Background/Purpose: Relapsing polychondritis (RP) is a rare rheumatic disease of unknown etiology characterized by inflammations of cartilaginous structures and other tissues, particularly the ears, nose, joints, airway, and blood vessels. Familial clustering in RP has been observed, which suggests a possible causal role of germline genetic variation. The objective of this study was to examine the contribution of ultra-rare genetic variations in RP. We hypothesized that ultra-rare genetic variants with large deleterious effects contribute to the development of RP.

Methods: We performed a case-control exome-wide rare variant association analysis including 66 unrelated RP cases and 2923 sex-matched controls of Caucasian ancestry. Stringent quality control steps were used to select high-quality exonic variants with balanced coverage between cases and controls. Principal component analysis and identity-by-descent analysis was performed to confirm biological unrelatedness and ancestry homogeneity. Five collapsing models were designed based on variant allele frequency in the Genome Aggregation Database (gnomAD) and predicted deleterious effects based on Combined Annotation Dependent Depletion (CADD) scoring. Gene-level collapsing analysis was performed using Firth’s logistics regression adjusting for sex and first 3 principal components. Pathway analysis was performed on the “Hallmark Gene Sets” from the Molecular Signatures Database with three different methods: Gene Set Enrichment Analysis (GSEA), sequence kernel association test (SKAT), higher criticism (HC) test. The HC test was performed with both unweighted and weighted approach. The weighted HC test allows incorporation of external information including gene intolerance metrics and centrality measures in protein interaction networks. The weight was based on the Residual Variation Intolerance Score (RVIS), degree centrality, eigenvector centrality and RankPage centrality, respectively. The gene interaction data from the bioGRID database was used to calculate centrality.

Results: In the collapsing analysis, RP was associated with a significantly higher burden of ultra-rare damaging variants in the DCBLD2 gene (7.6% vs 0.1%, p = 2.93 x 10^-7) compared to controls. Patients with RP with ultra-rare damaging variants in DCBLD2 had a numerically higher prevalence of cardiovascular manifestations, including cardiac involvement, aortitis, Raynaud phenomena and venous thromboembolism, compared to other patients with RP. Pathway analysis showed statistically significant enrichment of genes in the tumor necrosis factor (TNF) signaling pathway by the HC test weighted by degree and eigenvector centrality in the ultra-rare damaging (p = 0.039 and p < 0.001, weighted by degree and eigenvector centrality respectively) and rare damaging models (p = 0.039 and p < 0.001, weighted by degree and eigenvector centrality respectively).

Conclusion: This study identified specific rare variants in DCBLD2 as putative genetic risk factors for RP. Rare genetic variation within the TNF pathway is also potentially associated with development of RP. These findings should be validated in additional patients with RP and supported by future functional experiments.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/ultra-rare-genetic-variation-in-relapsing-polychondritis-a-whole-exome-sequencing-study/