Key Genes of the Immune System and Predisposition to Acquired Hemophilia A: Evidence from a Spanish Cohort of 49 Patients Using Next-Generation Sequencing
Por:
Pardos-Gea, J, Martin-Fernandez, L, Closa, L, Ferrero, A, Marzo, C, Rubio-Rivas, M, Mitjavila, F, González-Porras, JR, Bastida, JM, Mateo, J, Carrasco, M, Bernardo, A, Astigarraga, I, Aguinaco, R, Corrales, I, Garcia-Martínez, I, Vidal, F
Publicada:
1 nov 2023
Resumen:
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 x 103, 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 (nallele = 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.
Filiaciones:
Pardos-Gea, J:
Vall dHebron Univ Hosp, Dept Internal Med, Syst Autoimmune Dis Unit, Barcelona 08035, Spain
Martin-Fernandez, L:
Congenital Coagulopathies Lab, Blood & Tissue Bank, Barcelona 08005, Spain
Autonomous Univ Barcelona VHIR UAB, Vall dHebron Res Inst, Transfus Med Grp, Barcelona 08035, Spain
Closa, L:
Autonomous Univ Barcelona VHIR UAB, Vall dHebron Res Inst, Transfus Med Grp, Barcelona 08035, Spain
Blood & Tissue Bank, Histocompatibil & Immunogenet Lab, Barcelona 08005, Spain
Ferrero, A:
Arnau Vilanova Univ Hosp, Hematol Serv, Lleida 25198, Spain
Marzo, C:
Arnau Vilanova Univ Hosp, Hematol Serv, Lleida 25198, Spain
Rubio-Rivas, M:
Univ Barcelona, Bellvitge Univ Hosp, Bellvitge Biomed Res Inst IDIBELL, Dept Internal Med, L'Hospitalet De Llobregat 08908, Barcelona, Spain
Mitjavila, F:
Univ Barcelona, Bellvitge Univ Hosp, Bellvitge Biomed Res Inst IDIBELL, Dept Internal Med, L'Hospitalet De Llobregat 08908, Barcelona, Spain
González-Porras, JR:
Univ Salamanca USAL, Complejo Asistencial Univ Salamanca CAUSA, Fac Med, Dept Hematol,Inst Deinvest Biomed Salamanca IBSAL, Salamanca 37007, Spain
Bastida, JM:
Univ Salamanca USAL, Complejo Asistencial Univ Salamanca CAUSA, Fac Med, Dept Hematol,Inst Deinvest Biomed Salamanca IBSAL, Salamanca 37007, Spain
Mateo, J:
St Pau Campus Salut Barcelona, Thrombosis & Hemostasis Unit, Barcelona 08025, Spain
Carrasco, M:
St Pau Campus Salut Barcelona, Thrombosis & Hemostasis Unit, Barcelona 08025, Spain
Bernardo, A:
Cent Univ Hosp Asturias, Hematol Serv, Oviedo 33011, Spain
Astigarraga, I:
Univ Basque Country UPV EHU, Hosp Univ Cruces, Biobizkaia Hlth Res Inst, Dept Pediat, Baracaldo 48903, Spain
Aguinaco, R:
Univ Hosp Joan XXIII, Hematol Serv, Tarragona 43002, Spain
Corrales, I:
Congenital Coagulopathies Lab, Blood & Tissue Bank, Barcelona 08005, Spain
Autonomous Univ Barcelona VHIR UAB, Vall dHebron Res Inst, Transfus Med Grp, Barcelona 08035, Spain
Inst Carlos III ISCIII, Ctr Invest Biomed Red Enfermedades Cardiovasc CIBE, Madrid 28029, Spain
Garcia-Martínez, I:
Congenital Coagulopathies Lab, Blood & Tissue Bank, Barcelona 08005, Spain
Autonomous Univ Barcelona VHIR UAB, Vall dHebron Res Inst, Transfus Med Grp, Barcelona 08035, Spain
Vidal, F:
Congenital Coagulopathies Lab, Blood & Tissue Bank, Barcelona 08005, Spain
Autonomous Univ Barcelona VHIR UAB, Vall dHebron Res Inst, Transfus Med Grp, Barcelona 08035, Spain
Inst Carlos III ISCIII, Ctr Invest Biomed Red Enfermedades Cardiovasc CIBE, Madrid 28029, Spain
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