Unraveling the Genetics of Shared Clinical and Serological Manifestations in Patients With Systemic Inflammatory Autoimmune Diseases

Matteo Bianchi; Sergey V Kozyrev; Antonella Notarnicola; Johanna K Sandling; Mats Pettersson; Dag Leonard; Christopher Sjöwall; Iva Gunnarsson; Solbritt Rantapää-Dahlqvist; Anders A Bengtsson; Andreas Jönsen; Elisabet Svenungsson; Helena Enocsson; Marika Kvarnström; Helena Forsblad-d'Elia; Sara Magnusson Bucher; Katrine B Norheim; Eva Baecklund; Roland Jonsson; Daniel Hammenfors; Per Eriksson; Thomas Mandl; Roald Omdal; Leonid Padyukov; Helena Andersson; Øyvind Molberg; Louise Pyndt Diederichsen; Ann-Christine Syvänen; Marie Wahren-Herlenius; Gunnel Nordmark; Ingrid E Lundberg; Lars Rönnblom; Kerstin Lindblad-Toh

doi:10.1002/art.42988

Unraveling the Genetics of Shared Clinical and Serological Manifestations in Patients With Systemic Inflammatory Autoimmune Diseases

Matteo Bianchi^*, Sergey V Kozyrev, Antonella Notarnicola, Johanna K Sandling, Mats Pettersson, Dag Leonard, Christopher Sjöwall, Iva Gunnarsson, Solbritt Rantapää-Dahlqvist, Anders A Bengtsson, Andreas Jönsen, Elisabet Svenungsson, Helena Enocsson, Marika Kvarnström, Helena Forsblad-d'Elia, Sara Magnusson Bucher, Katrine B Norheim, Eva Baecklund, Roland Jonsson, Daniel HammenforsPer Eriksson, Thomas Mandl, Roald Omdal, Leonid Padyukov, Helena Andersson, Øyvind Molberg, Louise Pyndt Diederichsen, Ann-Christine Syvänen, Marie Wahren-Herlenius, Gunnel Nordmark, Ingrid E Lundberg, Lars Rönnblom, Kerstin Lindblad-Toh^*

^*Corresponding author af dette arbejde

Afdeling for Rygkirurgi, Led- og Bindevævssygdomme HOC

6 Citationer (Scopus)

Abstract

OBJECTIVE: Systemic inflammatory autoimmune diseases (SIADs) such as systemic lupus erythematosus (SLE), primary Sjögren disease (pSS), and idiopathic inflammatory myopathies (myositis) are complex conditions characterized by shared circulating autoantibodies and clinical manifestations, including skin rashes, among others. This study was aimed at elucidating the genetics underlying these common features.

METHODS: We performed targeted DNA sequencing of coding and regulatory regions from approximately 1,900 immune-related genes in a large cohort of 2,292 well-characterized Scandinavian patients with SIADs with SLE, pSS, and myositis as well as 1,252 controls. A gene-based functionally weighted genetic score for aggregate testing of all genetic variants, including rare variants, was complemented by in silico functional analyses and in vitro reporter experiments.

RESULTS: Case-control association analysis detected known and potentially novel genetic loci in agreement with previous genetic and transcriptomics findings linked to the SIAD autoimmune background. Intriguingly, case-case comparisons between patient subgroups with and without specific autoantibodies revealed that the subgroups defined by antinuclear antibodies and anti-double-stranded DNA antibodies have unique genetic profiles reflecting their heterogeneity. When focusing on clinical features, we overall showed that dual-specificity phosphatase 1 (DUSP1) protective genetic variants lead to increased gene expression and potentially to anti-inflammatory effects on the SIAD-associated skin phenotype. This is consistent with recent genetic findings on eczema and with the previously reported down-regulation of the MAPK signaling-related gene DUSP1 in other skin disorders.

