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Hereditary α tryptasemia is a valid genetic biomarker for severe mediator-related symptoms in mastocytosis.

遗传性 α 胰蛋白酶血症是肥大细胞增多症中严重介质相关症状的有效遗传生物标志物。

  • 影响因子:7.27
  • DOI:10.1182/blood.2020006157
  • 作者列表:"Greiner G","Sprinzl B","Górska A","Ratzinger F","Gurbisz M","Witzeneder N","Schmetterer KG","Gisslinger B","Uyanik G","Hadzijusufovic E","Esterbauer H","Gleixner KV","Krauth MT","Pfeilstöcker M","Keil F","Gisslinger H","Nedoszytko B","Niedoszytko M","Sperr WR","Valent P","Hoermann G
  • 发表时间:2021-01-14
Abstract

:Mastocytosis is a hematopoietic neoplasm characterized by expansion of KIT D816V-mutated clonal mast cells in various organs and severe or even life-threatening anaphylactic reactions. Recently, hereditary α-tryptasemia (HαT) has been described as a common genetic trait with increased copy numbers of the α-tryptase encoding gene, TPSAB1, and associated with an increased basal serum tryptase level and a risk of mast cell activation. The purpose of our study was to elucidate the clinical relevance of HαT in patients with mastocytosis. TPSAB1 germline copy number variants were assessed by digital polymerase chain reaction in 180 mastocytosis patients, 180 sex-matched control subjects, 720 patients with other myeloid neoplasms, and 61 additional mastocytosis patients of an independent validation cohort. α-Tryptase encoding TPSAB1 copy number gains, compatible with HαT, were identified in 17.2% of mastocytosis patients and 4.4% of the control population (P < .001). Patients with HαT exhibited higher tryptase levels than patients without HαT (median tryptase in HαT+ cases: 49.6 ng/mL vs HαT- cases: 34.5 ng/mL, P = .004) independent of the mast cell burden. Hymenoptera venom hypersensitivity reactions and severe cardiovascular mediator-related symptoms/anaphylaxis were by far more frequently observed in mastocytosis patients with HαT than in those without HαT. Results were confirmed in an independent validation cohort. The high prevalence of HαT in mastocytosis hints at a potential pathogenic role of germline α-tryptase encoding TPSAB1 copy number gains in disease evolution. Together, our data suggest that HαT is a novel emerging robust biomarker in mastocytosis that is useful for determining the individual patient´s risk of developing severe anaphylaxis.

摘要

: 肥大细胞增多症是一种造血肿瘤,其特征是KIT D816V-mutated克隆性肥大细胞在各种器官中扩增,出现严重甚至危及生命的过敏反应。最近,遗传性 α-胰蛋白酶血症 (h α t) 被描述为 α-类胰蛋白酶编码基因TPSAB1拷贝数增加的常见遗传性状,并与基础血清类胰蛋白酶水平升高和肥大细胞活化风险相关。我们研究的目的是阐明肥大细胞增生症患者中h α t的临床相关性。在独立验证队列的180例肥大细胞增生症患者、180例性别匹配的对照受试者、720例其他髓系肿瘤患者和61例其他肥大细胞增生症患者中,通过数字聚合酶链反应评估了TPSAB1种系拷贝数变异。在17.2% 的肥大细胞增多症患者和4.4% 的对照人群中鉴定出编码TPSAB1拷贝数增加的 α-类胰蛋白酶,与h α t相容 (P <.001)。具有h α t的患者表现出比不具有h α t的患者更高的类胰蛋白酶水平 (h α t + 病例中的类胰蛋白酶中值: 49.6 ng/mL vs h α t-病例: 34.5 ng/mL,P = .004),独立于肥大细胞负荷。在患有h α t的肥大细胞增多症患者中,观察到的超敏反应和严重的心血管介质相关症状/过敏反应的频率远远高于未患有h α t的患者。结果在独立的验证队列中得到证实。肥大细胞增多症中h α t的高流行率提示生殖系 α-类胰蛋白酶编码的TPSAB1拷贝数增加在疾病进化中的潜在致病作用。总之,我们的数据表明,h α t是肥大细胞增生症中一种新出现的稳健生物标志物,可用于确定个体患者发生严重过敏反应的风险。

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