Genetics of Childhood-onset Systemic Lupus Erythematosus (cSLE)

Raffaella Carlomagno; Nicholas Gold; Fangming Liao; Jingjing Cao; Paul D Arnold; Christie L Burton; Jennifer Crosbie; Daniela Dominguez; Dafna D Gladman; Mariko Ishimori; Caroline Jefferies; Diane L Kamen; Sylvia Kamphuis; Marisa S Klein-Gitelman; Andrea M Knight; Chia-Chi J Lee; Deborah M Levy; Karen B Onel; Andrew D Paterson; Christine A Peschken; Janet E Pope; Russell J Schachar; Earl D Silverman; Lisa Strug; Zahi Touma; Murray B Urowitz; Daniel J Wallace; Cheng Wang; Declan Webber; Joan E Wither; Linda T Hiraki

doi:10.1002/art.43227

Genetics of Childhood-onset Systemic Lupus Erythematosus (cSLE)

Arthritis Rheumatol. 2025 May 12. doi: 10.1002/art.43227. Online ahead of print.

Authors

Raffaella Carlomagno^{1

2}, Nicholas Gold¹, Fangming Liao¹, Jingjing Cao³, Paul D Arnold^{4

5}, Christie L Burton⁶, Jennifer Crosbie^{6

7}, Daniela Dominguez¹, Dafna D Gladman^{8

9}, Mariko Ishimori¹⁰, Caroline Jefferies^{10

11}, Diane L Kamen¹², Sylvia Kamphuis¹³, Marisa S Klein-Gitelman¹⁴, Andrea M Knight¹, Chia-Chi J Lee¹¹, Deborah M Levy¹, Karen B Onel¹⁵, Andrew D Paterson^{3

16}, Christine A Peschken¹⁷, Janet E Pope¹⁸, Russell J Schachar^{6

7}, Earl D Silverman^{1

19}, Lisa Strug^{3

16}, Zahi Touma^{8

9}, Murray B Urowitz⁸, Daniel J Wallace¹¹, Cheng Wang³, Declan Webber¹, Joan E Wither^{8

9}, Linda T Hiraki^{1

3}

Affiliations

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

PMID: 40356234
DOI: 10.1002/art.43227

Abstract

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

Methods: Patients met ACR and/or SLICC SLE classification criteria, had documented age at diagnosis and were genotyped on multiethnic arrays. Ungenotyped SNPs and HLA alleles were imputed to multi-ethnic 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 PCs (significance threshold P<1.6x10^-4). We also completed a GWAS of 346 cSLE patients and 4080 non-SLE children/adolescents of European and East Asian ancestry (genome-wide significance P<5x10^-8).

Results: We included 1489 SLE patients, 51% cSLE, 88% female, 39% of European ancestry, 19% East Asian, 17% Admixed. The median age at diagnosis was 17.7 years (IQR:14.0, 30.9). One SLE risk SNP, intronic to CCDC113 (chr.16), was associated with younger age of SLE diagnosis (beta=-0.12, SE=0.03, P=6.3x10^-6), and with cSLE versus adult-onset SLE (aSLE). GWAS of cSLE compared to non-SLE controls identified significant chr.6 SNP rs9268469, intronic to TSBP1-AS1 (OR=2.04, [95%CI: 1.59, 2.63], P=1.79x10^-8), and HLA-DQA1.

Conclusions: We identified a significant locus for younger age of SLE diagnosis, intronic to CCDC113, among a large multi-ancestral 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.