[en] [en] OBJECTIVE: Our 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).
METHODS: Targeted 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.
RESULTS: Sequencing 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.
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. This suggests that HLH variants may contribute to the pathophysiology of sJIA, even without MAS.
Disciplines :
Rheumatology
Author, co-author :
Correia Marques, Mariana ; National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland
Rubin, Danielle; National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland
Shuldiner, Emily G; National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland
Datta, Mallika; National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland
Schmitz, Elizabeth; National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland
Gutierrez Cruz, Gustavo; National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland
Patt, Andrew; National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland
Bennett, Elizabeth; National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland
Grom, Alexei; Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Foell, Dirk ; University Hospital Muenster, Muenster, Germany
Gattorno, Marco ; IRCCS Istituto G. Gaslini, Genoa, Italy
Bohnsack, John; University of Utah Eccles School of Medicine, Salt Lake City
Yeung, Rae S M; University of Toronto, Toronto, Ontario, Canada
Prahalad, Sampath ; Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia
Mellins, Elizabeth; Stanford University, Stanford, California
Anton, Jordi; Hospital Sant Joan de Déu, Universitat de Barcelona, Barcelona, Spain
Len, Claudio A; São Paulo Federal University, São Paulo, Brazil
Oliveira, Sheila; Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
Woo, Patricia; University College London, London, United Kingdom
Ozen, Seza ; Hacettepe University, Ankara, Turkey
Deng, Zuoming; National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland
Ombrello, Michael J ; National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland
INCHARGE Consortium
Docampo Martínez, Elisa ; Université de Liège - ULiège > Département des sciences cliniques ; Centre Hospitalier Universitaire de Liège - CHU > > Service de génétique ; Centre Hospitalier Universitaire de Liège - CHU > > Service de rhumatologie
NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases NIH - National Institutes of Health
Funding text :
Supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Disease, NIH (grant Z01\u2010AR\u2010041198). The work used the computational resources of the NIH high\u2010performance computing cluster Biowulf ( http://hpc.nih.gov ). The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, NIH, Department of Health and Human Services (under contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, and HHSN268201700005I). Ms Shuldiner's work was supported by the Tobacco\u2010Related Disease Research Program predoctoral fellowship (grant T33DT6556). Dr Prahalad's work was supported in part by The Marcus Foundation Inc.
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