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A scan of pleiotropic immune mediated disease genes identifies novel determinants of baseline FVIII inhibitor status in hemophilia A

Genes & Immunity volume 26, pages 179–189 (2025)Cite this article

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A Correction to this article was published on 25 September 2025

This article has been updated

Abstract

Hemophilia-A (HA) is the X-linked bleeding disorder caused by heterogeneous factor (F)VIII gene (F8)-mutations and deficiencies in plasma-FVIII-activity that prevent intrinsic-pathway mediated coagulation-amplification. Severe-HA patients (HAPs) require life-long infusions of therapeutic-FVIII-proteins (tFVIIIs) but ~30% develop neutralizing-tFVIII-antibodies called “FVIII-inhibitors (FEIs)”. We investigated the genetics underlying the variable risk of FEI-development in 450 North American HAPs (206 and 244 respectively self-reporting black-African- or white-European-ancestry) by analyzing the genotypes of single-nucleotide-variations (SNVs) in candidate immune-mediated-disease (IMD)-genes using a binary linear-mixed model of genetic association with baseline-FEI-status, the dependent variable, while simultaneously accounting for their genetic relationships and heterogeneous-F8-mutations to prevent the statistical problem of non-independence. We a priori selected gene-centric-association-scans of pleiotropic-IMD-genes implicated in the development of either ≥2 autoimmune-/autoinflammatory-disorders (AADs) or FEIs and ≥1 AAD. We found that baseline-FEI-status was significantly associated with NOS2A (rs117382854; p = 3.2 × 10−6) and B3GNT2 (rs10176009; p = 5.1 × 10−6)—pleiotropic-IMD-genes known previously to function in anti-microbial-/-tumoral-immunity but not in the development of FEIs—and confirmed associations with CTLA4 (rs231780; p = 2.2 × 10−5). We also found that baseline-FEI-status has a substantial heritability (~55%) that involves (i) a F8-mutation-specific component of ~8%, (ii) an additive-genetic contribution from SNVs in IMD-genes of ~47%, and (iii) race, which is a significant determinant independent of F8-mutation-types and non-F8-genetics.

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Fig. 1
Fig. 2: Manhattan plot of PATH study results from the association scan of baseline FEI status against the IMD genes on the IC and their assigned SNVs.
Fig. 3: Focused Manhattan plots of the GCAS results from the three pleiotropic IMD genes with SNVs that demonstrated significant genotype-specific associations with baseline FEI status.
Fig. 4: Plots of ORs of the effect of IMD-genes/-gene-variants and race as covariates on the outcome of baseline FEI status under the additive (A–E) and interaction (F–J) models.

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Data availability

In addition to the data and methods reported in this article and its Supplementary Appendix, data are available upon request pending data transfer agreements approved by local authorities.

Change history

  • 09 July 2025

    The original online version of this article was revised: In this article the author’s name R. Rajalingam was incorrectly written as R. Raja.

  • 25 September 2025

    A Correction to this paper has been published: https://doi.org/10.1038/s41435-025-00345-3

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Acknowledgements

We thank all patients that participated in the PATH study as well as all nurses, other care-givers, and research staff at the participating HTCs that cared for and enrolled their patients, as well as collected, processed and shipped their data and samples to PATH Study research staff at the LA-VAMC, Texas Biomedical Research Institute, Bloodworks NW, and UCSF including Valerie Crenshaw, Mary Katherine Noa, Katherine Bianchi, April Morris, Melinda Nolte, Erika Martin, Janice Kuhn, Lisa Jacobs, Kimberly Gray, Mary Strickland, Rhonda Aikens, Glenda Thomas, Shannon Webert, Pamela Bryant, Robin Kellerman, Dan Dalton, Mary Camille Fournet, Kristy Enderlen, Janice Withycombe, Judith Strange, Brynnan Gilgour, and Johanna (Joan) McCarthy. We also thank: (1) the HTC directors not listed as co-authors for overseeing the essential clinical aspects of this study at their sites including Drs. John Barrett, Alexis Thompson, Rebecca Kruse-Jarres, Victor Blanchette, Dana Matthews, Chris Walsh, Rathi Iyer, Christine Kempton, Nigel Key, Jerry Teitel, Manuel Carcao, and Georges Rivard; and (2) Drs. Ken Mann and Saulius Butenas for (i) help in securing study funding, and (ii) designing/performing fluorescence FVIII antibody assays to be used in another analysis. Finally, we thank: Drs. Christine Kempton, Alexis Thompson, and Nigel Key for serving on the PATH Study’s Publications & Presentation Committee; and Drs. Ken Mann, Craig Kessler, and the late Jeanne Lusher for serving on the PATH Study’s Steering & Oversight Committee.

