Effect of DNA methylation on inhibitor development in people with hemophilia A treated with FVIII concentrates
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...
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2025-03-01
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| author | Himani Chand Shermarke Hassan Andrea Cairo Roberta Palla Flora Peyvandi Flora Peyvandi Pier M. Mannucci Isabella Garagiola Amal El-Beshlawy Mohsen Elalfy Vijay Ramanan Peyman Eshghi Suresh Hanagavadi Ramabadran Varadarajan Mehran Karimi Mamta V. Manglani Cecil Ross Guy Young Tulika Seth Shashikant Apte Dinesh M. Nayak Elena Santagostino Maria Elisa Mancuso Adriana C. Sandoval Gonzalez Johnny N. Mahlangu Santiago Bonanad Boix Monica Cerqueira Nadia P. Ewing Christoph Male Tarek Owaidah Veronica Soto Arellano Nathan L. Kobrinsky Suvankar Majumdar Rosario Perez Garrido Anupam Sachdeva Mindy Simpson Mathew Thomas Ezio Zanon Bulent Antmen Kaan Kavakli Marilyn J. Manco-Johnson Monica Martinez Esperanza Marzouka Maria G. Mazzucconi Daniela Neme Angeles Palomo Bravo Rogelio Paredes Aguilera Alessandra Prezotti Klaus Schmitt Brian M. Wicklund Bulent Zulfikar Frits R. Rosendaal |
| author_facet | Himani Chand Shermarke Hassan Andrea Cairo Roberta Palla Flora Peyvandi Flora Peyvandi Pier M. Mannucci Isabella Garagiola Amal El-Beshlawy Mohsen Elalfy Vijay Ramanan Peyman Eshghi Suresh Hanagavadi Ramabadran Varadarajan Mehran Karimi Mamta V. Manglani Cecil Ross Guy Young Tulika Seth Shashikant Apte Dinesh M. Nayak Elena Santagostino Maria Elisa Mancuso Adriana C. Sandoval Gonzalez Johnny N. Mahlangu Santiago Bonanad Boix Monica Cerqueira Nadia P. Ewing Christoph Male Tarek Owaidah Veronica Soto Arellano Nathan L. Kobrinsky Suvankar Majumdar Rosario Perez Garrido Anupam Sachdeva Mindy Simpson Mathew Thomas Ezio Zanon Bulent Antmen Kaan Kavakli Marilyn J. Manco-Johnson Monica Martinez Esperanza Marzouka Maria G. Mazzucconi Daniela Neme Angeles Palomo Bravo Rogelio Paredes Aguilera Alessandra Prezotti Klaus Schmitt Brian M. Wicklund Bulent Zulfikar Frits R. Rosendaal |
| author_sort | Himani Chand |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-36fd1556762445ae8f3fe81e41a531cd |
| institution | DOAJ |
| issn | 2475-0379 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
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| series | Research and Practice in Thrombosis and Haemostasis |
| spelling | doaj-art-36fd1556762445ae8f3fe81e41a531cd2025-08-20T03:10:24ZengElsevierResearch and Practice in Thrombosis and Haemostasis2475-03792025-03-019310285810.1016/j.rpth.2025.102858Effect of DNA methylation on inhibitor development in people with hemophilia A treated with FVIII concentratesHimani Chand0Shermarke Hassan1Andrea Cairo2Roberta Palla3Flora Peyvandi4Flora Peyvandi5Pier M. Mannucci6Isabella Garagiola7Amal El-Beshlawy8Mohsen Elalfy9Vijay Ramanan10Peyman Eshghi11Suresh Hanagavadi12Ramabadran Varadarajan13Mehran Karimi14Mamta V. Manglani15Cecil Ross16Guy Young17Tulika Seth18Shashikant Apte19Dinesh M. Nayak20Elena Santagostino21Maria Elisa Mancuso22Adriana C. Sandoval Gonzalez23Johnny N. Mahlangu24Santiago Bonanad Boix25Monica Cerqueira26Nadia P. Ewing27Christoph Male28Tarek Owaidah29Veronica Soto Arellano30Nathan L. Kobrinsky31Suvankar Majumdar32Rosario Perez Garrido33Anupam Sachdeva34Mindy Simpson35Mathew Thomas36Ezio Zanon37Bulent Antmen38Kaan Kavakli39Marilyn J. Manco-Johnson40Monica Martinez41Esperanza Marzouka42Maria G. Mazzucconi43Daniela Neme44Angeles Palomo