Meghan Nelson, Shanta Murthy, Sushma Maddipatla, Sreekala Shenoy, Lori Ponder, Shanmuganathan Chandrakasan, Subra Kugathasan, Dave Cutler, Sampath Prahalad
{"title":"Genetic determinants of childhood onset systemic lupus erythematosus.","authors":"Meghan Nelson, Shanta Murthy, Sushma Maddipatla, Sreekala Shenoy, Lori Ponder, Shanmuganathan Chandrakasan, Subra Kugathasan, Dave Cutler, Sampath Prahalad","doi":"10.1136/lupus-2025-001874","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>Childhood-onset systemic lupus erythematosus (cSLE) is associated with significant morbidity and mortality. While numerous variants have been associated with adult-onset SLE, limited data exist on genetic variation within cSLE. We aimed to investigate genetic factors of early-onset cSLE, defined as onset of cSLE prior to age 10.</p><p><strong>Methods: </strong>Employing a case-only design, we performed whole genome sequencing analysis on 37 subjects with early onset cSLE. We hypothesised that rare, functional variants with large effects in genes associated with SLE contribute to the risk of early-onset cSLE and that the polygenic risk score (PRS) would be inversely associated with age of onset and presence of nephritis. A total of 153 linkage disequilibrium-independent variants were analysed and compared with previously reported SLE single-nucleotide polymorphisms. Rare (minor allele frequency (MAF) ≤1%), damaging protein-altering (Combined Annotation Dependent Depletion; CADD≥20) variants, including variants isolated to previously reported monogenic SLE genes (n=49), were prioritised for secondary analysis.</p><p><strong>Results: </strong>37.8% of our cSLE cohort carried at least one rare, pathogenic variant in monogenic SLE genes. We identified 31, 012 rare, damaging, pathogenic variants in our cSLE cohort, including two genes implicated in mitochondrial protein degradation (<i>AFG3L2, SPG7</i>) and several genes in the interferon pathway (<i>IFIH1, IFNGR1</i>). We found that higher PRS scores were associated with increased nephritis odds (p=0.0092) but not age of onset (p>0.05). Burden testing using the optimal sequence kernel association test (SKAT-O) revealed nominal enrichment of rare variants (MAF≤ 5%) in immune-related genes, including <i>ISG15, PSMB9</i> and <i>RNASEH2A</i>, several of which are involved in type I interferon and antigen presentation pathways.</p><p><strong>Conclusion: </strong>These results have the potential to enhance our understanding of cSLE. Further studies must be conducted to expand our findings.</p>","PeriodicalId":18126,"journal":{"name":"Lupus Science & Medicine","volume":"13 1","pages":""},"PeriodicalIF":4.2000,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13295832/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Lupus Science & Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1136/lupus-2025-001874","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"RHEUMATOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Introduction: Childhood-onset systemic lupus erythematosus (cSLE) is associated with significant morbidity and mortality. While numerous variants have been associated with adult-onset SLE, limited data exist on genetic variation within cSLE. We aimed to investigate genetic factors of early-onset cSLE, defined as onset of cSLE prior to age 10.
Methods: Employing a case-only design, we performed whole genome sequencing analysis on 37 subjects with early onset cSLE. We hypothesised that rare, functional variants with large effects in genes associated with SLE contribute to the risk of early-onset cSLE and that the polygenic risk score (PRS) would be inversely associated with age of onset and presence of nephritis. A total of 153 linkage disequilibrium-independent variants were analysed and compared with previously reported SLE single-nucleotide polymorphisms. Rare (minor allele frequency (MAF) ≤1%), damaging protein-altering (Combined Annotation Dependent Depletion; CADD≥20) variants, including variants isolated to previously reported monogenic SLE genes (n=49), were prioritised for secondary analysis.
Results: 37.8% of our cSLE cohort carried at least one rare, pathogenic variant in monogenic SLE genes. We identified 31, 012 rare, damaging, pathogenic variants in our cSLE cohort, including two genes implicated in mitochondrial protein degradation (AFG3L2, SPG7) and several genes in the interferon pathway (IFIH1, IFNGR1). We found that higher PRS scores were associated with increased nephritis odds (p=0.0092) but not age of onset (p>0.05). Burden testing using the optimal sequence kernel association test (SKAT-O) revealed nominal enrichment of rare variants (MAF≤ 5%) in immune-related genes, including ISG15, PSMB9 and RNASEH2A, several of which are involved in type I interferon and antigen presentation pathways.
Conclusion: These results have the potential to enhance our understanding of cSLE. Further studies must be conducted to expand our findings.
期刊介绍：
Lupus Science & Medicine is a global, peer reviewed, open access online journal that provides a central point for publication of basic, clinical, translational, and epidemiological studies of all aspects of lupus and related diseases. It is the first lupus-specific open access journal in the world and was developed in response to the need for a barrier-free forum for publication of groundbreaking studies in lupus. The journal publishes research on lupus from fields including, but not limited to: rheumatology, dermatology, nephrology, immunology, pediatrics, cardiology, hepatology, pulmonology, obstetrics and gynecology, and psychiatry.
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