Genetics of Childhood-Onset Systemic Lupus Erythematosus

Raffaella Carlomagno¹, Nicholas Gold², Fangming Liao³, Jingjing Cao³, Paul D Arnold⁴, Christie L Burton⁵, Jennifer Crosbie⁶, Daniela Dominguez², Dafna D Gladman⁷, Mariko Ishimori⁸, Caroline Jefferies⁹, Diane L Kamen¹⁰, Sylvia Kamphuis¹¹, Marisa S Klein-Gitelman¹², Andrea M Knight², Chia-Chi J Lee¹³, Deborah M Levy², Karen B Onel¹⁴, Andrew D Paterson¹⁵, Christine A Peschken¹⁶, Janet E Pope¹⁷, Russell J Schachar⁶, Earl D Silverman², Lisa Strug¹⁵, Zahi Touma⁷, Murray B Urowitz¹⁸, Daniel J Wallace¹³, Cheng Wang³, Declan Webber², Joan E Wither⁷, Linda T Hiraki¹⁹

Affiliations

¹ Division of Rheumatology, The Hospital for Sick Children, Toronto, Ontario, Canada, and Unit of Rheumatology, Immunology and Allergology, Department of Pediatrics, Lausanne University Hospital, Lausanne, Switzerland.
² Division of Rheumatology, The Hospital for Sick Children, Toronto, Ontario, Canada.
³ Genetics & Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁴ Mathison Centre for Mental Health Research and Education, Departments of Psychiatry, and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
⁵ Neurosciences and Mental Health, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
⁶ Neurosciences and Mental Health, Research Institute, Hospital for Sick Children, and Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
⁷ Schroeder Arthritis Institute, Toronto Western Hospital, University of Toronto, and Krembil Research Institute, Toronto Western Hospital, Toronto, Ontario, Canada.
⁸ Kao Autoimmunity Institute, Cedars-Sinai Medical Center, Los Angeles, California.
⁹ Kao Autoimmunity Institute, Cedars-Sinai Medical Center, Los Angeles, California, and Division of Rheumatology, Department of Medicine, Cedars Sinai Medical Center, Los Angeles.
¹⁰ Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston.
¹¹ Department of Pediatric Rheumatology, Sophia Children's Hospital, Erasmus University Medical Center, Rotterdam, The Netherlands.
¹² Division of Rheumatology, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.
¹³ Division of Rheumatology, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, California.
¹⁴ Pediatric Rheumatology, Hospital for Special Surgery, New York, New York.
¹⁵ Genetics & Genome Biology, Research Institute, The Hospital for Sick Children, and Divisions of Biostatistics and Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
¹⁶ Departments of Medicine and Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
¹⁷ Department of Medicine, University of Western Ontario, St. Joseph's Health Centre, London, Ontario, Canada.
¹⁸ Schroeder Arthritis Institute, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada.
¹⁹ Division of Rheumatology, The Hospital for Sick Children, Toronto, Ontario, Canada, and Genetics & Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada, and Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.

PMID: 40356234
DOI: 10.1002/art.43227

Genetics of Childhood-Onset Systemic Lupus Erythematosus

Raffaella Carlomagno et al. Arthritis Rheumatol. 2025 Nov.

. 2025 Nov;77(11):1524-1532.

doi: 10.1002/art.43227. Epub 2025 Sep 21.

Authors

Affiliations

¹ Division of Rheumatology, The Hospital for Sick Children, Toronto, Ontario, Canada, and Unit of Rheumatology, Immunology and Allergology, Department of Pediatrics, Lausanne University Hospital, Lausanne, Switzerland.
² Division of Rheumatology, The Hospital for Sick Children, Toronto, Ontario, Canada.
³ Genetics & Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁴ Mathison Centre for Mental Health Research and Education, Departments of Psychiatry, and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
⁵ Neurosciences and Mental Health, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
⁶ Neurosciences and Mental Health, Research Institute, Hospital for Sick Children, and Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
⁷ Schroeder Arthritis Institute, Toronto Western Hospital, University of Toronto, and Krembil Research Institute, Toronto Western Hospital, Toronto, Ontario, Canada.
⁸ Kao Autoimmunity Institute, Cedars-Sinai Medical Center, Los Angeles, California.
⁹ Kao Autoimmunity Institute, Cedars-Sinai Medical Center, Los Angeles, California, and Division of Rheumatology, Department of Medicine, Cedars Sinai Medical Center, Los Angeles.
¹⁰ Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston.
¹¹ Department of Pediatric Rheumatology, Sophia Children's Hospital, Erasmus University Medical Center, Rotterdam, The Netherlands.
¹² Division of Rheumatology, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.
¹³ Division of Rheumatology, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, California.
¹⁴ Pediatric Rheumatology, Hospital for Special Surgery, New York, New York.
¹⁵ Genetics & Genome Biology, Research Institute, The Hospital for Sick Children, and Divisions of Biostatistics and Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
¹⁶ Departments of Medicine and Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
¹⁷ Department of Medicine, University of Western Ontario, St. Joseph's Health Centre, London, Ontario, Canada.
¹⁸ Schroeder Arthritis Institute, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada.
¹⁹ Division of Rheumatology, The Hospital for Sick Children, Toronto, Ontario, Canada, and Genetics & Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada, and Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.