Funding

This research was funded by: National Institutes of Health (NIH) grants R01 HL169763, RC2 HL101851, R01 HL71130, K08 HL72533, P01 HL045522, R01 MH078143, R01 MH078111, R01 MH083824, R01 MH059490, R01 MD012564, and U54 HG013247; a USC CTSI pilot grant; and investigator-initiated grants from Bayer Healthcare, the Bayer Hemophilia Awards Program, and Baxter Healthcare. Portions of the research were conducted in facilities constructed with support from NIH grants C06 RR013556, C06 RR017515, and C06 RR020547 and leveraged state-of-the-art instrumentation and capabilities established as part of the Valley Baptist Legacy Foundation-supported Project THRIVE and U54 HG013247.

Author information

Author notes

  1. These authors contributed equally: Marcio A. Almeida, Vincent P. Diego, Kevin R. Viel, Bernadette W. Luu.

Authors and Affiliations

  1. South Texas Diabetes and Obesity Institute, and Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley, Brownsville, TX, USA

    Marcio A. Almeida, Vincent P. Diego, Eron G. Manusov, Juan M. Peralta, Satish Kumar, Sarah Williams-Blangero, John Blangero & Tom E. Howard

  2. Histonis, Inc., Portsmouth, NH, USA

    Kevin R. Viel

  3. Haplogenics Corporation, Brownsville, TX, USA

    Bernadette W. Luu, Long V. Dinh, Jerry S. Powell & Tom E. Howard

  4. Population Health Program, Texas Biomedical Research Institute, San Antonio, TX, USA

    Karin Haack & Shelley A. Cole

  5. Immunogenetics and Transplantation Laboratory, Department of Surgery, School of Medicine, University of California at San Francisco, San Francisco, CA, USA

    Raja Rajalingam

  6. Department of Pediatrics, Division of Hematology and Oncology, Georgia Health Sciences University, Augusta, GA, USA

    Afshin Ameri

  7. Children’s Hospital of Michigan, Wayne State University, Pediatric Hematology and Oncology, Detroit, MI, USA

    Meera Chitlur

  8. Division of Hematology and Hematological Malignancies, Department of Medicine, University of Calgary, Calgary, AB, Canada

    Natalia Rydz

  9. Department of Pathology and Molecular Medicine, Queen’s University at Kingston, Kingston, ON, Canada

    David Lillicrap

  10. Louisiana State University Health Sciences Center, New Orleans, LA, USA

    Raymond G. Watts

  11. Georgetown University, Washington, DC, USA

    Craig M. Kessler

  12. Clever Culture Systems, San Diego, CA, USA

    Christopher Ramsey

  13. Consultant, Brisbane, CA, USA

    Benjamin Kim

  14. Division of Hematology and Oncology, Department of Internal Medicine, School of Medicine, University of California at Davis, Davis, CA, USA

    Jerry S. Powell

  15. School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX, USA

    Ruayda Bouls

  16. Division of Hematology and Oncology, Department of Pediatrics, School of Medicine, University of New Mexico, Albuquerque, NM, USA

    Shirley M. Abraham

  17. Division of Hematology and Oncology, Department of Internal Medicine, School of Medicine, University of Texas Southwestern, Dallas, TX, USA

    Yu-Min Shen

  18. Servicio de Hematologia, Hospital General de México “Dr. Eduardo Liceaga” and Facultad de Medicina, Universidad Nacional Autonóma de México, Ciudad de México, Distrito Federal, Mexico

    Carlos M. Murillo

  19. Global Medical Affairs, BioMarin, Novato, CA, USA

    Henry Mead

  20. Departments of Pathology and Neurology, Case Western Reserve University School of Medicine, Cleveland, OH, USA

    Paul V. Lehmann

  21. Cellular Technology Ltd, Shaker Heights, OH, USA

    Paul V. Lehmann

  22. Consultant, Atlanta, GA, USA

    Eli J. Fine

  23. Division of Hematology and Oncology, Department of Medicine, University of Texas Health Science Center and Gulf States Hemophilia and Thrombophilia Center, Houston, TX, USA

