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


ABSTRACT:

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.

SUBMITTER: Thorlacius GE 

PROVIDER: S-EPMC7850528 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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

Thorlacius Guðný Ella GE   Hultin-Rosenberg Lina L   Sandling Johanna K JK   Bianchi Matteo M   Imgenberg-Kreuz Juliana J   Pucholt Pascal P   Theander Elke E   Kvarnström Marika M   Forsblad-d'Elia Helena H   Bucher Sara Magnusson SM   Norheim Katrine B KB   Johnsen Svein Joar Auglænd SJA   Hammenfors Daniel D   Skarstein Kathrine K   Jonsson Malin V MV   Baecklund Eva E   Aqrawi Lara A LA   Jensen Janicke Liaaen JL   Palm Øyvind Ø   Morris Andrew P AP   Meadows Jennifer R S JRS   Rantapää-Dahlqvist Solbritt S   Mandl Thomas T   Eriksson Per P   Lind Lars L   Omdal Roald R   Jonsson Roland R   Lindblad-Toh Kerstin K   Rönnblom Lars L   Wahren-Herlenius Marie M   Nordmark Gunnel G  

Rheumatology (Oxford, England) 20210201 2


<h4>Objectives</h4>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.<h4>Methods</h4>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  ...[more]

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