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  • 1
    Online Resource
    Online Resource
    Schizophrenia Genetics and Neuropsychiatric Features in Childhood-onset Systemic Lupus Erythematosus
    The Journal of Rheumatology ; 2022
    In:  The Journal of Rheumatology Vol. 49, No. 2 ( 2022-02), p. 192-196
    Details
    In: The Journal of Rheumatology, The Journal of Rheumatology, Vol. 49, No. 2 ( 2022-02), p. 192-196
    Abstract: We examined the association between schizophrenia genetic susceptibility loci and neuropsychiatric systemic lupus erythematosus (NPSLE) features in childhood-onset SLE (cSLE) participants. Methods Study participants from the Lupus Clinic at the Hospital for Sick Children, Toronto, met ≥ 4 of the American College of Rheumatology and/or SLE International Collaborating Clinics SLE classification criteria and were genotyped using the Illumina Multi-Ethnic Global Array or the Global Screening Array. Ungenotyped single-nucleotide polymorphisms (SNPs) were imputed, and ancestry was genetically inferred. We calculated 2 additive schizophrenia-weighted polygenic risk scores (PRS) using (1) genome-wide significant SNPs ( P 〈 5 × 10 –8 ), and (2) an expanded list of SNPs with significance at P 〈 0.05. We defined 2 outcomes compared to absence of NPSLE features: (1) any NPSLE feature, and (2) subtypes of NPSLE features (psychosis and nonpsychosis NPSLE). We completed logistic and multinomial regressions, first adjusted for inferred ancestry only and then added for variables significantly associated with NPSLE in our cohort ( P 〈 0.05). Results We included 513 participants with cSLE. Median age at diagnosis was 13.8 years (IQR 11.2–15.6), 83% were female, and 31% were of European ancestry. An increasing schizophrenia genome-wide association PRS was not associated with NPSLE (OR 1.04, 95% CI 0.87–1.26, P = 0.62), nor with the NPSLE subtypes, psychosis (OR 0.97, 95% CI 0.73–1.29, P = 0.84) and other nonpsychosis NPSLE (OR 1.08, 95% CI 0.88–1.34, P = 0.45), in ancestry-adjusted models. Results were similar for the model including covariates (ancestry, malar rash, oral/nasal ulcers, arthritis, lymphopenia, Coombs-positive hemolytic anemia, lupus anticoagulant, and anticardiolipin antibodies) and for the expanded PRS estimates. Conclusion We did not observe an association between known risk loci for schizophrenia and NPSLE in a multiethnic cSLE cohort. This work warrants further validation.
    Type of Medium: Online Resource
    ISSN: 0315-162X , 1499-2752
    URL: Article
    DOI: 10.3899/jrheum.210363
    RVK:
    XA 10000
    Language: English
    Publisher: The Journal of Rheumatology
    Publication Date: 2022
    Location Call Number Limitation Availability
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  • 2
    Online Resource
    Online Resource
    Genome-Wide Sequencing Identified Rare Genetic Variants for Childhood-Onset Monogenic Lupus
    The Journal of Rheumatology ; 2023
    In:  The Journal of Rheumatology Vol. 50, No. 5 ( 2023-05), p. 671-675
    Details
    In: The Journal of Rheumatology, The Journal of Rheumatology, Vol. 50, No. 5 ( 2023-05), p. 671-675
    Abstract: Genetics play an important role in systemic lupus erythematosus (SLE) pathogenesis. We calculated the prevalence of rare variants in known monogenic lupus genes among children suspected of monogenic lupus. Methods We completed paired-end genome-wide sequencing (whole genome sequencing [WGS] or whole exome sequencing) in patients suspected of monogenic lupus, and focused on 36 monogenic lupus genes. We prioritized rare (minor allele frequency 〈 1%) exonic, nonsynonymous, and splice variants with predicted pathogenicity classified as deleterious variants (Combined Annotation Dependent Depletion [CADD], PolyPhen2, and Sorting Intolerant From Tolerant [SIFT] scores). Additional filtering restricted to predicted damaging variants by considering reported zygosity. In those with WGS (n = 69), we examined copy number variants (CNVs) 〉 1 kb in size. We created additive non-HLA and HLA SLE genetic risk scores (GRSs) using common SLE-risk single-nucleotide polymorphisms. We tested the relationship between SLE GRSs and the number of rare variants with multivariate logistic models, adjusted for sex, ancestry, and age of diagnosis. Results The cohort included 71 patients, 80% female, with a mean age at diagnosis of 8.9 (SD 3.2) years. We identified predicted damaging variants in 9 (13%) patients who were significantly younger at diagnosis compared to those without a predicted damaging variant (6.8 [SD 2.1] years vs 9.2 [SD 3.2] years, P = 0.01). We did not identify damaging CNVs. There was no significant association between non-HLA or HLA SLE GRSs and the odds of carrying ≥ 1 rare variant in multivariate analyses. Conclusion In a cohort of patients with suspected monogenic lupus who underwent genome-wide sequencing, 13% carried rare predicted damaging variants for monogenic lupus. Additional studies are needed to validate our findings.
