Background: Hemophilia A (HA) is a hereditary X-linked hemorrhagic disorder. Following the first treatment with exogenous factor (F)VIII, one-third of patients with severe HA develop anti-FVIII antibodies (inhibitors), which render treatment ineffective. Recent findings underlined the critical role of DNA methylation in several autoimmune diseases by altering gene expression profiles. This study was designed to evaluate potential differences in DNA methylation profiles of previously untreated patients (PUPs) who develop inhibitors against FVIII and those who do not, with the aim of identifying immune-regulatory genes that may contribute to the risk of inhibitor formation. Objectives: In this study, we aimed to understand whether CpG sites are differentially methylated in peripheral blood mononuclear cells (PBMCs) of PUPs and have a role in inhibitor development to better understand the biological pathways that lead to inhibitor development. Methods: A case-control study was performed using 45 inhibitor-positive and 67 inhibitor-negative PUPs from the Survey of Inhibitors in Plasma-Product Exposed Toddlers study cohort. Enrichment bisulfite sequencing was performed on DNA samples from PBMCs of HA patients and differentially methylated CpG sites (DMCs) were identified with bioinformatic approach. Results: Overall, information on 621,121 CpG sites was obtained. Two thousand seven hundred seventy-two sites were significantly differentially methylated (unadjusted P value < .05). Association of CpG sites to a few genes involved in active immune response (JAK1, CD1C, PIGR, TOLLIP, BLNK, CD44, IL23R, IFNLR1, SOCS2, TLR1, etc.) was seen in inhibitor-positive patients, but it did not indicate specific pathways associated with inhibitor development. Conclusion: DMCs were identified in PBMC samples from HA patients with inhibitors. However, our data could not confirm the role of these CpG sites in affecting immune-regulatory pathways.
Effect of DNA methylation on inhibitor development in people with hemophilia A treated with FVIII concentrates / H. Chand, S. Hassan, A. Cairo, R. Palla, F. Peyvandi, F. Peyvandi, P.M. Mannucci, I. Garagiola, A. El-Beshlawy, M. Elalfy, V. Ramanan, P. Eshghi, S. Hanagavadi, R. Varadarajan, M. Karimi, M.V. Manglani, C. Ross, G. Young, T. Seth, S. Apte, D.M. Nayak, E. Santagostino, M.E. Mancuso, A.C. Sandoval Gonzalez, J.N. Mahlangu, S. Bonanad Boix, M. Cerqueira, N.P. Ewing, C. Male, T. Owaidah, V. Soto Arellano, N.L. Kobrinsky, S. Majumdar, R.P. Garrido, A. Sachdeva, M. Simpson, M. Thomas, E. Zanon, B. Antmen, K. Kavakli, M.J. Manco-Johnson, M. Martinez, E. Marzouka, M.G. Mazzucconi, D. Neme, A. Palomo Bravo, R. Paredes Aguilera, A. Prezotti, K. Schmitt, B.M. Wicklund, B. Zulfikar, F.R. Rosendaal. - In: RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS. - ISSN 2475-0379. - 9:3(2025), pp. e102858.1-e102858.9. [10.1016/j.rpth.2025.102858]
Effect of DNA methylation on inhibitor development in people with hemophilia A treated with FVIII concentrates
H. ChandPrimo
;S. Hassan;R. Palla;F. Peyvandi
;P.M. Mannucci;I. Garagiola;M.E. Mancuso;
2025
Abstract
Background: Hemophilia A (HA) is a hereditary X-linked hemorrhagic disorder. Following the first treatment with exogenous factor (F)VIII, one-third of patients with severe HA develop anti-FVIII antibodies (inhibitors), which render treatment ineffective. Recent findings underlined the critical role of DNA methylation in several autoimmune diseases by altering gene expression profiles. This study was designed to evaluate potential differences in DNA methylation profiles of previously untreated patients (PUPs) who develop inhibitors against FVIII and those who do not, with the aim of identifying immune-regulatory genes that may contribute to the risk of inhibitor formation. Objectives: In this study, we aimed to understand whether CpG sites are differentially methylated in peripheral blood mononuclear cells (PBMCs) of PUPs and have a role in inhibitor development to better understand the biological pathways that lead to inhibitor development. Methods: A case-control study was performed using 45 inhibitor-positive and 67 inhibitor-negative PUPs from the Survey of Inhibitors in Plasma-Product Exposed Toddlers study cohort. Enrichment bisulfite sequencing was performed on DNA samples from PBMCs of HA patients and differentially methylated CpG sites (DMCs) were identified with bioinformatic approach. Results: Overall, information on 621,121 CpG sites was obtained. Two thousand seven hundred seventy-two sites were significantly differentially methylated (unadjusted P value < .05). Association of CpG sites to a few genes involved in active immune response (JAK1, CD1C, PIGR, TOLLIP, BLNK, CD44, IL23R, IFNLR1, SOCS2, TLR1, etc.) was seen in inhibitor-positive patients, but it did not indicate specific pathways associated with inhibitor development. Conclusion: DMCs were identified in PBMC samples from HA patients with inhibitors. However, our data could not confirm the role of these CpG sites in affecting immune-regulatory pathways.
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