Rare and common single nucleotide variants in childhood-onset systemic lupus erythematosus
Background SLE is a systemic autoimmune disease with a large number of common risk gene variants, but several rare gene variants can cause monogenic SLE. The relationship between common and rare variants in SLE is unclear. We therefore investigated the occurrence of rare deleterious variants in pati...
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2025-02-01
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| Series: | Lupus Science and Medicine |
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| author | Elisabet Svenungsson Iva Gunnarsson Lars Rönnblom Ingrid E Lundberg Andreas Jönsen Niklas Hagberg Leonid Padyukov Marie Wahren-Herlenius Christopher Sjöwall Solbritt Rantapää-Dahlqvist Sule Yavuz Øyvind Molberg Dag Leonard Andrei Alexsson Maija-Leena Eloranta Ann-Christine Syvänen Johanna K Sandling Gunnel Nordmark Roland Jonsson Roald Omdal Christine Bengtsson Anders A Bengtsson Pascal Pucholt Kerstin Lindblad-Toh Sergey V Kozyrev Peter Söderkvist Johanna Dahlqvist Jonas Carlsson Almlöf Daniel Eriksson Ahmed Sayadi Åsa Karlsson Gerli Rosengren Pielberg Anna Lobell Eva Murén Kerstin M Ahlgren Nils Landegren Olle Kämpe Fabiana HG Farias Argyri Mathioudaki Jennifer Meadows Jessika Nordin |
| author_facet | Elisabet Svenungsson Iva Gunnarsson Lars Rönnblom Ingrid E Lundberg Andreas Jönsen Niklas Hagberg Leonid Padyukov Marie Wahren-Herlenius Christopher Sjöwall Solbritt Rantapää-Dahlqvist Sule Yavuz Øyvind Molberg Dag Leonard Andrei Alexsson Maija-Leena Eloranta Ann-Christine Syvänen Johanna K Sandling Gunnel Nordmark Roland Jonsson Roald Omdal Christine Bengtsson Anders A Bengtsson Pascal Pucholt Kerstin Lindblad-Toh Sergey V Kozyrev Peter Söderkvist Johanna Dahlqvist Jonas Carlsson Almlöf Daniel Eriksson Ahmed Sayadi Åsa Karlsson Gerli Rosengren Pielberg Anna Lobell Eva Murén Kerstin M Ahlgren Nils Landegren Olle Kämpe Fabiana HG Farias Argyri Mathioudaki Jennifer Meadows Jessika Nordin |
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| description | Background SLE is a systemic autoimmune disease with a large number of common risk gene variants, but several rare gene variants can cause monogenic SLE. The relationship between common and rare variants in SLE is unclear. We therefore investigated the occurrence of rare deleterious variants in patients with childhood-onset SLE (cSLE) and adult-onset SLE (aSLE) and compared the frequency of these variants with their individual SLE polygenic risk score (PRS).Materials and methods Targeted sequencing of 1832 gene regions, including coding regions of 31 genes associated with monogenic SLE, was performed in 958 patients with SLE and 1026 healthy individuals. A total of 116 patients with SLE had disease onset before the age of 18 (cSLE). An SLE common variant PRS was created from 37 SLE genome-wide association study single nucleotide variants (SNVs).Results Rare coding deleterious SNVs (RD SNVs) were observed in 23 of the monogenic SLE-associated genes. Six per cent of patients with cSLE, compared with 3.2% of controls and 4.6% of patients with aSLE, carried rare deleterious alleles. In cSLE, RD SNVs were observed in the C1S, DDX58, IFIH1, IKZF1, RNASEH2A and C8A genes. A PRS analysis showed that patients with cSLE with any of these gene variants had a similar average PRS as control individuals.Conclusion RD SNVs were observed in a small proportion of cSLE and carriers of these RD SNVs had a PRS similar to healthy individuals, suggesting the importance of rare coding heterozygous variants in driving disease risk in a subset of children with SLE. |
| format | Article |
| id | doaj-art-1a13294ee4964e2cb0b357930af2ac0b |
| institution | Kabale University |
| issn | 2053-8790 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Lupus Science and Medicine |
| spelling | doaj-art-1a13294ee4964e2cb0b357930af2ac0b2025-02-11T17:50:10ZengBMJ Publishing GroupLupus Science and Medicine2053-87902025-02-0112110.1136/lupus-2024-001436Rare and common single nucleotide variants in childhood-onset systemic lupus erythematosus 0Elisabet Svenungsson1Iva Gunnarsson2Lars Rönnblom3Ingrid E Lundberg4Andreas Jönsen5Niklas Hagberg6Leonid Padyukov7Marie Wahren-Herlenius8Christopher Sjöwall9Solbritt Rantapää-Dahlqvist10Sule Yavuz11Øyvind Molberg12Dag Leonard13Andrei Alexsson14Maija-Leena Eloranta15Ann-Christine Syvänen16Johanna K Sandling17Gunnel Nordmark18Roland Jonsson19Roald Omdal20Christine Bengtsson21Anders A Bengtsson22Pascal Pucholt23Kerstin Lindblad-Toh24Sergey V Kozyrev25Peter Söderkvist26Johanna Dahlqvist27Jonas Carlsson Almlöf28Daniel Eriksson29Ahmed Sayadi30Åsa Karlsson31Gerli Rosengren PielbergAnna LobellEva MurénKerstin M AhlgrenNils LandegrenOlle KämpeFabiana HG FariasArgyri MathioudakiJennifer MeadowsJessika NordinKenya National Bureau of Statistics, Nairobi, Nairobi, KenyaDivision of Rheumatology, Department of Medicine, Karolinska Institute, Stockholm, SwedenDivision of Rheumatology, Department of Medicine, Karolinska Institute, Stockholm, SwedenDepartment of Medical Sciences, Rheumatology, Uppsala University, Uppsala, Sweden6 Department of Medicine, Division of Rheumatology, Karolinska