严重成人噬血细胞性淋巴组织细胞增生症 (HLHa) 与 HLH 相关基因突变相关。
Severe adult hemophagocytic lymphohistiocytosis (HLHa) correlates with HLH-related gene variants.
机构信息
Clinical Research Unit, Avicenne University Hospital, AP-HP, Bobigny, France; Paris 13 University, Sorbonne Paris Cité, Paris, France; Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, INSERM UMR1163/CNRS URL 8254, Paris, France; French National Center for Primary Immunodeficiencies, Necker University Hospital, AP-HP, Paris, France; Imagine Institute, Université Paris Cité, Paris, France.
Imagine Institute, Université Paris Cité, Paris, France; Biostatistic Unit, Necker University Hospital, AP-HP, Paris, France; Human Genetics of Infectious Diseases: Complex Predisposition, INSERM UMR1163, Paris, France.
出版信息
J Allergy Clin Immunol. 2024 Jan;153(1):256-264. doi: 10.1016/j.jaci.2023.07.023. Epub 2023 Sep 9.
BACKGROUND
The contribution of genetic factors to the severity of adult hemophagocytic lymphohistiocytosis (HLHa) remains unclear.
OBJECTIVE
We sought to assess a potential link between HLHa outcomes and HLH-related gene variants.
METHODS
Clinical characteristics of 130 HLHa patients (age ≥ 18 years and HScore ≥ 169) and genotype of 8 HLH-related genes (LYST, PRF1, UNC13-D, STX11, STXBP2, RAB27A, XIAP, and SAP) were collected. A total of 34 variants found in only 6 genes were selected on the basis of their frequency and criteria predicted to impair protein function. Severity was defined by refractory disease to HLH treatment, death, or transfer to an intensive care unit.
RESULTS
HLHa-associated diseases (ADs) were neoplasia (n = 49 [37.7%]), autoimmune/inflammatory disease (n = 33 [25.4%]), or idiopathic when no AD was identified (n = 48 [36.9%]). Infectious events occurred in 76 (58.5%) patients and were equally distributed in all ADs. Severe and refractory HLHa were observed in 80 (61.5%) and 64 (49.2%) patients, respectively. HScore, age, sex ratio, AD, and infectious events showed no significant association with HLHa severity. Variants were identified in 71 alleles and were present in 56 (43.1%) patients. They were distributed as follows: 44 (34.4%), 9 (6.9%), and 3 (2.3%) patients carrying 1, 2, and 3 variant alleles, respectively. In a logistic regression model, only the number of variants was significantly associated with HLHa severity (1 vs 0: 3.86 [1.73-9.14], P = .0008; 2-3 vs 0: 29.4 [3.62-3810], P = .0002) and refractoriness (1 vs 0: 2.47 [1.17-5.34], P = .018; 2-3 vs 0: 13.2 [2.91-126.8], P = .0003).
CONCLUSIONS
HLH-related gene variants may be key components to the severity and refractoriness of HLHa.
背景
遗传因素对成人噬血细胞性淋巴组织细胞增生症（HLHa）严重程度的影响仍不清楚。
目的
我们旨在评估 HLHa 结局与 HLH 相关基因变异之间的潜在联系。
方法
收集了 130 例 HLHa 患者（年龄≥18 岁且 HScore≥169）的临床特征和 8 个 HLH 相关基因（LYST、PRF1、UNC13-D、STX11、STXBP2、RAB27A、XIAP 和 SAP）的基因型。基于其频率和预测蛋白功能受损的标准，选择仅在 6 个基因中发现的 34 个变异体。严重程度定义为 HLH 治疗难治、死亡或转入重症监护病房。
结果
HLHa 相关疾病（ADs）为肿瘤（n=49 [37.7%]）、自身免疫/炎症性疾病（n=33 [25.4%]）或无 AD 时为特发性疾病（n=48 [36.9%]）。76 例（58.5%）患者发生感染事件，且在所有 AD 中分布均匀。80 例（61.5%）和 64 例（49.2%）患者分别出现严重和难治性 HLHa。HScore、年龄、性别比、AD 和感染事件与 HLHa 严重程度无显著相关性。在 71 个等位基因中发现了变异体，存在于 56 例（43.1%）患者中。它们的分布如下：1、2 和 3 变异等位基因患者分别为 44（34.4%）、9（6.9%）和 3（2.3%）例。在逻辑回归模型中，只有变异体数量与 HLHa 严重程度显著相关（1 与 0：3.86 [1.73-9.14]，P=0.0008；2-3 与 0：29.4 [3.62-3810]，P=0.0002）和难治性（1 与 0：2.47 [1.17-5.34]，P=0.018；2-3 与 0：13.2 [2.91-126.8]，P=0.0003）。
结论
HLH 相关基因变异可能是 HLHa 严重程度和难治性的关键因素。
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