Journal Article

Next generation sequencing analysis reveals complex genetic architecture of childhood-onset systemic lupus erythematosus

Aksentijevich, Ivona, Barrera-Vargas, Ana, Dalgard, Clifton L, Hiraki, Linda, Hasni, Sarfaraz, Lu, Shajia, Hupalo, Daniel, Musolf, Anthony M, Gadina, Massimo, Scott, Christiaan, Paul, Subrata, Romo Tena, Jorge, Ombrello, Michael J, Gómez-Martín, Diana, Kaplan, Mariana J, Lewandowski, Laura, Silverman, Earl D, Deng, Zuoming

2025

Overview

ObjectivesOur current understanding of the genetic architecture of childhood-onset SLE (cSLE) is limited by a dearth of comprehensive genomic studies in cSLE. We have quantified the number of known rare and common SLE risk variants in a diverse cSLE cohort. We characterised type I interferon (IFN) gene expression scores along with genomic data.MethodsWe performed whole genome sequencing on 83 patients with cSLE and 109 unaffected parents and analysed sequences for known common and rare SLE-associated risk variants. Type I IFN gene expression was quantified on a subset of patients. We investigated the relationship between clinical phenotype, genomic profile and type I IFN signatures in this cohort.ResultsPatients with cSLE were enriched for common SLE risk variants compared with unaffected parents and controls. We identified rare SLE risk variants in 11% of individuals with cSLE; those with rare variants had earlier disease onset (<12 years) than those without variants. Patients with cSLE had elevated type I IFN gene expression compared with unaffected parents and controls, even though most patients were treated with immunosuppressive therapy.ConclusionsPatients with cSLE from this ancestrally and geographically diverse cohort are enriched for common cSLE risk variants compared with controls, and 11% carry a rare variant in known monogenic SLE risk genes. The relationship between rare and common risk variant burden is more complex than previously hypothesised. Our findings indicate that studying patients with cSLE is important for understanding genetic contributions to SLE pathogenesis.

• Publisher: Lupus Foundation of America,BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Adolescent / Age of Onset / Case-Control Studies / Child / Child, Preschool / Childhood / Cohort Studies / Disease / Female / Genetic Predisposition to Disease / Genetics / Genomes / Health risk assessment / High-Throughput Nucleotide Sequencing / Humans / Interferon Type I / Interferon Type I - genetics / Lupus / Lupus Erythematosus, Systemic / Lupus Erythematosus, Systemic - drug therapy / Lupus Erythematosus, Systemic - genetics / Male / Original Research / Pathogenesis / Patients / Phenotype / Polymorphism, Genetic / Software / Whole Genome Sequencing