CONCLUSION: Together, this suggests common molecular mechanisms potentially underlying overlapping clinical manifestations shared among different disorders and informs clinical heterogeneity, which could be translated to improve disease diagnostic and treatment, also in more generalized disease frameworks.

Originalsprog	Engelsk
Tidsskrift	Arthritis and Rheumatology
Vol/bind	77
Udgave nummer	2
Sider (fra-til)	212-225
Antal sider	14
ISSN	2326-5191
DOI	https://doi.org/10.1002/art.42988
Status	Udgivet - feb. 2025

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Bianchi, M., Kozyrev, S. V., Notarnicola, A., Sandling, J. K., Pettersson, M., Leonard, D., Sjöwall, C., Gunnarsson, I., Rantapää-Dahlqvist, S., Bengtsson, A. A., Jönsen, A., Svenungsson, E., Enocsson, H., Kvarnström, M., Forsblad-d'Elia, H., Magnusson Bucher, S., Norheim, K. B., Baecklund, E., Jonsson, R., ... Lindblad-Toh, K. (2025). Unraveling the Genetics of Shared Clinical and Serological Manifestations in Patients With Systemic Inflammatory Autoimmune Diseases. Arthritis and Rheumatology, 77(2), 212-225. https://doi.org/10.1002/art.42988

Bianchi, M, Kozyrev, SV, Notarnicola, A, Sandling, JK, Pettersson, M, Leonard, D, Sjöwall, C, Gunnarsson, I, Rantapää-Dahlqvist, S, Bengtsson, AA, Jönsen, A, Svenungsson, E, Enocsson, H, Kvarnström, M, Forsblad-d'Elia, H, Magnusson Bucher, S, Norheim, KB, Baecklund, E, Jonsson, R, Hammenfors, D, Eriksson, P, Mandl, T, Omdal, R, Padyukov, L, Andersson, H, Molberg, Ø, Pyndt Diederichsen, L, Syvänen, A-C, Wahren-Herlenius, M, Nordmark, G, Lundberg, IE, Rönnblom, L & Lindblad-Toh, K 2025, 'Unraveling the Genetics of Shared Clinical and Serological Manifestations in Patients With Systemic Inflammatory Autoimmune Diseases', Arthritis and Rheumatology, bind 77, nr. 2, s. 212-225. https://doi.org/10.1002/art.42988

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title = "Unraveling the Genetics of Shared Clinical and Serological Manifestations in Patients With Systemic Inflammatory Autoimmune Diseases",

abstract = "OBJECTIVE: Systemic inflammatory autoimmune diseases (SIADs) such as systemic lupus erythematosus (SLE), primary Sj{\"o}gren disease (pSS), and idiopathic inflammatory myopathies (myositis) are complex conditions characterized by shared circulating autoantibodies and clinical manifestations, including skin rashes, among others. This study was aimed at elucidating the genetics underlying these common features.METHODS: We performed targeted DNA sequencing of coding and regulatory regions from approximately 1,900 immune-related genes in a large cohort of 2,292 well-characterized Scandinavian patients with SIADs with SLE, pSS, and myositis as well as 1,252 controls. A gene-based functionally weighted genetic score for aggregate testing of all genetic variants, including rare variants, was complemented by in silico functional analyses and in vitro reporter experiments.RESULTS: Case-control association analysis detected known and potentially novel genetic loci in agreement with previous genetic and transcriptomics findings linked to the SIAD autoimmune background. Intriguingly, case-case comparisons between patient subgroups with and without specific autoantibodies revealed that the subgroups defined by antinuclear antibodies and anti-double-stranded DNA antibodies have unique genetic profiles reflecting their heterogeneity. When focusing on clinical features, we overall showed that dual-specificity phosphatase 1 (DUSP1) protective genetic variants lead to increased gene expression and potentially to anti-inflammatory effects on the SIAD-associated skin phenotype. This is consistent with recent genetic findings on eczema and with the previously reported down-regulation of the MAPK signaling-related gene DUSP1 in other skin disorders.CONCLUSION: Together, this suggests common molecular mechanisms potentially underlying overlapping clinical manifestations shared among different disorders and informs clinical heterogeneity, which could be translated to improve disease diagnostic and treatment, also in more generalized disease frameworks.",

