Key Genes of the Immune System and Predisposition to Acquired Hemophilia A : Evidence from a Spanish Cohort of 49 Patients Using Next-Generation Sequencing
Pardos-Gea, Josep (Hospital Universitari Vall d'Hebron)
Martin-Fernandez, Laura (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Closa, Laia (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Ferrero, Ainara (Hospital Universitari Arnau de Vilanova)
Marzo, Cristina (Hospital Universitari Arnau de Vilanova)
Rubio Rivas, Manuel (Institut d'Investigació Biomèdica de Bellvitge)
Mitjavila, Francesca (Institut d'Investigació Biomèdica de Bellvitge)
González-Porras, José Ramón (Universidad de Salamanca)
Bastida, José María (Universidad de Salamanca)
Mateo, José (Institut d'Investigació Biomèdica Sant Pau)
Carrasco, Marina (Institut d'Investigació Biomèdica Sant Pau)
Bernardo, Ángel (Hospital Universitario Central de Asturias)
Astigarraga, Itziar (Hospital Universitario Cruces)
Aguinaco, Reyes (Hospital Universitari Joan XXIII de Tarragona)
Corrales Insa, Irene (Hospital Universitari Vall d'Hebron. Institut de Recerca)
García-Martinez, Iris (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Vidal, Francisco (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Universitat Autònoma de Barcelona

Data:	2023
Resum:	Acquired hemophilia A (AHA) is a rare bleeding disorder caused by the presence of autoantibodies against factor VIII (FVIII). As with other autoimmune diseases, its etiology is complex and its genetic basis is unknown. The aim of this study was to identify the immunogenetic background that predisposes individuals to AHA. HLA and KIR gene clusters, as well as KLRK1, were sequenced using next-generation sequencing in 49 AHA patients. Associations between candidate genes involved in innate and adaptive immune responses and AHA were addressed by comparing the alleles, genotypes, haplotypes, and gene frequencies in the AHA cohort with those in the donors' samples or Spanish population cohort. Two genes of the HLA cluster, as well as rs1049174 in KLRK1, which tags the natural killer (NK) cytotoxic activity haplotype, were found to be linked to AHA. Specifically, A*03:01 (p = 0. 024; odds ratio (OR) = 0. 26[0. 06-0. 85]) and DRB1*13:03 (p = 6. 8 × 10 3, OR = 7. 56[1. 64-51. 40]), as well as rs1049174 (p = 0. 012), were significantly associated with AHA. In addition, two AHA patients were found to carry one copy each of the low-frequency allele DQB1*03:09 (n = 2, 2. 04%), which was completely absent in the donors. To the best of our knowledge, this is the first time that the involvement of these specific alleles in the predisposition to AHA has been proposed. Further molecular and functional studies will be needed to unravel their specific contributions. We believe our findings expand the current knowledge on the genetic factors involved in susceptibility to AHA, which will contribute to improving the diagnosis and prognosis of AHA patients.
Ajuts:	Instituto de Salud Carlos III PI18/01492
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Acquired hemophilia A ; Autoantibodies ; Genetic predisposition to disease ; Immunogenetics ; Next-generation sequencing ; Rare bleeding disorders
Publicat a:	International journal of molecular sciences, Vol. 24 (november 2023) , ISSN 1422-0067

DOI: 10.3390/ijms242216372
PMID: 38003562

14 p, 643.3 KB

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