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

Marcio A Almeida^#¹, Vincent P Diego^#², Kevin R Viel^#³, Bernadette W Luu^#⁴, Karin Haack⁵, Raja Rajalingam⁶, Afshin Ameri⁷, Meera Chitlur⁸, Natalia Rydz⁹, David Lillicrap¹⁰, Raymond G Watts¹¹, Craig M Kessler¹², Christopher Ramsey¹³, Long V Dinh⁴, Benjamin Kim¹⁴, Jerry S Powell^{4

15}, Eron G Manusov², Juan M Peralta², Ruayda Bouls¹⁶, Shirley M Abraham¹⁷, Yu-Min Shen¹⁸, Carlos M Murillo¹⁹, Henry Mead²⁰, Paul V Lehmann^{21

22}, Eli J Fine²³, Miguel A Escobar²⁴, Satish Kumar², Barbara A Konkle²⁵, Sarah Williams-Blangero², Carol K Kasper²⁶, Laura Almasy²⁷, Shelley A Cole⁵, John Blangero², Tom E Howard^{28

29

30}

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.Almeida@utrgv.edu.
² South Texas Diabetes and Obesity Institute, and Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley, Brownsville, TX, USA.
³ Histonis, Inc., Portsmouth, NH, USA.
⁴ Haplogenics Corporation, Brownsville, TX, USA.
⁵ Population Health Program, Texas Biomedical Research Institute, San Antonio, TX, USA.
⁶ Immunogenetics and Transplantation Laboratory, Department of Surgery, School of Medicine, University of California at San Francisco, San Francisco, CA, USA.
⁷ Department of Pediatrics, Division of Hematology and Oncology, Georgia Health Sciences University, Augusta, GA, USA.
⁸ Children's Hospital of Michigan, Wayne State University, Pediatric Hematology and Oncology, Detroit, MI, USA.
⁹ Division of Hematology and Hematological Malignancies, Department of Medicine, University of Calgary, Calgary, AB, Canada.
¹⁰ Department of Pathology and Molecular Medicine, Queen's University at Kingston, Kingston, ON, Canada.
¹¹ Louisiana State University Health Sciences Center, New Orleans, LA, USA.
¹² Georgetown University, Washington, DC, USA.
¹³ Clever Culture Systems, San Diego, CA, USA.
¹⁴ Consultant, Brisbane, CA, USA.
¹⁵ Division of Hematology and Oncology, Department of Internal Medicine, School of Medicine, University of California at Davis, Davis, CA, USA.
¹⁶ School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX, USA.
¹⁷ Division of Hematology and Oncology, Department of Pediatrics, School of Medicine, University of New Mexico, Albuquerque, NM, USA.
¹⁸ Division of Hematology and Oncology, Department of Internal Medicine, School of Medicine, University of Texas Southwestern, Dallas, TX, USA.
¹⁹ 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.
²⁰ Global Medical Affairs, BioMarin, Novato, CA, USA.
²¹ Departments of Pathology and Neurology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
²² Cellular Technology Ltd, Shaker Heights, OH, USA.
²³ Consultant, Atlanta, GA, USA.
²⁴ Division of Hematology and Oncology, Department of Medicine, University of Texas Health Science Center and Gulf States Hemophilia and Thrombophilia Center, Houston, TX, USA.
²⁵ Research Institute, Bloodworks and Department of Medicine, University of Washington, Seattle, WA, USA.
²⁶ Division of Hematology, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
²⁷ 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.
²⁸ South Texas Diabetes and Obesity Institute, and Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley, Brownsville, TX, USA. Tom.Howard@utrgv.edu.
²⁹ Haplogenics Corporation, Brownsville, TX, USA. Tom.Howard@utrgv.edu.
³⁰ Department of Pathology and Laboratory Medicine, VA-Valley Coastal Bend Healthcare System, Harlingen, TX, USA. Tom.Howard@utrgv.edu.

^# Contributed equally.

PMID: 40263602
DOI: 10.1038/s41435-025-00325-7

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

Marcio A Almeida et al. Genes Immun. 2025 Jun.

. 2025 Jun;26(3):179-189.

doi: 10.1038/s41435-025-00325-7. Epub 2025 Apr 22.

