Genome-wide association study and gene expression analysis identifies CD84 as a predictor of response to etanercept
Jing Cui1, Eli A Stahl, Saedis Saevarsdottir
1Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
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 (ΔDAS) 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 ΔDAS 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.
Insights
A genome-wide study found a genetic marker linked to better response in rheumatoid arthritis patients treated with etanercept. This marker influences CD84 gene expression, which correlates with disease activity, suggesting a potential biomarker for etanercept therapy.
Area of Science:
- Immunogenetics
- Rheumatology
- Pharmacogenomics
Background:
- Anti-tumor necrosis factor alpha (anti-TNF) therapy is a common rheumatoid arthritis (RA) treatment.
- Predicting patient response to anti-TNF therapy remains a clinical challenge.
- Understanding genetic factors influencing treatment response is crucial for personalized medicine.
Purpose of the Study:
- To identify genetic variants associated with response to anti-TNF therapy in rheumatoid arthritis (RA).
- To investigate the role of the identified genetic variants and their associated genes in RA disease activity and treatment response.
- To explore potential biomarkers for predicting etanercept treatment outcomes in RA patients.
Main Methods:
- Genome-wide association study (GWAS) meta-analysis of over 2 million variants in 2,706 RA patients treated with etanercept, infliximab, or adalimumab.
- Analysis of single nucleotide polymorphism (SNP) rs6427528 association with change in disease activity score (ΔDAS).
- Investigation of CD84 gene expression in peripheral blood mononuclear cells and its correlation with disease activity and treatment response.
Main Results:
- A significant association was found between SNP rs6427528 and ΔDAS in the etanercept subset (P = 8 × 10(-8)).
- The risk allele for rs6427528 was linked to higher CD84 gene expression (P = 1 × 10(-11) in non-RA, P = 0.004 in RA).
- Higher CD84 expression correlated with lower disease activity and showed a trend towards better ΔDAS in etanercept-treated RA patients.
Conclusions:
- CD84 genotype and expression are associated with response to etanercept therapy in rheumatoid arthritis.
- CD84 may serve as a potential predictive biomarker for etanercept treatment efficacy in RA patients of European ancestry.
- These findings contribute to understanding the biological basis of anti-TNF therapy response and developing personalized treatment strategies.
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