Institutet, Karolinska University Hospital, Stockholm, SwedenDepartment of Clinical Sciences, Rheumatology, Lund University, Lund, Sweden2Uppsala University, Dept of Medical Sciences, Rheumatology, Uppsala, Sweden11 Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, SwedenDepartment of Medicine, Karolinska Institutet, Stockholm, SwedenDepartment of Biomedical and Clinical Sciences, Division of Inflammation and Infection/Rheumatology, Linköping University, Linköping, SwedenDepartment of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden56 Department of Rheumatology, Istanbul Bilim University, Istanbul, TurkeyInstitute of Clinical Medicine, University of Oslo, Oslo, NorwayAcademic Hospital, Rheumatology, Uppsala, SwedenRheumatology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden5Uppsala University, Medical Sciences, Uppsala, Sweden1Uppsala University, UppsalaRheumatology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden28Uppsala Univ, Uppsala, SwedenBroegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Hordaland, NorwayResearch Department, Stavanger University Hospital, Stavanger, Norway6 Department of Public Health and Clinical Medicine/Rheumatology, Umeå University, Umeå, SwedenDepartment of Clinical Sciences, Rheumatology, Lund University, Lund, SwedenDepartment of Medical Sciences and Science for Life Laboratory, Uppsala University, Uppsala, SwedenDepartment of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, SwedenScience for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, SwedenDepartment of Biomedical and Clinical Sciences, Linköping University, Linköping, SwedenDepartment of Medical Sciences, Uppsala University, Uppsala, Sweden1Molecular Medicine and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden5 Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, SwedenRheumatology, Department of Medical Sciences, Uppsala University, Uppsala, SwedenDepartment of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, SwedenBackground SLE is a systemic autoimmune disease with a large number of common risk gene variants, but several rare gene variants can cause monogenic SLE. The relationship between common and rare variants in SLE is unclear. We therefore investigated the occurrence of rare deleterious variants in patients with childhood-onset SLE (cSLE) and adult-onset SLE (aSLE) and compared the frequency of these variants with their individual SLE polygenic risk score (PRS).Materials and methods Targeted sequencing of 1832 gene regions, including coding regions of 31 genes associated with monogenic SLE, was performed in 958 patients with SLE and 1026 healthy individuals. A total of 116 patients with SLE had disease onset before the age of 18 (cSLE). An SLE common variant PRS was created from 37 SLE genome-wide association study single nucleotide variants (SNVs).Results Rare coding deleterious SNVs (RD SNVs) were observed in 23 of the monogenic SLE-associated genes. Six per cent of patients with cSLE, compared with 3.2% of controls and 4.6% of patients with aSLE, carried rare deleterious alleles. In cSLE, RD SNVs were observed in the C1S, DDX58, IFIH1, IKZF1, RNASEH2A and C8A genes. A PRS analysis showed that patients with cSLE with any of these gene variants had a similar average PRS as control individuals.Conclusion RD SNVs were observed in a small proportion of cSLE and carriers of these RD SNVs had a PRS similar to healthy individuals, suggesting the importance of rare coding heterozygous variants in driving disease risk in a subset of children with SLE.https://lupus.bmj.com/content/12/1/e001436.full |
| spellingShingle | Elisabet Svenungsson Iva Gunnarsson Lars Rönnblom Ingrid E Lundberg Andreas Jönsen Niklas Hagberg Leonid Padyukov Marie Wahren-Herlenius Christopher Sjöwall Solbritt Rantapää-Dahlqvist Sule Yavuz Øyvind Molberg Dag Leonard Andrei Alexsson Maija-Leena Eloranta Ann-Christine Syvänen Johanna K Sandling Gunnel Nordmark Roland Jonsson Roald Omdal Christine Bengtsson Anders A Bengtsson Pascal Pucholt Kerstin Lindblad-Toh Sergey V Kozyrev Peter Söderkvist Johanna Dahlqvist Jonas Carlsson Almlöf Daniel Eriksson Ahmed Sayadi Åsa Karlsson Gerli Rosengren Pielberg Anna Lobell Eva Murén Kerstin M Ahlgren Nils Landegren Olle Kämpe Fabiana HG Farias Argyri Mathioudaki Jennifer Meadows Jessika Nordin Rare and common single nucleotide variants in childhood-onset systemic lupus erythematosus Lupus Science and Medicine |
| title | Rare and common single nucleotide variants in childhood-onset systemic lupus erythematosus |
| title_full | Rare and common single nucleotide variants in childhood-onset systemic lupus erythematosus |
| title_fullStr | Rare and common single nucleotide variants in childhood-onset systemic lupus erythematosus |
| title_full_unstemmed | Rare and common single nucleotide variants in childhood-onset systemic lupus erythematosus |
| title_short | Rare and common single nucleotide variants in childhood-onset systemic lupus erythematosus |
| title_sort | rare and common single nucleotide variants in childhood onset systemic lupus erythematosus |
| url | https://lupus.bmj.com/content/12/1/e001436.full |
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