Bravo45Rogelio Paredes Aguilera46Alessandra Prezotti47Klaus Schmitt48Brian M. Wicklund49Bulent Zulfikar50Frits R. Rosendaal51Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, ItalyDepartment of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, ItalyAngelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, ItalyDepartment of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, ItalyDepartment of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy; Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; Correspondence Flora Peyvandi, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Pace 9, 20122 Milano, Italy.Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, ItalyAngelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, ItalyDepartment of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, ItalyPediatric Hematology Department, Cairo University Pediatric Hospital, Cairo, EgyptDepartment of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, EgyptJehangir Clinical Development Center, Department of Hematology, Jehangir Hospital Premises, Pune, IndiaCongenital Pediatric Hematologic Disorders Research Center, Shahid Beheshti University of Medical Sciences, Tehran, IranJagadguru Jayadeva Murugarajendra Medical College, Davangere, IndiaCenter for Blood Disorders, Chennai, IndiaHematology Research Center, Shiraz University of Medical Sciences, Shiraz, IranLokmanya Tilak Municipal Medical College and General Hospital, Mumbai, IndiaSt. John’s Medical College Hospital, BangaloreChildren’s Hospital Los Angeles, Los Angeles, California, USADepartment of Hematology, All India Institute of Medical Sciences, New Delhi, IndiaSahyadri Speciality Hospital, Pune, Maharashtra, IndiaMelaka-Manipal Medical College, Manipal University, Manipal, IndiaAngelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca’ Granda Ospedale Maggiore Policlinico, Milan, ItalyAngelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca’ Granda Ospedale Maggiore Policlinico, Milan, ItalyHospital de Especialidades Unidad Médica de Alta Especialidad, Instituto Mexicano del Seguro Social, Monterrey, MexicoFaculty of Health Sciences, School of Pathology, University of the Witwatersrand, National Health Laboratory Service and Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South AfricaHospital Universitario La Fe, Unidad Coagulopatias Congenitas, Valencia, SpainCentro de Pesquisa Clinica Hemorio–Instituto Estadual de Hematología Arthur de Siqueira Cavalcanti, Rio de Janeiro, BrazilCity of Hope National Medical Center, Duarte, California, USAMedizinische Universität Wien, Department of Pediatrics, Vienna, AustriaKing Faisal Specialist Hospital and Research Center, Riyadh, Saudi ArabiaCentro de Hemofílicos del Hospital de Niños Dr. Roberto del Río, Santiago, ChileSanford Roger Maris Cancer Center, Fargo, North Dakota, USADivision of Pediatric Hematology–Oncology, University of Mississippi Medical Center, Jackson, Mississippi, USAHospital Universitario Virgen del Rocío, Unidad de Hemofilia, Seville, SpainPediatric Hematology–Oncology and Bone Marrow Transplantation, Institute for Child Health, Sir Ganga Ram Hospital, New Delhi, IndiaRush Hemophilia and Thrombophilia Center, Rush University Medical Center, Chicago, USAKerala Institute of Medical Science, Trivandrum, IndiaClinica Medica II, Azienda Ospedaliera di Padova, Centro Emofilia, Padua, ItalyCukurova Universitesi, Tip Fakultesi Pediatrik Hematoloji Bilim Dali, Adana, TurkeyEge Universitesi Tip Fakultesi Cocuk Sagligi