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Ultra-Rare Genetic Variation in Relapsing Polychondritis: A Whole-Exome Sequencing Study.
Luo, Yiming; Ferrada, Marcela A; Sikora, Keith A; Rankin, Cameron; Alessi, Hugh; Kastner, Daniel L; Deng, Zuoming; Zhang, Mengqi; Merkel, Peter A; Kraus, Virginia B; Allen, Andrew S; Grayson, Peter C.
Afiliación
  • Luo Y; Division of Rheumatology, Department of Medicine, Columbia University Irving Medical Center, New York, NY.
  • Ferrada MA; Vasculitis Translational Research Program, Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD.
  • Sikora KA; Vasculitis Translational Research Program, Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD.
  • Rankin C; Pediatric Translational Research Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD.
  • Alessi H; Vasculitis Translational Research Program, Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD.
  • Kastner DL; Vasculitis Translational Research Program, Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD.
  • Deng Z; Metabolic, Cardiovascular and Inflammatory Disease Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.
  • Zhang M; Biodata Mining and Discovery Section, Office of Science and Technology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD.
  • Merkel PA; Biostatistics and Research Decision Sciences, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • Kraus VB; Division of Rheumatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
  • Allen AS; Division of Rheumatology, Department of Medicine, Duke University School of Medicine, Durham, NC.
  • Grayson PC; Division of Integrative Genomics, Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC.
medRxiv ; 2023 Apr 17.
Article en En | MEDLINE | ID: mdl-37292664
Objective: Relapsing polychondritis (RP) is a systemic inflammatory disease of unknown etiology. The study objective was to examine the contribution of rare genetic variations in RP. Methods: We performed a case-control exome-wide rare variant association analysis including 66 unrelated European American RP cases and 2923 healthy controls. Gene-level collapsing analysis was performed using Firth's logistics regression. Pathway analysis was performed on an exploratory basis with three different methods: Gene Set Enrichment Analysis (GSEA), sequence kernel association test (SKAT) and higher criticism test. Plasma DCBLD2 levels were measured in patients with RP and healthy controls using enzyme-linked immunosorbent assay (ELISA). Results: In the collapsing analysis, RP was associated with higher burden of ultra-rare damaging variants in the DCBLD2 gene (7.6% vs 0.1%, unadjusted odds ratio = 79.8, p = 2.93 × 10-7). Patients with RP and ultra-rare damaging variants in DCBLD2 had a higher prevalence of cardiovascular manifestations. Plasma DCBLD2 protein levels were significantly higher in RP than healthy controls (5.9 vs 2.3, p < 0.001). Pathway analysis showed statistically significant enrichment of genes in the tumor necrosis factor (TNF) signaling pathway driven by rare damaging variants in RELB, RELA and REL using higher criticism test weighted by degree and eigenvector centrality. Conclusions: This study identified specific rare variants in DCBLD2 as putative genetic risk factors for RP. 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.

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies / Risk_factors_studies Idioma: En Revista: MedRxiv Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies / Risk_factors_studies Idioma: En Revista: MedRxiv Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos