在严重血友病A和抑制剂患者中，有害变异聚集在因子VIII的A3结构域

IF 3.4 3区医学 Q2 HEMATOLOGY

Research and Practice in Thrombosis and Haemostasis Pub Date : 2025-08-01 DOI:10.1016/j.rpth.2025.103006

Luciana Werneck Zuccherato , Renan Pedra Souza , Ricardo Mesquita Camelo , Márcio Antônio Portugal Santana , Maíse Moreira Dias , Letícia Lemos Jardim , Andrea Gonçalves de Oliveira , Claudia Santos Lorenzato , Monica Hermida Cerqueira , Vivian Karla Brognoli Franco , Rosangela de Albuquerque Ribeiro , Leina Yukari Etto , Maria do Rosario Ferraz Roberti , Fábia Michelle Rodrigues de Araújo Callado , Maria Aline Ferreira de Cerqueira , Ieda Solange de Souza Pinto , Andrea Aparecida Garcia , Tania Hissa Anegawa , Daniele Campos Fontes Neves , Daniel Gonçalves Chaves , Suely Meireles Rezende

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引用次数: 0

摘要

血友病A （HA）是一种由因子VIII （FVIII）基因（F8）的有害变异引起的x连锁疾病。很少有来自大型队列的研究探索了除北美和欧洲以外的HA患者的F8基因型。目的评估严重血友病a患者抑制剂发展背景下F8变异和单倍型谱以及受影响的FVIII结构域和链。方法使用定制基因面板和全外显子组测序对内含子1和内含子22倒置（Inv22）进行基因分型和F8测序。结果：我们纳入了265例严重a型血友病患者，在98.1%的患者中发现了有害变异，共有97个独特突变，其中32个（33.0%）是新突变。在Inv22中，无义、小插入/缺失、大缺失和错义变异分别占所鉴定变异的48.3%、14.7%、11.3%、9.8%和7.5%。聚集在FVIII A3结构域的变异与HA抑制剂（INH+）患者的相关性高于无抑制剂（INH -）患者（21.0% vs 0.0%; P < .001）；聚集在A1结构域的变异与INH−个体的相关性高于与INH+个体的相关性（33.3% vs 7.7%; P < 0.001）。Inv22与先前未治疗的患者发生抑制剂的风险增加4.8倍相关（优势比，4.81;95% CI, 2.02-12.01）。相反，错义变异可以防止抑制剂的发展（优势比，0.09;95% CI, 0.01-0.50）。结论这些发现强调了F8基因型和特异性FVIII结构域在HA混合人群抑制剂发展中的作用。这可能有助于设计针对免疫原性降低的FVIII分子的治疗方法。

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Deleterious variants cluster in the A3 domain of factor VIII in people with severe hemophilia A and inhibitors

Background

Hemophilia A (HA) is an X-linked disorder due to deleterious variants in the factor VIII (FVIII) gene (F8). Few studies from large cohorts have explored F8 genotype in people with HA with origins other than North American and European.

Objectives

We aimed to evaluate the spectrum of F8 variants and haplotypes and affected FVIII domains and chains in the context of inhibitor development in people with severe hemophilia A.

Methods

We performed genotyping of intron 1 and intron 22 inversions (Inv22) and F8 sequencing using a customized gene panel and whole exome sequencing.

Results

We included 265 people with severe hemophilia A. We identified deleterious variants in 98.1% of them, totaling 97 unique mutations, of which 32 (33.0%) are novel. Inv22, nonsense, small insertion/deletion, large deletion, and missense variants accounted for 48.3%, 14.7%, 11.3%, 9.8%, and 7.5% of the variants identified. Variants clustered in the FVIII A3 domain were more often associated with people with HA with inhibitors (INH+) than those without inhibitors (INH−) (21.0% vs 0.0%; P < .001); variants clustered in the A1 domain were more often associated with INH− than with INH+ individuals (33.3% vs 7.7%; P < .001). Inv22 was associated with a 4.8-fold increased risk of developing inhibitors in previously untreated patients (odds ratio, 4.81; 95% CI, 2.02-12.01). Conversely, missense variants protected against inhibitor development (odds ratio, 0.09; 95% CI, 0.01-0.50).

Conclusion

These findings highlight the role of F8 genotype and specific FVIII domains in inhibitor development in an admixed population of people with HA. This could help engineer therapeutic approaches targeting FVIII molecules with reduced immunogenicity.

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