Enrichment of Rare Variants of Hemophagocytic Lymphohistiocytosis Genes in Systemic Juvenile Idiopathic Arthritis
Authors' conclusion
We 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.
Study context
- Population
- Patients with systemic juvenile idiopathic arthritis (sJIA) with or without macrophage activation syndrome (MAS) from an established cohort, and in silico controls524 cases sequenced
- Participants
- 480 / 2,924 / 32 / 90
- Comparison
- sJIA cases vs ancestrally matched controls
- sJIAn = 480
- Controlsn = 2,924reference
- MASn = 32
- Without MASn = 90
- Outcome
- Enrichment of rare variants in familial HLH-associated genes (LYST, PRF1, RAB27A, STX11, STXBP2, UNC13D)
Methodological detailstargeted sequencing, in silico controls (dbGaP), ancestrally matched controls, rare variant association testing (SKAT), 100,000 permutations
- Targeted sequencing
- In silico controls (dbGaP)
- Ancestrally matched controls
- Rare variant association testing (SKAT)
- 100,000 permutations
Main finding
As reported in the abstract
Rare variant association, cases vs controls
- sJIA vs Controls: P = 0.020
- sJIA vs Controls: P = 0.006
- sJIA vs Controls: P = 0.046
Observational data: associations, not effects.
Further findings
| Outcome | P value |
|---|---|
| Distribution of rare UNC13D variants, sJIA with vs without MAS (subanalysis)32 cases with known MAS and 90 without | P = 0.0047 |
| Carriage of two or more HLH variantssJIA vs Controls | P = 0.007 |
- Carriage of two or more hemophagocytic lymphohistiocytosis (HLH) variants: more often in sJIA; driven largely by digenic combinations involving LYST
Original publication
Enrichment of Rare Variants of Hemophagocytic Lymphohistiocytosis Genes in Systemic Juvenile Idiopathic Arthritis. Arthritis Rheumatol. Published 9 August 2024. doi:10.
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