P. Lahiry, MD, PhD, FRCPC, D. Dominguez, MD, MSc, D.M. Levy, MD, MSc, FRCPC, L.W.K. Ng, BSc, Division of Rheumatology, SickKids.
S. Naumenko, PhD, The Centre for Computational Medicine, Research Institute, SickKids.
J Rheumatol. 2022 Oct;49(10):1146-1151. doi: 10.3899/jrheum.211200. Epub 2022 Jun 1.
Macrophage activation syndrome (MAS), a life-threatening complication of systemic lupus erythematosus (SLE), resembles familial hemophagocytic lymphohistiocytosis (HLH), an inherited disorder of hyperinflammation. We compared the proportion of patients with childhood-onset SLE (cSLE) with and without MAS who carried low-frequency HLH nonsynonymous variants.
We enrolled patients from the Lupus Clinic at SickKids, Toronto. Demographic and clinical features were extracted from the SLE database and ancestry was genetically inferred using multiethnic genotyping array data. Patients with MAS (based on expert diagnosis) underwent either paired-end whole-exome sequencing (WES; read depth: 70-118X) or whole-genome sequencing (WGS). Patients without MAS had WGS (read depth: 37-40X). In 16 HLH genes, we prioritized low-frequency (minor allele frequency [MAF] < 0.05) exonic nonsynonymous variants. We compared the proportion of patients with and without MAS carrying HLH variants (Fisher exact test, < 0.05). MAFs were compared to an ancestrally matched general population (Trans-Omics for Precision Medicine [TOPMed] and Genome Aggregation Database [gnomAD]).
The study included 81 patients with cSLE, 19 of whom had MAS. We identified 47 unique low-frequency nonsynonymous HLH variants. There was no difference in the proportion of patients with and without MAS carrying ≥ 1 HLH variants (37% vs 47%, = 0.44). The MAS cohort did not carry more HLH variants when compared to an ancestrally matched general population.
In a single-center multiethnic cSLE cohort, we found no difference in the proportion of patients with MAS carrying nonsynonymous HLH genetic variants compared to patients without MAS. To our knowledge, this is the first study to examine the frequency of HLH genetic variants in relation to MAS among patients with cSLE. Future studies are required to validate our findings.
巨噬细胞活化综合征（MAS）是系统性红斑狼疮（SLE）的一种危及生命的并发症，类似于家族性噬血细胞性淋巴组织细胞增生症（HLH），这是一种遗传性过度炎症疾病。我们比较了幼年起病的系统性红斑狼疮（cSLE）患者中伴有和不伴有 MAS 的患者携带低频 HLH 非同义变异体的比例。
我们从多伦多 SickKids 狼疮诊所招募了患者。从 SLE 数据库中提取人口统计学和临床特征，并使用多民族基因分型阵列数据推断遗传背景。有 MAS（基于专家诊断）的患者接受了靶向全外显子组测序（WES；测序深度：70-118X）或全基因组测序（WGS）。没有 MAS 的患者进行了 WGS（测序深度：37-40X）。在 16 个 HLH 基因中，我们优先考虑低频（次要等位基因频率 [MAF] < 0.05）外显子非同义突变。我们比较了有和没有 MAS 的患者携带 HLH 变异体的比例（Fisher 精确检验， < 0.05）。MAF 与一个遗传匹配的一般人群（精准医学的跨组学研究 [TOPMed]和基因组聚集数据库 [gnomAD]）进行了比较。
该研究纳入了 81 例 cSLE 患者，其中 19 例有 MAS。我们鉴定了 47 个独特的低频非同义 HLH 变异体。有 MAS 和没有 MAS 的患者携带≥1 个 HLH 变异体的比例没有差异（37% vs 47%， = 0.44）。与遗传匹配的一般人群相比，MAS 队列携带的 HLH 变异体并不多。
在一个单中心的多民族 cSLE 队列中，我们发现伴有 MAS 的患者携带非同义 HLH 遗传变异体的比例与不伴有 MAS 的患者没有差异。据我们所知，这是第一项研究 cSLE 患者 MAS 与 HLH 遗传变异体频率之间关系的研究。需要进一步的研究来验证我们的发现。