    Miguel A. Escobar

  24. Research Institute, Bloodworks and Department of Medicine, University of Washington, Seattle, WA, USA

    Barbara A. Konkle

  25. Division of Hematology, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Carol K. Kasper

  26. Department of Biomedical and Health Informatics, Lifespan Brain Institute, Children’s Hospital of Philadelphia and Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Laura Almasy

  27. Department of Pathology and Laboratory Medicine, VA-Valley Coastal Bend Healthcare System, Harlingen, TX, USA

    Tom E. Howard

Authors
  1. Marcio A. Almeida
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  2. Vincent P. Diego
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  3. Kevin R. Viel
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  4. Bernadette W. Luu
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  5. Karin Haack
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  6. Raja Rajalingam
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  7. Afshin Ameri
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  8. Meera Chitlur
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  9. Natalia Rydz
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  10. David Lillicrap
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  11. Raymond G. Watts
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  12. Craig M. Kessler
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  13. Christopher Ramsey
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  14. Long V. Dinh
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  15. Benjamin Kim
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  16. Jerry S. Powell
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  17. Eron G. Manusov
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  18. Juan M. Peralta
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  19. Ruayda Bouls
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  20. Shirley M. Abraham
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  21. Yu-Min Shen
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  22. Carlos M. Murillo
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  23. Henry Mead
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  24. Paul V. Lehmann
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  25. Eli J. Fine
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  26. Miguel A. Escobar
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  27. Satish Kumar
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  28. Barbara A. Konkle
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  29. Sarah Williams-Blangero
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  30. Carol K. Kasper
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  31. Laura Almasy
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  32. Shelley A. Cole
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  33. John Blangero
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  34. Tom E. Howard
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Contributions

MAA, VPD, and BWL contributed equally. Conceptualization: KRV, DL, CKK, LA, SAC, TEH. IRB approval, patient informed consent and enrollment, data collection, sample acquisition, processing, and shipment: AA, MC, NR, DL, RGW, CMK. Methodology: KRV, BWL, KH, CR, BK, SAC, TEH. Investigation: MAA, VPD, KRV, BWL, KH, CR, LVD, BK, SK, CKK, LA, SAC, TEH. Formal Analysis: MAA, VPD, KRV, JMP, JB. Resources: RR, AA, MC, DL, RGW, CMK, SWV, SAC, JB, TEH. Data Curation: MAA, VPD, KRV, BWL, KH, SAC, TEH. Project Administration: CMK, BAK, CKK, SAC, TEH. Supervision: KRV, DL, CMK, BAK, CKK, SAC, TEH. Writing original manuscript draft: MAA, VPD, TEH. Writing subsequent manuscript drafts: MAA, VPD, TEH. Reviewing and editing of manuscript: MAA, VPD, KRV, BWL, KH, RR, AA, MC, NR, DL, RGW, CMK, CR, LVD, BK, JSP, EGM, JMP, RB, SMA, Y-MS, CMM, HM, PVL, EJF, MAE, SK, BAK, SW-B, CKK, LA, SAC, JB, TEH.

Corresponding authors

Correspondence to Marcio A. Almeida or Tom E. Howard.

Ethics declarations

Competing interests

There are NO relevant conflicts for any co-author. BWL, LVD, JSP, and TEH are respectively the Director of Technical Operations, Director of Drug Discovery, Chief Medical Officer and Chief Scientific Officer of Haplogenics Corporation. Dr. Henry Mead was an employee of BioMarin and is currently a consultant for Haplogenics Corporation. Dr. Paul Lehmann is the Co-Founder, President and CEO of Cellular Technology Limited.

IRB / ethics committee approval and consent to participate

All methods used in the PATH study were performed in accordance with the relevant guidelines and regulations. All human subjects research components of the PATH study were approved by the IRB Committees at the Los Angeles Veterans Affairs Medical Center (IRB: 2009-091280) and Bloodworks Northwest (IRB: 13018). All participants in the PATH study gave informed consent.

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Almeida, M.A., Diego, V.P., Viel, K.R. et al. A scan of pleiotropic immune mediated disease genes identifies novel determinants of baseline FVIII inhibitor status in hemophilia A. Genes Immun 26, 179–189 (2025). https://doi.org/10.1038/s41435-025-00325-7

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