PMID: 40356234
DOI: 10.1002/art.43227

Abstract

Objective: Genome-wide association studies (GWAS) have identified >100 loci for systemic lupus erythematosus (SLE). These loci may also affect age at diagnosis. We aimed to identify genetic variants for age at SLE diagnosis and to complete a GWAS of childhood-onset SLE (cSLE) in children diagnosed <18 years of age.

Methods: Patients met American College of Rheumatology and/or Systemic Lupus Erythematosus International Collaborative Clinics classification criteria, had documented age at diagnosis, and were genotyped on multiethnic arrays. Ungenotyped single nucleotide polymorphisms (SNPs) and HLA alleles were imputed to multiethnic referents. Ancestry was genetically inferred. We tested known SLE loci (142 non-HLA, 166 HLA) with log-transformed age of SLE diagnosis, adjusted for sex and five principal components (significance threshold P < 1.6 × 10^-4). We also completed a GWAS of 346 patients with cSLE and 4,080 children and adolescents without SLE of European and East Asian ancestry (genome-wide significance P < 5 × 10^-8).

Results: We included 1,489 patients with SLE, 51% of patients had cSLE, 88% of patients were female, 39% of patients were of European ancestry, 19% of patients were of East Asian ancestry, and 17% of patients were of Admixed ancestry. The median age at diagnosis was 17.7 years (interquartile range 14.0-30.9). One SLE-risk SNP, intronic to coiled-coil domain containing 113 (CCDC113) (chromosome 16), was associated with younger age at SLE diagnosis (β = -0.12, SE = 0.03, P = 6.3 × 10^-6) and with cSLE versus adult-onset SLE (aSLE). GWAS of cSLE compared to controls without SLE identified significant chromosome 6 SNP rs9268469, intronic to TSBP1-AS1 (odds ratio 2.04 [95% confidence interval 1.59-2.63], P = 1.79 × 10^-8) and HLA-DQA1.

Conclusion: We identified a significant locus for younger age at SLE diagnosis, intronic to CCDC113, among a large multiancestral cohort of children and adults with SLE. In the first GWAS of cSLE, we identified a TSBP1-AS1 locus and an HLA-DQA1 previously identified for aSLE.

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References

REFERENCES

1. Woo JMP, Parks CG, Jacobsen S, et al. The role of environmental exposures and gene‐environment interactions in the etiology of systemic lupus erythematous. J Intern Med 2022;291(6):755–778.
1. Lawrence JS, Martins CL, Drake GL. A family survey of lupus erythematosus. 1. Heritability. J Rheumatol 1987;14(5):913–921.
1. Alarcón‐Segovia D, Alarcón‐Riquelme ME, Cardiel MH, et al; Grupo Latinoamericano de Estudio del Lupus Eritematoso (GLADEL). Familial aggregation of systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune diseases in 1,177 lupus patients from the GLADEL cohort. Arthritis Rheum 2005;52(4):1138–1147.
1. Langefeld CD, Ainsworth HC, Cunninghame Graham DS, et al. Transancestral mapping and genetic load in systemic lupus erythematosus. Nat Commun 2017;8(1):16021.
1. Bentham J, Morris DL, Graham DSC, et al. Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus. Nat Genet 2015;47(12):1457–1464.

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Genetics of Childhood-Onset Systemic Lupus Erythematosus

Affiliations

Genetics of Childhood-Onset Systemic Lupus Erythematosus

Authors

Affiliations

Abstract

References

REFERENCES

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous