系统性幼年特发性关节炎中嗜血细胞淋巴组织细胞增多症基因罕见变异的富集

Mariana Correia Marques, Danielle Rubin, Emily Shuldiner, Mallika Datta, Elizabeth Schmitz, Gustavo Gutierrez Cruz, Andrew Patt, Elizabeth Bennett, Alexei Grom, Dirk Foell, Marco Gattorno, John Bohnsack, Rae S. M. Yeung, Sampath Prahalad, Elizabeth Mellins, Jordi Anton, Claudio Arnaldo Len, Sheila Oliveira, Patricia Woo, Seza Ozen, INCHARGE Consortium, Zuoming Deng, Michael J. Ombrello
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引用次数: 0

摘要

目的评估家族性嗜血细胞淋巴组织细胞增多症(HLH)基因的罕见变异与伴有或不伴有巨噬细胞活化综合征(MAS)的全身性幼年特发性关节炎(sJIA)是否存在富集:方法:在已建立队列的sJIA受试者中对HLH基因(LYST、PRF1、RAB27A、STX11、STXBP2、UNC13D)进行了靶向测序。对照受试者的序列数据是通过硅学方法获得的(dbGaP:phs000280.v8.p2)。罕见变异关联测试(RVT)使用序列核关联测试(SKAT)软件包进行。100,000次排列后,显著性定义为p<0.05:来自 524 个 sJIA 病例的测序数据与来自 3000 个对照组的外显子衍生目标数据进行了联合调用和统一。质量控制操作产生了一组 481 个病例和 2924 个祖先匹配的对照受试者。对 sJIA 病例和对照组的 RVT 分析显示,STXBP2(p=0.020)的罕见蛋白质改变变异(小等位基因频率 [MAF]<0.01 )与 STXBP2(p=0.007)和 UNC13D(p=0.045)的超罕见变异(MAF<0.001)有显著关联。对 32 例已知有 MAS 的病例和 90 例没有 MAS 的病例进行的子分析表明,罕见的 UNC13D 变异与此有显著关联(p=0.0047)。此外,与对照组相比,sJIA 患者更常携带≥2 个 HLH 变异(p=0.007),这主要是由涉及 LYST 的二基因组合引起的。结论在 STXBP2 和 UNC13D 的驱动下,我们发现与健康对照组相比,sJIA 患者中罕见的 HLH 变异更为丰富。在 LYST 的驱动下,HLH 基因的双唇变异与 sJIA 相关。只有 UNC13D 在 MAS 患者中显示出富集。这表明,即使没有 MAS,HLH 变异也可能对 sJIA 的病理生理学起作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Enrichment of Rare Variants of Hemophagocytic Lymphohistiocytosis Genes in Systemic Juvenile Idiopathic Arthritis
Objective: To 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). Methods: Targeted 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 obtained in 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. Results: Sequencing 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) of STXBP2 (p=0.020), and ultra-rare variants (MAF<0.001) of STXBP2 (p=0.007) and UNC13D (p=0.045). A subanalysis of 32 cases with known MAS and 90 without revealed significant association of rare UNC13D variants (p=0.0047). Additionally, sJIA patients more often carried ≥2 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 sJIA patients compared with healthy 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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