keywords = "Adult, Antibodies, Antinuclear/immunology, Autoantibodies/immunology, Autoimmune Diseases/genetics, Case-Control Studies, Female, Humans, Lupus Erythematosus, Systemic/genetics, Male, Middle Aged, Myositis/genetics, Sjogren's Syndrome/genetics",

author = "Matteo Bianchi and Kozyrev, {Sergey V} and Antonella Notarnicola and Sandling, {Johanna K} and Mats Pettersson and Dag Leonard and Christopher Sj{\"o}wall and Iva Gunnarsson and Solbritt Rantap{\"a}{\"a}-Dahlqvist and Bengtsson, {Anders A} and Andreas J{\"o}nsen and Elisabet Svenungsson and Helena Enocsson and Marika Kvarnstr{\"o}m and Helena Forsblad-d'Elia and {Magnusson Bucher}, Sara and Norheim, {Katrine B} and Eva Baecklund and Roland Jonsson and Daniel Hammenfors and Per Eriksson and Thomas Mandl and Roald Omdal and Leonid Padyukov and Helena Andersson and {\O}yvind Molberg and {Pyndt Diederichsen}, Louise and Ann-Christine Syv{\"a}nen and Marie Wahren-Herlenius and Gunnel Nordmark and Lundberg, {Ingrid E} and Lars R{\"o}nnblom and Kerstin Lindblad-Toh",

year = "2025",

month = feb,

doi = "10.1002/art.42988",

language = "English",

volume = "77",

pages = "212--225",

journal = "Arthritis and Rheumatology",

issn = "2326-5191",

publisher = "John Wiley and Sons Ltd",

number = "2",

}

TY - JOUR

T1 - Unraveling the Genetics of Shared Clinical and Serological Manifestations in Patients With Systemic Inflammatory Autoimmune Diseases

