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

Guðný Ella Thorlacius; Lina Hultin-Rosenberg; Johanna K Sandling; Matteo Bianchi; Juliana Imgenberg-Kreuz; Pascal Pucholt; Elke Theander; Marika Kvarnström; Helena Forsblad-d'Elia; Sara Magnusson Bucher; Katrine B Norheim; Svein Joar Auglænd Johnsen; Daniel Hammenfors; Kathrine Skarstein; Malin V Jonsson; Eva Baecklund; Lara A Aqrawi; Janicke Liaaen Jensen; Øyvind Palm; Andrew P Morris; Jennifer R S Meadows; Solbritt Rantapää-Dahlqvist; Thomas Mandl; Per Eriksson; Lars Lind; Roald Omdal; Roland Jonsson; Kerstin Lindblad-Toh; Lars Rönnblom; Marie Wahren-Herlenius; Gunnel Nordmark; DISSECT consortium

doi:10.1093/rheumatology/keaa367

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

Guðný Ella Thorlacius, Lina Hultin-Rosenberg, Johanna K Sandling, Matteo Bianchi, Juliana Imgenberg-Kreuz, Pascal Pucholt, Elke Theander, Marika Kvarnström, Helena Forsblad-d'Elia, Sara Magnusson Bucher, Katrine B Norheim, Svein Joar Auglænd Johnsen, Daniel Hammenfors, Kathrine Skarstein, Malin V Jonsson, Eva Baecklund, Lara A Aqrawi, Janicke Liaaen Jensen, Øyvind Palm, Andrew P MorrisJennifer R S Meadows, Solbritt Rantapää-Dahlqvist, Thomas Mandl, Per Eriksson, Lars Lind, Roald Omdal, Roland Jonsson, Kerstin Lindblad-Toh, Lars Rönnblom, Marie Wahren-Herlenius, Gunnel Nordmark, DISSECT consortium

Forskningsoutput: Tidskriftsbidrag › Artikel i vetenskaplig tidskrift › Peer review

6 Citeringar (SciVal)

Sammanfattning

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.

Originalspråk	engelska
Tidskrift	Rheumatology (Oxford, England)
DOI	https://doi.org/10.1093/rheumatology/keaa367
Status	E-pub ahead of print - 2020 aug. 21
Externt publicerad	Ja

Bibliografisk information

Ämnesklassifikation (UKÄ)

Reumatologi och inflammation

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10.1093/rheumatology/keaa367

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Thorlacius, G. E., Hultin-Rosenberg, L., Sandling, J. K., Bianchi, M., Imgenberg-Kreuz, J., Pucholt, P., Theander, E., Kvarnström, M., Forsblad-d'Elia, H., Bucher, S. M., Norheim, K. B., Johnsen, S. J. A., Hammenfors, D., Skarstein, K., Jonsson, M. V., Baecklund, E., Aqrawi, L. A., Jensen, J. L., Palm, Ø., ... DISSECT consortium (2020). Genetic and clinical basis for two distinct subtypes of primary Sjögren's syndrome. Rheumatology (Oxford, England). https://doi.org/10.1093/rheumatology/keaa367

Thorlacius, Guðný Ella ; Hultin-Rosenberg, Lina ; Sandling, Johanna K ; Bianchi, Matteo ; Imgenberg-Kreuz, Juliana ; Pucholt, Pascal ; Theander, Elke ; Kvarnström, Marika ; Forsblad-d'Elia, Helena ; Bucher, Sara Magnusson ; Norheim, Katrine B ; Johnsen, Svein Joar Auglænd ; Hammenfors, Daniel ; Skarstein, Kathrine ; Jonsson, Malin V ; Baecklund, Eva ; Aqrawi, Lara A ; Jensen, Janicke Liaaen ; Palm, Øyvind ; Morris, Andrew P ; Meadows, Jennifer R S ; Rantapää-Dahlqvist, Solbritt ; Mandl, Thomas ; Eriksson, Per ; Lind, Lars ; Omdal, Roald ; Jonsson, Roland ; Lindblad-Toh, Kerstin ; Rönnblom, Lars ; Wahren-Herlenius, Marie ; Nordmark, Gunnel ; DISSECT consortium. / Genetic and clinical basis for two distinct subtypes of primary Sjögren's syndrome. I: Rheumatology (Oxford, England). 2020.

