Background/Purpose: Joint damage manifested by bony erosions and joint space narrowing is a major contributor to the morbidity and mortality of RA. Reports in Caucasians (EA) indicate that as much as 58% of radiographic severity of RA may be heritable, but little is known about the heritability of this phenotype, especially in African Americans (AA).

Methods: 175 AA RA patients with longstanding ACPA-positive RA that never progressed to radiographic damage, and 264 autoantibody-positive AA RA patients with radiographic joint damage were genotyped using Illumina Omni 1M and 1S arrays. Whole genome sequence (WGS) data (Complete Genomics) was obtained on a subset of 62 autoantibody-positive AA RA patients (31 with radiographic damage, 31 without damage). DMARD/biologic use, disease duration, sex, smoking status, and the top 10 principal components were included as covariates. We sought variants associated with radiographic damage using a genome-wide significance threshold of p <10-8. Using our WGS data, we analyzed 126 loci for association with damage: 101 loci associated with susceptibility in EA and 25 loci previously reported to be associated with radiographic severity of RA among EA. We conducted covariate-controlled gene based testing (α = 4*10-4) on these loci using SKAT-O and then conducted immune cell enhancer burden tests (α = 1.6*10-5) in these regions.

Results: We did not detect any associations of SNP variants with damage at a genome wide level of significance with Illumina 1M/1S data; the most strongly associated variant with radiographic damage was rs4743949 (chr9:92722181, p = 5.76*10-7, OR= 0.60) located in an enhancer region nearest mir4290, a non-coding RNA, and about 800kB 5’ of Syk. Gene burden testing of WGS data revealed loci having an enrichment of variants that have previously associated with radiographic severity of RA. 3 of the 25 gene burden tests showed evidence of association; these were ILF3 (1.31*10-4, gene based burden test), ATG5 (7.27*10-7, T-cell enhancer region), and CXCR5 (p=1.28*10-5, B-cell enhancer region). We did not detect association of radiographic severity with the HLA-DRB1 locus in either single variant or burden testing.

Conclusion: Consistent with recent reports, variation in enhancer regions, many of which are T-cell enhancers, were associated with damage. For example, the enhancer region of ATG5, a gene important for T and B cell lymphocyte development and required for appropriate processing of antigens for presentation by MHC class II, was significantly associated. The HLA region was not found to be associated with RA severity in this study, possibly because the whole cohort is ACPA positive. Appropriate parsing of NGS data may elucidate associated loci that are missed using array-based GWA studies.

« Back to 2015 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/genome-wide-association-analysis-and-whole-genome-sequencing-identify-variants-associated-with-radiographic-severity-of-rheumatoid-arthritis-in-african-americans/