TY - JOUR
T1 - Effect of DNA methylation on inhibitor development in people with hemophilia A treated with FVIII concentrates
AU - Survey of Inhibitors in Plasma-Product Exposed Toddlers Study Group
AU - Chand, Himani
AU - Hassan, Shermarke
AU - Cairo, Andrea
AU - Palla, Roberta
AU - Peyvandi, Flora
AU - Mannucci, Pier M.
AU - Garagiola, Isabella
AU - El-Beshlawy, Amal
AU - Elalfy, Mohsen
AU - Ramanan, Vijay
AU - Eshghi, Peyman
AU - Hanagavadi, Suresh
AU - Varadarajan, Ramabadran
AU - Karimi, Mehran
AU - Manglani, Mamta V.
AU - Ross, Cecil
AU - Young, Guy
AU - Seth, Tulika
AU - Apte, Shashikant
AU - Nayak, Dinesh M.
AU - Santagostino, Elena
AU - Mancuso, Maria Elisa
AU - Sandoval Gonzalez, Adriana C.
AU - Mahlangu, Johnny N.
AU - Bonanad Boix, Santiago
AU - Cerqueira, Monica
AU - Ewing, Nadia P.
AU - Male, Christoph
AU - Owaidah, Tarek
AU - Soto Arellano, Veronica
AU - Kobrinsky, Nathan L.
AU - Majumdar, Suvankar
AU - Garrido, Rosario Perez
AU - Sachdeva, Anupam
AU - Simpson, Mindy
AU - Thomas, Mathew
AU - Zanon, Ezio
AU - Antmen, Bulent
AU - Kavakli, Kaan
AU - Manco-Johnson, Marilyn J.
AU - Martinez, Monica
AU - Marzouka, Esperanza
AU - Mazzucconi, Maria G.
AU - Neme, Daniela
AU - Palomo Bravo, Angeles
AU - Paredes Aguilera, Rogelio
AU - Prezotti, Alessandra
AU - Schmitt, Klaus
AU - Wicklund, Brian M.
AU - Zulfikar, Bulent
N1 - Publisher Copyright:
© 2025 The Authors
PY - 2025/3
Y1 - 2025/3
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/105005778152
UR - https://www.scopus.com/pages/publications/105005778152#tab=citedBy
U2 - 10.1016/j.rpth.2025.102858
DO - 10.1016/j.rpth.2025.102858
M3 - Article
AN - SCOPUS:105005778152
SN - 2475-0379
VL - 9
JO - Research and Practice in Thrombosis and Haemostasis
JF - Research and Practice in Thrombosis and Haemostasis
IS - 3
M1 - 102858
ER -