Enrichment of Rare Variants of Hemophagocytic Lymphohistiocytosis Genes in Systemic Juvenile Idiopathic Arthritis

Abstract

AbstractObjectiveTo evaluate whether there is an enrichment of rare variants in familial hemophagocytic lymphohistiocytosis (HLH) genes and 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 sJIA subjects from an established cohort. Sequence data from control subjects were obtainedin silico(dbGaP:phs000280.v8.p2). Rare variant association testing (RVT) was performed with sequence kernel association test (SKAT) 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 3000 controls. Quality control operations produced a set of 481 cases and 2924 ancestrally-matched control subjects. RVT of sJIA cases and controls revealed a significant association with rare protein-altering variants (minor allele frequency [MAF]<0.01) ofSTXBP2(p=0.020), and ultra-rare variants (MAF<0.001) ofSTXBP2(p=0.007) andUNC13D(p=0.045). A subanalysis of 32 cases with known MAS and 90 without revealed significant association of rareUNC13Dvariants (p=0.0047). Additionally, sJIA patients more often carried ≥2 HLH variants than did controls (p=0.007), driven largely by digenic combinations involvingLYST.ConclusionWe identified an enrichment of rare HLH variants in sJIA patients compared with healthy controls, driven bySTXBP2andUNC13D. Biallelic variation in HLH genes was associated with sJIA, driven byLYST. OnlyUNC13Ddisplayed enrichment in patients with MAS. This suggests that HLH variants may contribute to the pathophysiology of sJIA, even without MAS.