@article{3646e53615d24a7382923d59accc268b,

title = "Genetic and clinical basis for two distinct subtypes of primary Sj{\"o}gren's syndrome",

abstract = "OBJECTIVES: Clinical presentation of primary Sj{\"o}gren'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.",

author = "Thorlacius, {Gu{\dh}n{\'y} Ella} and Lina Hultin-Rosenberg and Sandling, {Johanna K} and Matteo Bianchi and Juliana Imgenberg-Kreuz and Pascal Pucholt and Elke Theander and Marika Kvarnstr{\"o}m and Helena Forsblad-d'Elia and Bucher, {Sara Magnusson} and Norheim, {Katrine B} and Johnsen, {Svein Joar Augl{\ae}nd} and Daniel Hammenfors and Kathrine Skarstein and Jonsson, {Malin V} and Eva Baecklund and Aqrawi, {Lara A} and Jensen, {Janicke Liaaen} and {\O}yvind Palm and Morris, {Andrew P} and Meadows, {Jennifer R S} and Solbritt Rantap{\"a}{\"a}-Dahlqvist and Thomas Mandl and Per Eriksson and Lars Lind and Roald Omdal and Roland Jonsson and Kerstin Lindblad-Toh and Lars R{\"o}nnblom and Marie Wahren-Herlenius and Gunnel Nordmark and {DISSECT consortium}",

note = "{\textcopyright} The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.",

year = "2020",

month = aug,

day = "21",

doi = "10.1093/rheumatology/keaa367",

language = "English",

journal = "Rheumatology",

issn = "1462-0332",

publisher = "Oxford University Press",

}

Thorlacius, GE, Hultin-Rosenberg, L, Sandling, JK, Bianchi, M, Imgenberg-Kreuz, J, Pucholt, P, Theander, E, Kvarnström, M, Forsblad-d'Elia, H, Bucher, SM, Norheim, KB, Johnsen, SJA, Hammenfors, D, Skarstein, K, Jonsson, MV, Baecklund, E, Aqrawi, LA, Jensen, JL, Palm, Ø, Morris, AP, Meadows, JRS, Rantapää-Dahlqvist, S, Mandl, T, Eriksson, P, Lind, L, Omdal, R, Jonsson, R, Lindblad-Toh, K, Rönnblom, L, Wahren-Herlenius, M, Nordmark, G & DISSECT consortium 2020, 'Genetic and clinical basis for two distinct subtypes of primary Sjögren's syndrome', Rheumatology (Oxford, England). https://doi.org/10.1093/rheumatology/keaa367

Genetic and clinical basis for two distinct subtypes of primary Sjögren's syndrome. / Thorlacius, Guðný Ella; Hultin-Rosenberg, Lina; Sandling, Johanna K; Bianchi, Matteo; Imgenberg-Kreuz, Juliana; Pucholt, Pascal; Theander, Elke; Kvarnström, Marika; Forsblad-d'Elia, Helena; Bucher, Sara Magnusson; Norheim, Katrine B; Johnsen, Svein Joar Auglænd; Hammenfors, Daniel; Skarstein, Kathrine; Jonsson, Malin V; Baecklund, Eva; Aqrawi, Lara A; Jensen, Janicke Liaaen; Palm, Øyvind; Morris, Andrew P; Meadows, Jennifer R S; Rantapää-Dahlqvist, Solbritt; Mandl, Thomas; Eriksson, Per; Lind, Lars; Omdal, Roald; Jonsson, Roland; Lindblad-Toh, Kerstin; Rönnblom, Lars; Wahren-Herlenius, Marie; Nordmark, Gunnel; DISSECT consortium.

I: Rheumatology (Oxford, England), 21.08.2020.

Forskningsoutput: Tidskriftsbidrag › Artikel i vetenskaplig tidskrift › Peer review

TY - JOUR

T1 - Genetic and clinical basis for two distinct subtypes of primary Sjögren's syndrome

AU - Thorlacius, Guðný Ella

AU - Hultin-Rosenberg, Lina

AU - Sandling, Johanna K

AU - Bianchi, Matteo

AU - Imgenberg-Kreuz, Juliana

AU - Pucholt, Pascal

AU - Theander, Elke

AU - Kvarnström, Marika

AU - Forsblad-d'Elia, Helena

AU - Bucher, Sara Magnusson

AU - Norheim, Katrine B

AU - Johnsen, Svein Joar Auglænd

AU - Hammenfors, Daniel

AU - Skarstein, Kathrine

AU - Jonsson, Malin V

AU - Baecklund, Eva

AU - Aqrawi, Lara A

AU - Jensen, Janicke Liaaen

AU - Palm, Øyvind

AU - Morris, Andrew P

AU - Meadows, Jennifer R S

AU - Rantapää-Dahlqvist, Solbritt

AU - Mandl, Thomas

AU - Eriksson, Per

AU - Lind, Lars

AU - Omdal, Roald

AU - Jonsson, Roland

AU - Lindblad-Toh, Kerstin

AU - Rönnblom, Lars

AU - Wahren-Herlenius, Marie

AU - Nordmark, Gunnel

AU - DISSECT consortium

PY - 2020/8/21

Y1 - 2020/8/21

N2 - 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.

AB - 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.

U2 - 10.1093/rheumatology/keaa367

DO - 10.1093/rheumatology/keaa367

M3 - Article

C2 - 32889544

JO - Rheumatology

JF - Rheumatology

SN - 1462-0332

ER -

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

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