Schizophrenia Genetics and Neuropsychiatric Features in Childhood-Onset Systemic Lupus Erythematosus

2021 ◽  
pp. jrheum.210363
Author(s):  
Ana C. Ulloa ◽  
Fangming Liao ◽  
Raffaella L. Carlomagno ◽  
Talia Dia ◽  
Daniela Dominguez ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Significant Snps ◽  
Anticardiolipin Antibodies ◽  
European Ancestry ◽  
Risk Scores ◽  
Childhood Onset ◽  
Systemic Lupus ◽  
Sick Children ◽  
Study Participants

Objective 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 ACR and/or SLICC SLE classification criteria and were genotyped using the Illumina MEGA or GSA arrays. Ungenotyped SNPs were imputed, and ancestry was genetically inferred. We calculated two additive schizophrenia weighted polygenic risk scores (PRSs) using: 1) genome-wide significant SNPs (P<5×10-8) and 2) expanded list of SNPs with significance P<0.05. We defined two outcomes compared to absence of NPSLE features: 1) any NPSLE feature and 2) subtypes of NPSLE features: psychosis and non-psychosis NPSLE. We completed logistic and multinomial regressions, first adjusted for inferred ancestry only and second including 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 GWAS PRS was not significantly associated with NPSLE (OR=1.04, [95%CI 0.87,1.26];P=0.62), nor with NPSLE subtypes: psychosis (OR=0.97, [95%CI 0.73,1.29];P=0.84) and other non-psychosis NPSLE (OR=1.08, [95%CI 0.88,1.34];v=0.44) 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.

scholarly journals Comparison of Sensitivities of American College of Rheumatology and Systemic Lupus International Collaborating Clinics Classification Criteria in Childhood-onset Systemic Lupus Erythematosus

2019 ◽  
Vol 46 (7) ◽  
pp. 731-738 ◽  
Author(s):  
Jessie J. Tao ◽  
Linda T. Hiraki ◽  
Deborah M. Levy ◽  
Earl D. Silverman
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Classification Criteria ◽  
Childhood Onset ◽  
Systemic Lupus ◽  
Specific Criterion ◽  
Primary Sjögren Syndrome ◽  
American College Of Rheumatology ◽  
Acr Criteria ◽  
Sick Children

Objective.Currently there are 2 different classification criteria for systemic lupus erythematosus (SLE): American College of Rheumatology (ACR) and Systemic Lupus International Collaborating Clinics (SLICC). The aim of this study was to compare the sensitivities of ACR and SLICC criteria in childhood-onset SLE (cSLE) using a large, multiethnic cohort.Methods.We conducted a retrospective study of 722 patients diagnosed with cSLE at The Hospital for Sick Children (SickKids). Prospectively collected data from SickKids’ Lupus Database were reviewed/validated against medical records prior to ACR and SLICC scoring based on cumulative symptoms up to the last visit. Sensitivities were compared using McNemar’s test. Descriptive statistics were used to identify SLE features unique to each set of criteria and autoantibodies not included in either.Results.ACR and SLICC sensitivities were as follows: 92.4% and 96.3% overall (p = 0.001); 82.5% and 91.3% (p = 0.01) in those scored ≤ 1 year from diagnosis; 92.7% and 97.9% (p = 0.02) in those scored 2–3 years from diagnosis. Forty-eight of 55 (87.3%) patients who did not meet ACR criteria met SLICC criteria through SLICC-specific criterion or renal biopsy. Twenty of 27 (74.1%) patients who did not meet SLICC criteria met ACR criteria as a result of photosensitivity (73.9%) and ACR lymphopenia criteria (26.1%). Six of 7 patients (85.7%) who were clinically diagnosed with cSLE but did not meet either SLICC or ACR criteria had anti-Ro antibodies.Conclusion.SLICC criteria were significantly more sensitive than ACR criteria in cSLE classification, especially early in the disease course. Because of the extreme rarity of primary Sjögren syndrome in children, one may consider adding anti-Ro antibodies to the classification criteria for cSLE because they are present in ∼40% of patents with cSLE.

scholarly journals Identification of 38 novel loci for systemic lupus erythematosus and genetic heterogeneity between ancestral groups

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yong-Fei Wang ◽  
Yan Zhang ◽  
Zhiming Lin ◽  
Huoru Zhang ◽  
Ting-You Wang ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Genome Wide Association Study ◽  
Age Of Onset ◽  
Treatment Options ◽  
Human Leukocyte ◽  
Risk Scores ◽  
Systemic Lupus ◽  
Disease Manifestation ◽  
A Genome

AbstractSystemic lupus erythematosus (SLE), a worldwide autoimmune disease with high heritability, shows differences in prevalence, severity and age of onset among different ancestral groups. Previous genetic studies have focused more on European populations, which appear to be the least affected. Consequently, the genetic variations that underlie the commonalities, differences and treatment options in SLE among ancestral groups have not been well elucidated. To address this, we undertake a genome-wide association study, increasing the sample size of Chinese populations to the level of existing European studies. Thirty-eight novel SLE-associated loci and incomplete sharing of genetic architecture are identified. In addition to the human leukocyte antigen (HLA) region, nine disease loci show clear ancestral differences and implicate antibody production as a potential mechanism for differences in disease manifestation. Polygenic risk scores perform significantly better when trained on ancestry-matched data sets. These analyses help to reveal the genetic basis for disparities in SLE among ancestral groups.

