A longitudinal genome-wide association study of anti-tumor necrosis factor response among Japanese patients with rheumatoid arthritis

Abstract

BackgroundStudies of Caucasian patients with rheumatoid arthritis (RA) to identify genetic biomarkers of anti-tumor necrosis factor (TNF) response have used response at a single time point as the phenotype with which single nucleotide polymorphism (SNP) associations have been tested. The findings have been inconsistent across studies. Among Japanese patients, only a few SNPs have been investigated. We report here the first genome-wide association study (GWAS) to identify genetic biomarkers of anti-TNF response among Japanese RA patients, using response at 2 time-points for a more reliable clinical phenotype over time.MethodsDisease Activity Scores based on 28 joint counts (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 SNPs was genotyped and additional SNPs were imputed. Using change in DAS28 scores from baseline at both 3 (ΔDAS-3) and 6 months (ΔDAS-6) as the response phenotype, a longitudinal genome-wide association analysis was conducted using generalized estimating equations (GEE) models, adjusting for baseline DAS28, treatment duration, type of anti-TNF agent and concomitant methotrexate. Cross-sectional analyses were performed using multivariate linear regression models, with response from a single time point (ΔDAS-3 or ΔDAS-6) as phenotype; all other variables were the same as in the GEE models.ResultsIn the GEE models, borderline significant association was observed at 3 chromosomal regions (6q15: rs284515, p = 6.6x10−7; 6q27: rs75908454, p = 6.3x10−7 and 10q25.3: rs1679568, p = 8.1x10−7), extending to numerous SNPs in linkage disequilibrium (LD) across each region. Potential candidate genes in these regions include MAP3K7, BACH2 (6q15), GFRA1 (10q25.3), and WDR27 (6q27). The association at GFRA1 replicates a previous finding from a Caucasian dataset. In the cross-sectional analyses, ΔDAS-6 was significantly associated with the 6q15 locus (rs284511, p = 2.5x10−8). No other significant or borderline significant associations were identified.ConclusionThree genomic regions demonstrated significant or borderline significant associations with anti-TNF response in our dataset of Japanese RA patients, including a locus previously associated among Caucasians. Using repeated measures of response as phenotype enhanced the power to detect these associations.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-0920-6) contains supplementary material, which is available to authorized users.

Genetics of rheumatoid arthritis: 2018 status

“…While researchers believe that disease risk variants are responsible for the heterogeneous aetiology of RA, the use of genetic data in the prediction of clinical phenotype is challenging. Previous GWAS examining the response to biologics (mainly anti-TNF therapy) provided unsatisfactory evidence,63–67 which may suggest that genetic background of RA onset and that of clinical response are distinct. A crowd-sourced collaborative assessment of SNP data to predict anti-TNF treatment response was performed 68.…”

The genetic pathogenesis, diagnosis and therapeutic insight of rheumatoid arthritis

“…In addition, that study confirmed the association of 35 known non‐ HLA loci at the genome‐wide level of significance in Koreans. A Japanese GWAS was conducted to identify genetic biomarkers that can predict response to anti‐TNF agents in RA patients that showed three loci within the MAP3K7‐BACH2 , GFRA1 and WDR27 genes are associated with anti‐TNF response in Japanese RA patients . Recently a multinational Arab RA GWAS was undertaken in 794 RA cases and 573 controls that discovered two novel RA risk loci within the CDH6 and SMTNL2/GGT6 gene regions .…”

“…89 Eyre et al 58 GWAS was conducted to identify genetic biomarkers that can predict response to anti-TNF agents in RA patients that showed three loci within the MAP3K7-BACH2, GFRA1 and WDR27 genes are associated with anti-TNF response in Japanese RA patients. 95 Recently a multinational Arab RA GWAS was undertaken in 794 RA cases and 573 controls that discovered two novel RA risk loci within the CDH6 and SMTNL2/GGT6 gene regions. 96 RA-associated loci at a genomewide level of significance are shown in Table S1, Supporting…”

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

“…Environmental or clinical factors such as smoking, gender, age, baseline disability, or presence of autoantibodies account for only a small proportion of the variability in patient response [2, 3]. Unfortunately, genome-wide association studies (GWASs) have so far not revealed any clear evidence of predictive genetic markers, except for a large collection of nominally significant markers [4–8], or a few markers which, despite having approached acceptable levels of significance, are too weak to inform any clinical decisions (such as rs6427528 on CD84 with p  = 8 × 10 –8 in the etanercept subsets of patients) [9]. …”