Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Background/Purpose: Studies of patients with rheumatoid arthritis (RA) to identify genetic biomarkers of anti-tumor necrosis factor (TNF) response have been conducted mostly in Caucasian populations. These studies have used anti-TNF response at a single follow up time point as the phenotype with which single nucleotide polymorphisms (SNP) associations have been tested. There has been little overlap in findings across studies. To identify genetic biomarkers of anti-TNF response among Japanese RA patients, we have performed a genome-wide association study (GWAS) using response at 2 follow up time-points for a more reliable clinical phenotype over time.
Methods: Disease Activity Scores based on 28 joint counts and C-reactive protein (DAS28) were assessed at baseline (before initial therapy), and after 3 and 6 months in 487 Japanese RA patients starting anti-TNF therapy for the first time or switching to a new anti-TNF agent. A genome-wide panel of 1,133,484 SNPs was genotyped and additional SNPs were imputed. Using change in DAS28 scores from baseline (ΔDAS28) at both 3 and 6 months as the response phenotype, a longitudinal genome-wide association analysis was conducted using Generalized Estimating Equations (GEE) models to accommodate the repeated measures of the outcome, adjusting for baseline DAS28, time since initiation of therapy, type of anti-TNF agent and concomitant methotrexate.
Results: A total of 4,253,138 autosomal SNPs passed quality thresholds for association analysis. Suggestive evidence of association (p<1×10-6) with ΔDAS28 was observed at 3 chromosomal regions (6q15: rs284515, p=6.6×10-7; 6q27: rs75908454, p=6.3×10-7 and 10q25.3: rs1679568, p=8.1×10-7), extending to numerous SNPs in linkage disequilibrium (LD) with the index SNPs across each region. Potential candidate genes in these regions include MAP3K7 (6q15) a key player in TNFα-mediated inflammatory pathway signaling, GFRA1 (10q25.3) which was associated with anti-TNF response in an independent study, and WDR27 (6q27).
Conclusion: In this first GWAS of anti-TNF response among Japanese RA patients using a longitudinal analysis approach, three genomic regions demonstrated suggestive association with response to anti-TNF therapy. Using more than one assessment of response enhanced the power to detect these associations.
To cite this abstract in AMA style:Honne K, Hallgrimsdottir I, Wu C, Sebro R, Jewell N, Sakurai T, Iwamoto M, Minota S, Jawaheer D. A Longitudinal Genome-Wide Association Study of Anti-Tumor Necrosis Factor Response Among Japanese Patients with Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/a-longitudinal-genome-wide-association-study-of-anti-tumor-necrosis-factor-response-among-japanese-patients-with-rheumatoid-arthritis/. Accessed November 19, 2019.
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