scholarly journals Disease activity index is associated with subclinical atherosclerosis in childhood-onset systemic lupus erythematosus

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Priscila B. S. Medeiros ◽  
Roberta G. Salomão ◽  
Sara R. Teixeira ◽  
Diane M. Rassi ◽  
Luciana Rodrigues ◽  
...  
Keyword(s):  
Risk Factors ◽  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Activity Index ◽  
Subclinical Atherosclerosis ◽  
Disease Activity Index ◽  
Uncontrolled Hypertension ◽  
Childhood Onset ◽  
Systemic Lupus

Abstract Background Systemic lupus erythematosus (SLE) is an independent risk factor for cardiovascular events. The present study determined the prevalence of subclinical atherosclerosis in childhood-onset SLE using the carotid intima-media thickness (CIMT) measurement and investigated associations between traditional and nontraditional risk factors for atherosclerosis, such as medications, SLE Disease Activity Index - SLEDAI-2 K and SLICC-ACR damage index and CIMT. Methods Cross-sectional prospective study between 2017 and 2018. CIMT was assessed by ultrasonography. Data were collected by chart review, nutritional evaluation and laboratory tests and analyzed by Fisher, Wilcoxon-Mann-Whitney tests, multiple linear and log binomial regression. Results Twenty-eight patients (mean age 13.9 years, SD 3) were enrolled. The prevalence of subclinical atherosclerosis was 32% (95% CI 14.8, 49.4). The mean CIMT was 0.43 ± 0.035 mm. The most common traditional risk factors observed were dyslipidemia (82.1%), uncontrolled hypertension (14.2%), obesity (14.3%), and poor diet (78.6%). Uncontrolled hypertension (p = 0.04), proteinuria (p = 0.02), estimated glomerular filtration rate < 75 ml /min/1.73 m2 (p = 0.02) and SLEDAI-2 K > 5 (P = 0.04) were associated with subclinical atherosclerosis. SLEDAI-2 K > 5 maintained association with CIMT after adjusting for control variables. Conclusion Subclinical atherosclerosis is frequently observed in cSLE, mainly in patients with moderate to severe disease activity.

scholarly journals Arg206Cys substitution in DNASE1L3 causes a defect in DNASE1L3 protein secretion that confers risk of systemic lupus erythematosus

2021 ◽  
pp. annrheumdis-2020-218810
Author(s):  
Latanya N Coke ◽  
Hongxiu Wen ◽  
Mary Comeau ◽  
Mustafa H Ghanem ◽  
Andrew Shih ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Protein Secretion ◽  
Lupus Erythematosus ◽  
Conditional Analysis ◽  
Hek293 Cells ◽  
Enzyme Function ◽  
European Ancestry ◽  
Risk Haplotype ◽  
Systemic Lupus ◽  
Risk Association

ObjectivesTo determine if the polymorphism encoding the Arg206Cys substitution in DNASE1L3 explains the association of the DNASE1L3/PXK gene locus with systemic lupus erythematosus (SLE) and to examine the effect of the Arg206Cys sequence change on DNASE1L3 protein function.MethodsConditional analysis for rs35677470 was performed on cases and controls with European ancestry from the SLE Immunochip study, and genotype and haplotype frequencies were compared. DNASE1L3 protein levels were measured in cells and supernatants of HEK293 cells and monocyte-derived dendritic cells expressing recombinant and endogenous 206Arg and 206Cys protein variants.ResultsConditional analysis on rs35677470 eliminated the SLE risk association signal for lead single-nucleotide polymorphisms (SNPs) rs180977001 and rs73081554, which are found to tag the same risk haplotype as rs35677470. The modest effect sizes of the SLE risk genotypes (heterozygous risk OR=1.14 and homozygous risk allele OR=1.68) suggest some DNASE1L3 endonuclease enzyme function is retained. An SLE protective signal in PXK (lead SNP rs11130643) remained following conditioning on rs35677470. The DNASE1L3 206Cys risk variant maintained enzymatic activity, but secretion of the artificial and endogenous DNASE1L3 206Cys protein was substantially reduced.ConclusionsSLE risk association in the DNASE1L3 locus is dependent on the missense SNP rs35677470, which confers a reduction in DNASE1L3 protein secretion but does not eliminate its DNase enzyme function.

scholarly journals An Update on the Management of Childhood-Onset Systemic Lupus Erythematosus

2021 ◽  
Author(s):  
Vitor Cavalcanti Trindade ◽  
Magda Carneiro-Sampaio ◽  
Eloisa Bonfa ◽  
Clovis Artur Silva
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Childhood Onset ◽  
Systemic Lupus ◽  
Onset Systemic Lupus Erythematosus
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