Genetic and clinical basis for two distinct subtypes of primary Sjögren's syndrome.

Autor:	Thorlacius GE; Department of Medicine, Karolinska Institutet, Stockholm, Sweden., Hultin-Rosenberg L; Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala, Sweden., Sandling JK; Department of Medical Sciences, Rheumatology, and Science for Life Laboratory, Uppsala University, Uppsala, Sweden., Bianchi M; Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala, Sweden.; Department of Medical Sciences, Rheumatology, and Science for Life Laboratory, Uppsala University, Uppsala, Sweden., Imgenberg-Kreuz J; Department of Medical Sciences, Rheumatology, and Science for Life Laboratory, Uppsala University, Uppsala, Sweden., Pucholt P; Department of Medical Sciences, Rheumatology, and Science for Life Laboratory, Uppsala University, Uppsala, Sweden., Theander E; Department of Rheumatology, Skåne University Hospital, Malmö, Sweden., Kvarnström M; Department of Medicine, Karolinska Institutet, Stockholm, Sweden., Forsblad-d'Elia H; Department of Rheumatology and Inflammation Research, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.; Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden., Bucher SM; Department of Rheumatology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden., Norheim KB; Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway., Johnsen SJA; Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway., Hammenfors D; Department of Rheumatology, Haukeland University Hospital, Bergen, Norway., Skarstein K; Department of Clinical Science and Department of Clinical Dentistry, University of Bergen, Bergen, Norway., Jonsson MV; Department of Clinical Science and Department of Clinical Dentistry, University of Bergen, Bergen, Norway., Baecklund E; Department of Medical Sciences, Rheumatology, and Science for Life Laboratory, Uppsala University, Uppsala, Sweden., Aqrawi LA; Department of Oral Surgery and Oral Medicine, Faculty of Dentistry, University of Oslo, Oslo, Norway., Jensen JL; Department of Oral Surgery and Oral Medicine, Faculty of Dentistry, University of Oslo, Oslo, Norway., Palm Ø; Department of Rheumatology, Oslo University Hospital, Oslo, Norway., Morris AP; Division of Musculoskeletal and Dermatological Sciences, The University of Manchester, Manchester, UK., Meadows JRS; Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala, Sweden., Rantapää-Dahlqvist S; Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden., Mandl T; Department of Rheumatology, Skåne University Hospital, Malmö, Sweden., Eriksson P; Department of Clinical and Experimental Medicine, Rheumatology/Division of Neuro and Inflammation Sciences, Linköping University, Linköping, Sweden., Lind L; Department of Medical Sciences, Clinical Epidemiology, Uppsala University, Uppsala, Sweden., Omdal R; Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway.; Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway., Jonsson R; Department of Rheumatology, Haukeland University Hospital, Bergen, Norway.; Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway., Lindblad-Toh K; Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala, Sweden.; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Rönnblom L; Department of Medical Sciences, Rheumatology, and Science for Life Laboratory, Uppsala University, Uppsala, Sweden., Wahren-Herlenius M; Department of Medicine, Karolinska Institutet, Stockholm, Sweden., Nordmark G; Department of Medical Sciences, Rheumatology, and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Jazyk:	angličtina
Zdroj:	Rheumatology (Oxford, England) [Rheumatology (Oxford)] 2021 Feb 01; Vol. 60 (2), pp. 837-848.
DOI:	10.1093/rheumatology/keaa367
Abstrakt:	Objectives: Clinical presentation of primary Sjögren's syndrome (pSS) varies considerably. A shortage of evidence-based objective markers hinders efficient drug development and most clinical trials have failed to reach primary endpoints. Methods: We performed a multicentre study to identify patient subgroups based on clinical, immunological and genetic features. Targeted DNA sequencing of 1853 autoimmune-related loci was performed. After quality control, 918 patients with pSS, 1264 controls and 107 045 single nucleotide variants remained for analysis. Replication was performed in 177 patients with pSS and 7672 controls. Results: We found strong signals of association with pSS in the HLA region. Principal component analysis of clinical data distinguished two patient subgroups defined by the presence of SSA/SSB antibodies. We observed an unprecedented high risk of pSS for an association in the HLA-DQA1 locus of odds ratio 6.10 (95% CI: 4.93, 7.54, P=2.2×10-62) in the SSA/SSB-positive subgroup, while absent in the antibody negative group. Three independent signals within the MHC were observed. The two most significant variants in MHC class I and II respectively, identified patients with a higher risk of hypergammaglobulinaemia, leukopenia, anaemia, purpura, major salivary gland swelling and lymphadenopathy. Replication confirmed the association with both MHC class I and II signals confined to SSA/SSB antibody positive pSS. Conclusion: Two subgroups of patients with pSS with distinct clinical manifestations can be defined by the presence or absence of SSA/SSB antibodies and genetic markers in the HLA locus. These subgroups should be considered in clinical follow-up, drug development and trial outcomes, for the benefit of both subgroups. (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.)
Databáze:	MEDLINE
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