful biomarker for response to etanercept treatment in RA patients of European ancestry.

SUBMITTER: Cui J

PROVIDER: S-EPMC3610685 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Genome-wide association study and gene expression analysis identifies CD84 as a predictor of response to etanercept therapy in rheumatoid arthritis.

Cui Jing J Stahl Eli A EA Saevarsdottir Saedis S Miceli Corinne C Diogo Dorothee D Trynka Gosia G Raj Towfique T Mirkov Maša Umiċeviċ MU Canhao Helena H Canhao Helena H Ikari Katsunori K Terao Chikashi C Okada Yukinori Y Wedrén Sara S Askling Johan J Yamanaka Hisashi H Momohara Shigeki S Taniguchi Atsuo A Ohmura Koichiro K Matsuda Fumihiko F Mimori Tsuneyo T Gupta Namrata N Kuchroo Manik M Morgan Ann W AW Isaacs John D JD Wilson Anthony G AG Hyrich Kimme L KL Herenius Marieke M Doorenspleet Marieke E ME Tak Paul-Peter PP Crusius J Bart A JB van der Horst-Bruinsma Irene E IE Wolbink Gert Jan GJ van Riel Piet L C M PL van de Laar Mart M Guchelaar Henk-Jan HJ Shadick Nancy A NA Allaart Cornelia F CF Huizinga Tom W J TW Toes Rene E M RE Kimberly Robert P RP Bridges S Louis SL Criswell Lindsey A LA Moreland Larry W LW Fonseca João Eurico JE de Vries Niek N Stranger Barbara E BE De Jager Philip L PL Raychaudhuri Soumya S Weinblatt Michael E ME Gregersen Peter K PK Mariette Xavier X Barton Anne A Padyukov Leonid L Coenen Marieke J H MJ Karlson Elizabeth W EW Plenge Robert M RM

PLoS genetics 20130328 3

Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheumatoid arthritis (RA). It is unknown why some RA patients fail to respond adequately to anti-TNF therapy, which limits the development of clinical biomarkers to predict response or new drugs to target refractory cases. To understand the biological basis of response to anti-TNF therapy, we conducted a genome-wide association study (GWAS) meta-analysis of more than 2 million common variants in 2,706 RA ...[more]

PMID: 23555300

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Project description:Biologic drug therapies represent a huge advance in the treatment of rheumatoid arthritis (RA). However, very good disease control is achieved in only 30% of patients, making identification of biomarkers of response a research priority. We undertook this study to test our hypothesis that differential DNA methylation patterns may provide biomarkers predictive of response to tumor necrosis factor inhibitor (TNFi) therapy in patients with RA.An epigenome-wide association study was performed on pretreatment whole blood DNA from patients with RA. Patients who displayed good response (n?=?36) or no response (n?=?36) to etanercept therapy at 3 months were selected. Differentially methylated positions were identified using linear regression. Variance of methylation at differentially methylated positions was assessed for correlation with cis-acting single-nucleotide polymorphisms (SNPs). A replication experiment for prioritized SNPs was performed in an independent cohort of 1,204 RA patients.Five positions that were differentially methylated between responder groups were identified, with a false discovery rate of <5%. The top 2 differentially methylated positions mapped to exon 7 of the LRPAP1 gene on chromosome 4 (cg04857395, P?=?1.39 × 10(-8) and cg26401028, P?=?1.69 × 10(-8) ). The A allele of the SNP rs3468 was correlated with higher levels of methylation for both of the top 2 differentially methylated positions (P?=?2.63 × 10(-7) and P?=?1.05 × 10(-6) , respectively). Furthermore, the A allele of rs3468 was correlated with European League Against Rheumatism nonresponse in the discovery cohort (P?=?0.03; n?=?56) and in the independent replication cohort (P?=?0.003; n?=?1,204).We identify DNA methylation as a potential biomarker of response to TNFi therapy, and we report the association between response and the LRPAP1 gene, which encodes a chaperone of low-density lipoprotein receptor-related protein 1. Additional replication experiments in independent sample collections are now needed.

Dataset Information

Genome-wide association study and gene expression analysis identifies CD84 as a predictor of response to etanercept therapy in rheumatoid arthritis.

Publications

Genome-wide association study and gene expression analysis identifies CD84 as a predictor of response to etanercept therapy in rheumatoid arthritis.

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