ve Hastalikari Anabilim Dali, Pediatrik Hematoloji Bilim Dali, Izmir, TurkeyHemophilia and Thrombosis Center, University of Colorado Denver, Aurora, Colorado, USAHospital de Niños Sor María Ludovica La Plata, Servicio de Hematología, Buenos Aires, ArgentinaHospital de Niños Dr. Luis Calvo Mackenna, Centro Hemofílico, Santiago, ChileEmatologia, Unità Operativa Diagnostica Speciale e Terapia delle Malattie dell’Emostasi e della Trombosi, Università Sapienza, Policlinico Umberto I, Rome, ItalyFundación de la Hemofilia, Buenos Aires, ArgentinaHospital Regional Universitario Carlos Haya, Malaga, SpainInstituto Nacional de Pediatria, Mexico City, MexicoCentro de Hematología e Hemoterapia do Espírito Santo, Vitoria, BrazilDepartment of Pediatric and Adolescent Medicine, Kepler University Clinic, Linz, AustriaChildren’s Mercy Hospital, Kansas City, Missouri, USAIstanbul Universitesi Cerrahpasa Tip Fakultesi, Pediatrik Hematoloji Bilim Dali, Istanbul, TurkeyDepartment of Clinical Epidemiology, Leiden University Medical Center, Leiden, the NetherlandsBackground: 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.http://www.sciencedirect.com/science/article/pii/S2475037925001827antibodies, neutralzingDNA methylationblood coagulation disorders,inheritedfactor VIII/immunologyhemophilia A |
| spellingShingle | Himani Chand Shermarke Hassan Andrea Cairo Roberta Palla Flora Peyvandi Flora Peyvandi Pier M. Mannucci Isabella Garagiola Amal El-Beshlawy Mohsen Elalfy Vijay Ramanan Peyman Eshghi Suresh Hanagavadi Ramabadran Varadarajan Mehran Karimi Mamta V. Manglani Cecil Ross Guy Young Tulika Seth Shashikant Apte Dinesh M. Nayak Elena Santagostino Maria Elisa Mancuso Adriana C. Sandoval Gonzalez Johnny N. Mahlangu Santiago Bonanad Boix Monica Cerqueira Nadia P. Ewing Christoph Male Tarek Owaidah Veronica Soto Arellano Nathan L. Kobrinsky Suvankar Majumdar Rosario Perez Garrido Anupam Sachdeva Mindy Simpson Mathew Thomas Ezio Zanon Bulent Antmen Kaan Kavakli Marilyn J. Manco-Johnson Monica Martinez Esperanza Marzouka Maria G. Mazzucconi Daniela Neme Angeles Palomo Bravo Rogelio Paredes Aguilera Alessandra Prezotti Klaus Schmitt Brian M. Wicklund Bulent Zulfikar Frits R. Rosendaal Effect of DNA methylation on inhibitor development in people with hemophilia A treated with FVIII concentrates Research and Practice in Thrombosis and Haemostasis antibodies, neutralzing DNA methylation blood coagulation disorders,inherited factor VIII/immunology hemophilia A |
| title | Effect of DNA methylation on inhibitor development in people with hemophilia A treated with FVIII concentrates |
| title_full | Effect of DNA methylation on inhibitor development in people with hemophilia A treated with FVIII concentrates |
| title_fullStr | Effect of DNA methylation on inhibitor development in people with hemophilia A treated with FVIII concentrates |
| title_full_unstemmed | Effect of DNA methylation on inhibitor development in people with hemophilia A treated with FVIII concentrates |
| title_short | Effect of DNA methylation on inhibitor development in people with hemophilia A treated with FVIII concentrates |
| title_sort | effect of dna methylation on inhibitor development in people with hemophilia a treated with fviii concentrates |
| topic | antibodies, neutralzing DNA methylation blood coagulation disorders,inherited factor VIII/immunology hemophilia A |
| url | http://www.sciencedirect.com/science/article/pii/S2475037925001827 |
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