Association of theRPA3-UMAD1locus with interstitial lung diseases complicated with rheumatoid arthritis in Japanese

Abstract

ObjectivesThe genetic background of rheumatoid arthritis–interstitial lung disease (RA-ILD) has been evaluated in Europeans, but little knowledge has been obtained in non-Europeans. This study aimed to elucidate genome-wide risk of RA-ILD in non-Europeans.MethodsWe performed an initial genome-wide association study (GWAS) of RA-ILD in the Japanese population. By conducting the meta-analysis of the three GWAS datasets of the RA cohorts and biobank of Japanese, our study included 358 RA-ILD cases and 4550 RA subjects without ILD. We then conducted the stratified analysis of the effect of the GWAS risk allele in each CT image pattern.ResultsWe identified one novel RA-ILD risk locus at 7p21 that satisfied the genome-wide significance threshold (rs12702634 at RPA3-UMAD1, OR=2.04, 95% CI 1.59 to 2.60, p=1.5×10−8). Subsequent stratified analysis based on the CT image patterns demonstrated that the effect size of the RA-ILD risk allele (rs12702634-C) was large with the UIP pattern (OR=1.86, 95% CI 0.97 to 3.58, p=0.062) and the probable UIP pattern (OR=2.26, 95% CI 1.36 to 3.73, p=0.0015).ConclusionWe revealed one novel genetic association with RA-ILD in Japanese. The RA-ILD risk of the identified variant at RPA3-UMAD1 was relatively high in the CT image patterns related to fibrosis. Our study should contribute to elucidation of the complicated aetiology of RA-ILD.

Lack of Association of rs12702634 in RPA3-UMAD1 With Interstitial Lung Diseases in Japanese Rheumatoid Arthritis Patients

“…Meta-analysis of our data combined with the data from the previous report 4 was performed under the random effects model and did not reach the genome-wide significance threshold ( Supplemental Figure 1 ; P = .0996, OR 1.52, 95% CI 0.92-2.49; the weight of this study in the random effects model was 42.2%). The lack of heterogeneity was not confirmed between our data and the previously reported data on rs12702634 ( I 2 = 74.6%, τ 2 = 0.0980, H = 1.99, Q = 3.94, P = .0470); these data supported the analysis under the random effects model.…”

“…A recent genome-wide association study (GWAS) of ILD in RA in a Japanese population identified a significant association with a single nucleotide polymorphism (SNP), rs12702634, in the RPA3-UMAD1 gene. 4 An association of this SNP with ILD in Japanese RA patients was analyzed in the present study to replicate this association.…”

“…The 80% statistical power was estimated to be provided when the odds ratio (OR) was 1.84 or higher under the allele model ( http://biostat.mc.vanderbilt.edu/wiki/Main/PowerSampleSize ) 8 ; this threshold was lower than the previously reported OR. 4 Meta-analysis was conducted using EZR ( http://www.jichi.ac.jp/saitama-sct/SaitamaHP.files/statmed.html ) 9 with the DerSimonian-Laird method under the random effects model. 10 …”

Novel Biomarkers, Diagnostic and Therapeutic Approach in Rheumatoid Arthritis Interstitial Lung Disease—A Narrative Review

“…In a Japanese GWAS, the SNV rs12702634 in the RPA3-UMAD1 gene proved to have a major association with the development of RA-ILD. This genetic polymorphism was mostly associated with the UIP pattern [ 37 , 38 , 39 ].…”

Biomarkers for interstitial lung disease and acute-onset diffuse interstitial lung disease in rheumatoid arthritis

“…Genome-wide association studies (GWASs) have been conducted to determine the role of common variants on disease predisposition; a Japanese GWAS was performed for ILD in RA with the result that a significant association with SNV rs12702634 in the RPA3-UMAD1 gene was found. 76 Deleterious rare variants including loss of function variants and deleterious missense variants are causative in some diseases. 77 A role for rare variants in the genes responsible for IPF was reported in European RA patients with ILD.…”