    Type of Medium: Online Resource
    ISSN: 0315-162X , 1499-2752
    URL: Article
    DOI: 10.3899/jrheum.220513
    RVK:
    XA 10000
    Language: English
    Publisher: The Journal of Rheumatology
    Publication Date: 2023
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  • 3
    Online Resource
    Online Resource
    Predicting Macrophage Activation Syndrome in Childhood-onset Systemic Lupus Erythematosus Patients at Diagnosis
    The Journal of Rheumatology ; 2021
    In:  The Journal of Rheumatology Vol. 48, No. 9 ( 2021-09), p. 1450-1457
    Details
    In: The Journal of Rheumatology, The Journal of Rheumatology, Vol. 48, No. 9 ( 2021-09), p. 1450-1457
    Abstract: Macrophage activation syndrome (MAS), a life-threatening inflammatory complication, is increasingly recognized in childhood-onset systemic lupus erythematosus (cSLE). It can be a challenge to differentiate active cSLE from MAS. We generated decision rules for discriminating MAS from active cSLE in newly diagnosed patients. Methods We conducted a retrospective cohort study of consecutive, newly diagnosed, active cSLE patients with fever, requiring hospital admission to The Hospital for Sick Children from January 2003 to December 2007 (cohort 1) and January 2008 to December 2013 (cohort 2). All patients met ≥ 4 American College of Rheumatology or Systemic Lupus International Collaborating Clinics criteria, and were steroid-naïve and infection-free. MAS was diagnosed based on expert opinion. Recursive partitioning was applied to each cohort to derive a decision rule based on clinical and laboratory features, distinguishing MAS from non-MAS cSLE. Each decision rule was applied to the alternate, independent cohort. Sensitivity and specificity of these decision rules were compared to existing criteria. Results Cohort 1 (n = 34) and cohort 2 (n = 41) each had 10 patients with MAS. Recursive partitioning in cohort 1 identified ferritin ≥ 699 μg/L as the sole best discriminator between MAS and non-MAS patients (R 2 = 0.48), and in cohort 2, ferritin ≥ 1107 μg/L was the best discriminator for MAS, followed by lymphocytes 〈 0.72 × 10 3 /mm 3 (R 2 = 0.52). Cross-validation of our decision rules maintained 90–100% sensitivity and 65–85% specificity. Conclusion Our decision rule demonstrated improved performance compared to preliminary guidelines for MAS in cSLE from the Lupus Working Group of the Paediatric Rheumatology European Society and familial hemophagocytic lymphohistiocytosis diagnostic criteria. Validation in independent cohorts is required.
    Type of Medium: Online Resource
    ISSN: 0315-162X , 1499-2752
    URL: Article
    DOI: 10.3899/jrheum.200292
    RVK:
    XA 10000
    Language: English
    Publisher: The Journal of Rheumatology
    Publication Date: 2021
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  • 4
    Online Resource
    Online Resource
    Hemophagocytic Lymphohistiocytosis Gene Variants in Childhood-Onset Systemic Lupus Erythematosus With Macrophage Activation Syndrome
    The Journal of Rheumatology ; 2022
    In:  The Journal of Rheumatology Vol. 49, No. 10 ( 2022-10), p. 1146-1151
    Details
    In: The Journal of Rheumatology, The Journal of Rheumatology, Vol. 49, No. 10 ( 2022-10), p. 1146-1151
    Abstract: Macrophage activation syndrome (MAS), a life-threatening complication of systemic lupus erythematosus (SLE), resembles familial hemophagocytic lymphohistiocytosis (HLH), an inherited disorder of hyperinflammation. We compared the proportion of patients with childhood-onset SLE (cSLE) with and without MAS who carried low-frequency HLH nonsynonymous variants. Methods We enrolled patients from the Lupus Clinic at SickKids, Toronto. Demographic and clinical features were extracted from the SLE database and ancestry was genetically inferred using multiethnic genotyping array data. Patients with MAS (based on expert diagnosis) underwent either paired-end whole-exome sequencing (WES; read depth: 70-118X) or whole-genome sequencing (WGS). Patients without MAS had WGS (read depth: 37-40X). In 16 HLH genes, we prioritized low-frequency (minor allele frequency [MAF] 〈 0.05) exonic nonsynonymous variants. We compared the proportion of patients with and without MAS carrying HLH variants (Fisher exact test, P 〈 0.05). MAFs were compared to an ancestrally matched general population (Trans-Omics for Precision Medicine [TOPMed] and Genome Aggregation Database [gnomAD]). Results The study included 81 patients with cSLE, 19 of whom had MAS. We identified 47 unique low-frequency nonsynonymous HLH variants. There was no difference in the proportion of patients with and without MAS carrying ≥ 1 HLH variants (37% vs 47%, P = 0.44). The MAS cohort did not carry more HLH variants when compared to an ancestrally matched general population. Conclusion In a single-center multiethnic cSLE cohort, we found no difference in the proportion of patients with MAS carrying nonsynonymous HLH genetic variants compared to patients without MAS. To our knowledge, this is the first study to examine the frequency of HLH genetic variants in relation to MAS among patients with cSLE. Future studies are required to validate our findings.
    Type of Medium: Online Resource
    ISSN: 0315-162X , 1499-2752
    URL: Article
    DOI: 10.3899/jrheum.211200
    RVK:
    XA 10000
    Language: English
    Publisher: The Journal of Rheumatology
    Publication Date: 2022
    Location Call Number Limitation Availability
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