Risk of relapse of ANCA-associated vasculitis among patients homozygous for the proteinase 3 gene Val119Ile polymorphism.

Autor:	Casal Moura M; Pulmonary and Critical Care Medicine, Mayo Foundation for Medical Education and Research, Rochester, Minnesota, USA.; Biomedicina, Faculty of Medicine, University of Porto, Porto, Portugal., Deng Z; National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA., Brooks SR; Office of Science and Technology, Biodata Mining and Discovery Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA., Tew W; ITGR Diagnostics Discovery, Genentech Inc, South San Francisco, California, USA., Fervenza FC; Nephrology and Hypertension, Mayo Foundation for Medical Education and Research, Rochester, Minnesota, USA., Kallenberg CGM; Rheumatology and Clinical Immunology, University of Groningen, Groningen, The Netherlands., Langford CA; Rheumatic and Immunologic Disease, Cleveland Clinic, Cleveland, Ohio, USA., Merkel PA; Division of Rheumatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Monach PA; Department of Medicine, VA Boston Healthcare System, West Roxbury, Massachusetts, USA., Seo P; Rheumatology, Johns Hopkins, Baltimore, Maryland, USA., Spiera RF; Department of Medicine, Hospital for Special Surgery, New York, New York, USA., St Clair EW; Medicine, Duke University, Durham, North Carolina, USA., Stone JH; Vasculitis and Glomerulonephritis Center, Rheumatology, Immunology and Allergy Division, Massachusetts General Hospital, Boston, Massachusetts, USA., Prunotto M; School of Pharmaceutical Sciences, University of Geneva, Geneve, Switzerland., Grayson PC; Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA., Specks U; Pulmonary and Critical Care Medicine, Mayo Foundation for Medical Education and Research, Rochester, Minnesota, USA specks.ulrich@mayo.edu.
Jazyk:	angličtina
Zdroj:	RMD open [RMD Open] 2023 Mar; Vol. 9 (1).
DOI:	10.1136/rmdopen-2022-002935
Abstrakt:	Background: The frequency of proteinase 3 gene (PRTN3) polymorphisms in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is not fully characterised. We hypothesise that the presence of a PRTN3 gene polymorphism (single nucleotide polymorphism (SNP) rs351111) is relevant for clinical outcomes. Methods: DNA variant calling for SNP rs351111 (chr.19:844020, c.355G>A) in PRTN3 gene assessed the allelic frequency in patients with PR3-AAV included in the Rituximab in ANCA-Associated Vasculitis trial. This was followed by RNA-seq variant calling to characterise the mRNA expression. We compared clinical outcomes between patients homozygous for PRTN3-Ile 119 or PRTN3-Val 119 . Results: Whole blood samples for DNA calling were available in 188 patients. 75 patients with PR3-AAV had the allelic variant: 62 heterozygous PRTN3-Val 119 Ile and 13 homozygous for PRTN3-Ile 119 . RNA-seq was available for 89 patients and mRNA corresponding to the allelic variant was found in 32 patients with PR3-AAV: 25 heterozygous PRTN3-Val 119 Ile and 7 homozygous for PRTN3-Ile 119 . The agreement between the DNA calling results and mRNA expression of the 86 patients analysed by both methods was 100%. We compared the clinical outcomes of 64 patients with PR3-AAV: 51 homozygous for PRTN3-Val 119 and 13 homozygous for PRTN3-Ile 119 . The frequency of severe flares at 18 months in homozygous PRTN3-Ile 119 was significantly higher when compared with homozygous PRTN3-Val 119 (46.2% vs 19.6%, p=0.048). Multivariate analysis identified homozygous PR3-Ile 119 as main predictor of severe relapse (HR 4.67, 95% CI 1.16 to 18.86, p=0.030). Conclusion: In patients with PR3-AAV, homozygosity for PRTN3-Val 119 Ile polymorphism appears associated with higher frequency of severe relapse. Further studies are necessary to better understand the association of this observation with the risk of severe relapse. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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