ArticleArthritis & rheumatology (Hoboken, N.J.)2024
Enrichment of Rare Variants of Hemophagocytic Lymphohistiocytosis Genes in Systemic Juvenile Idiopathic Arthritis.
Article in Arthritis & rheumatology (Hoboken, N.J.), 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- Genetic determinants of childhood onset systemic lupus erythematosus.Lupus science & medicine · 2026Article
- Pathogenic and genetic landscape of Still's disease across ages, with new insights into age-related IL-18 patterns.Arthritis research & therapy · 2026Review
- Still's Disease and Autoinflammation: Positioning an Inflammatory Syndrome on the Autoinflammation-Autoimmunity Spectrum.Current rheumatology reports · 2026Review
- Case Report: Munc13-4 deficiency presenting with autoimmune neuropathy years before FLH: implications for early genetic screening and HSCT timing.Frontiers in immunology · 2026Article
- Genetic and molecular approaches for patients with familial hemophagocytic lymphohistiocytosis: a multi-center experience from Mexico.Frontiers in immunology · 2026Article
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- Beyond genotype: challenges in predicting disease risk for carriers of biallelic perforin variants.Blood · 2025Article
- T-ing up the storm: pathogenic cycling lymphocytes in the biology of macrophage activation syndrome.Pediatric rheumatology online journal · 2025Review
- Treating and triggering hyperinflammation: tackling hemophagocytic lymphohistiocytosis and HLH-like syndromes in the pediatric cell therapy and critical care setting.Frontiers in oncology · 2025Review
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23 authors.
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Abstract
objectiveOur objective was to evaluate whether there is an enrichment of rare variants in familial hemophagocytic lymphohistiocytosis (HLH)-associated genes among patients with systemic juvenile idiopathic arthritis (sJIA) with or without macrophage activation syndrome (MAS).
methodsTargeted sequencing of HLH genes (LYST, PRF1, RAB27A, STX11, STXBP2, UNC13D) was performed in patients with sJIA from an established cohort. Sequence data from control participants were obtained in silico (database of Genotypes and Phenotypes: phs000280.v8.p2). Rare variant association testing (RVT) was performed with sequence kernel association test package. Significance was defined as P < 0.05 after 100,000 permutations.
resultsSequencing data from 524 sJIA cases were jointly called and harmonized with exome-derived target data from 3,000 controls. Quality control operations produced a set of 480 cases and 2,924 ancestrally matched control participants. RVT of cases and controls revealed a significant association with rare protein-altering variants (minor allele frequency [MAF] < 0.01) of STXBP2 (P = 0.020) and ultrarare variants (MAF < 0.001) of STXBP2 (P = 0.006) and UNC13D (P = 0.046). A subanalysis of 32 cases with known MAS and 90 without revealed a significant difference in the distribution of rare UNC13D variants (P = 0.0047) between the groups. Additionally, patients with sJIA more often carried two or more HLH variants than did controls (P = 0.007), driven largely by digenic combinations involving LYST.
conclusionWe identified an enrichment of rare HLH variants in patients with sJIA compared with controls, driven by STXBP2 and UNC13D. Biallelic variation in HLH genes was associated with sJIA, driven by LYST. Only UNC13D displayed enrichment in patients with MAS. This suggests that HLH variants may contribute to the pathophysiology of sJIA, even without MAS.
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