AU - Bianchi, Matteo

AU - Kozyrev, Sergey V

AU - Notarnicola, Antonella

AU - Sandling, Johanna K

AU - Pettersson, Mats

AU - Leonard, Dag

AU - Sjöwall, Christopher

AU - Gunnarsson, Iva

AU - Rantapää-Dahlqvist, Solbritt

AU - Bengtsson, Anders A

AU - Jönsen, Andreas

AU - Svenungsson, Elisabet

AU - Enocsson, Helena

AU - Kvarnström, Marika

AU - Forsblad-d'Elia, Helena

AU - Magnusson Bucher, Sara

AU - Norheim, Katrine B

AU - Baecklund, Eva

AU - Jonsson, Roland

AU - Hammenfors, Daniel

AU - Eriksson, Per

AU - Mandl, Thomas

AU - Omdal, Roald

AU - Padyukov, Leonid

AU - Andersson, Helena

AU - Molberg, Øyvind

AU - Pyndt Diederichsen, Louise

AU - Syvänen, Ann-Christine

AU - Wahren-Herlenius, Marie

AU - Nordmark, Gunnel

AU - Lundberg, Ingrid E

AU - Rönnblom, Lars

AU - Lindblad-Toh, Kerstin

PY - 2025/2

Y1 - 2025/2

N2 - OBJECTIVE: Systemic inflammatory autoimmune diseases (SIADs) such as systemic lupus erythematosus (SLE), primary Sjögren disease (pSS), and idiopathic inflammatory myopathies (myositis) are complex conditions characterized by shared circulating autoantibodies and clinical manifestations, including skin rashes, among others. This study was aimed at elucidating the genetics underlying these common features.METHODS: We performed targeted DNA sequencing of coding and regulatory regions from approximately 1,900 immune-related genes in a large cohort of 2,292 well-characterized Scandinavian patients with SIADs with SLE, pSS, and myositis as well as 1,252 controls. A gene-based functionally weighted genetic score for aggregate testing of all genetic variants, including rare variants, was complemented by in silico functional analyses and in vitro reporter experiments.RESULTS: Case-control association analysis detected known and potentially novel genetic loci in agreement with previous genetic and transcriptomics findings linked to the SIAD autoimmune background. Intriguingly, case-case comparisons between patient subgroups with and without specific autoantibodies revealed that the subgroups defined by antinuclear antibodies and anti-double-stranded DNA antibodies have unique genetic profiles reflecting their heterogeneity. When focusing on clinical features, we overall showed that dual-specificity phosphatase 1 (DUSP1) protective genetic variants lead to increased gene expression and potentially to anti-inflammatory effects on the SIAD-associated skin phenotype. This is consistent with recent genetic findings on eczema and with the previously reported down-regulation of the MAPK signaling-related gene DUSP1 in other skin disorders.CONCLUSION: Together, this suggests common molecular mechanisms potentially underlying overlapping clinical manifestations shared among different disorders and informs clinical heterogeneity, which could be translated to improve disease diagnostic and treatment, also in more generalized disease frameworks.

AB - OBJECTIVE: Systemic inflammatory autoimmune diseases (SIADs) such as systemic lupus erythematosus (SLE), primary Sjögren disease (pSS), and idiopathic inflammatory myopathies (myositis) are complex conditions characterized by shared circulating autoantibodies and clinical manifestations, including skin rashes, among others. This study was aimed at elucidating the genetics underlying these common features.METHODS: We performed targeted DNA sequencing of coding and regulatory regions from approximately 1,900 immune-related genes in a large cohort of 2,292 well-characterized Scandinavian patients with SIADs with SLE, pSS, and myositis as well as 1,252 controls. A gene-based functionally weighted genetic score for aggregate testing of all genetic variants, including rare variants, was complemented by in silico functional analyses and in vitro reporter experiments.RESULTS: Case-control association analysis detected known and potentially novel genetic loci in agreement with previous genetic and transcriptomics findings linked to the SIAD autoimmune background. Intriguingly, case-case comparisons between patient subgroups with and without specific autoantibodies revealed that the subgroups defined by antinuclear antibodies and anti-double-stranded DNA antibodies have unique genetic profiles reflecting their heterogeneity. When focusing on clinical features, we overall showed that dual-specificity phosphatase 1 (DUSP1) protective genetic variants lead to increased gene expression and potentially to anti-inflammatory effects on the SIAD-associated skin phenotype. This is consistent with recent genetic findings on eczema and with the previously reported down-regulation of the MAPK signaling-related gene DUSP1 in other skin disorders.CONCLUSION: Together, this suggests common molecular mechanisms potentially underlying overlapping clinical manifestations shared among different disorders and informs clinical heterogeneity, which could be translated to improve disease diagnostic and treatment, also in more generalized disease frameworks.

KW - Adult

KW - Antibodies, Antinuclear/immunology

KW - Autoantibodies/immunology

KW - Autoimmune Diseases/genetics

KW - Case-Control Studies

KW - Female

KW - Humans

KW - Lupus Erythematosus, Systemic/genetics

KW - Male

KW - Middle Aged

KW - Myositis/genetics

KW - Sjogren's Syndrome/genetics

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U2 - 10.1002/art.42988

DO - 10.1002/art.42988

M3 - Journal article

C2 - 39284741

SN - 2326-5191

VL - 77

SP - 212

EP - 225

JO - Arthritis and Rheumatology

JF - Arthritis and Rheumatology

IS - 2

ER -

Unraveling the Genetics of Shared Clinical and Serological Manifestations in Patients With Systemic Inflammatory Autoimmune Diseases

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