Authors

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.Almeida@utrgv.edu.
² South Texas Diabetes and Obesity Institute, and Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley, Brownsville, TX, USA.
³ Histonis, Inc., Portsmouth, NH, USA.
⁴ Haplogenics Corporation, Brownsville, TX, USA.
⁵ Population Health Program, Texas Biomedical Research Institute, San Antonio, TX, USA.
⁶ Immunogenetics and Transplantation Laboratory, Department of Surgery, School of Medicine, University of California at San Francisco, San Francisco, CA, USA.
⁷ Department of Pediatrics, Division of Hematology and Oncology, Georgia Health Sciences University, Augusta, GA, USA.
⁸ Children's Hospital of Michigan, Wayne State University, Pediatric Hematology and Oncology, Detroit, MI, USA.
⁹ Division of Hematology and Hematological Malignancies, Department of Medicine, University of Calgary, Calgary, AB, Canada.
¹⁰ Department of Pathology and Molecular Medicine, Queen's University at Kingston, Kingston, ON, Canada.
¹¹ Louisiana State University Health Sciences Center, New Orleans, LA, USA.
¹² Georgetown University, Washington, DC, USA.
¹³ Clever Culture Systems, San Diego, CA, USA.
¹⁴ Consultant, Brisbane, CA, USA.
¹⁵ Division of Hematology and Oncology, Department of Internal Medicine, School of Medicine, University of California at Davis, Davis, CA, USA.
¹⁶ School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX, USA.
¹⁷ Division of Hematology and Oncology, Department of Pediatrics, School of Medicine, University of New Mexico, Albuquerque, NM, USA.
¹⁸ Division of Hematology and Oncology, Department of Internal Medicine, School of Medicine, University of Texas Southwestern, Dallas, TX, USA.
¹⁹ 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.
²⁰ Global Medical Affairs, BioMarin, Novato, CA, USA.
²¹ Departments of Pathology and Neurology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
²² Cellular Technology Ltd, Shaker Heights, OH, USA.
²³ Consultant, Atlanta, GA, USA.
²⁴ Division of Hematology and Oncology, Department of Medicine, University of Texas Health Science Center and Gulf States Hemophilia and Thrombophilia Center, Houston, TX, USA.
²⁵ Research Institute, Bloodworks and Department of Medicine, University of Washington, Seattle, WA, USA.
²⁶ Division of Hematology, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
²⁷ 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.
²⁸ South Texas Diabetes and Obesity Institute, and Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley, Brownsville, TX, USA. Tom.Howard@utrgv.edu.
²⁹ Haplogenics Corporation, Brownsville, TX, USA. Tom.Howard@utrgv.edu.
³⁰ Department of Pathology and Laboratory Medicine, VA-Valley Coastal Bend Healthcare System, Harlingen, TX, USA. Tom.Howard@utrgv.edu.

^# Contributed equally.

PMID: 40263602
DOI: 10.1038/s41435-025-00325-7

Erratum in

Correction: A scan of pleiotropic immune mediated disease genes identifies novel determinants of baseline FVIII inhibitor status in hemophilia A.
Almeida MA, Diego VP, Viel KR, Luu BW, Haack K, Rajalingam R, Ameri A, Chitlur M, Rydz N, Lillicrap D, Watts RG, Kessler CM, Ramsey C, Dinh LV, Kim B, Powell JS, Manusov EG, Peralta JM, Bouls R, Abraham SM, Shen YM, Murillo CM, Mead H, Lehmann PV, Fine EJ, Escobar MA, Kumar S, Konkle BA, Williams-Blangero S, Kasper CK, Almasy L, Cole SA, Blangero J, Howard TE. Almeida MA, et al. Genes Immun. 2025 Dec;26(6):626. doi: 10.1038/s41435-025-00345-3. Genes Immun. 2025. PMID: 40999024 No abstract available.

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.

PubMed Disclaimer

Conflict of interest statement

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.

Update of

A Scan of Pleiotropic Immune Mediated Disease Genes Identifies Novel Determinants of Baseline FVIII Inhibitor Status in Hemophilia-A.
Howard T, Almieda M, Diego V, Viel K, Luu B, Haack K, Raja R, Ameri A, Chitlur M, Rydz N, Lillicrap D, Watts R, Kessler C, Ramsey C, Dinh L, Kim B, Powell J, Peralta J, Bouls R, Abraham S, Shen YM, Murillo C, Mead H, Lehmann P, Fine E, Escobar M, Kumar S, Williams-Blangero S, Kasper C, Almasy L, Cole S, Blangero J, Konkle B. Howard T, et al. Res Sq [Preprint]. 2023 Oct 18:rs.3.rs-3371095. doi: 10.21203/rs.3.rs-3371095/v1. Res Sq. 2023. Update in: Genes Immun. 2025 Jun;26(3):179-189. doi: 10.1038/s41435-025-00325-7. PMID: 37886476 Free PMC article. Updated. Preprint.

References

1. Franchini M, Mannucci PM. Hemophilia A in the third millennium. Blood Rev. 2013;27:179–84. - PubMed - DOI
1. Klintman J, Berntorp E. Epidemiological aspects of inhibitor development in hemophilia and strategies of management. Expert Opin Orphan Drugs. 2016;4:153–68. - DOI
1. Lai JD, Lillicrap D. Factor VIII inhibitors: Advances in basic and translational science. Int J Lab Hematol. 2017;39:6–13. - PubMed - DOI
1. Cormier M, Batty P, Tarrant J, Lillicrap D. Advances in knowledge of inhibitor formation in severe haemophilia A. Br J Haematol. 2020;189:39–53. - PubMed - DOI
1. Graw J, Brackmann HH, Oldenburg J, Schneppenheim R, Spannagl M, Schwaab R. Haemophilia A: from mutation analysis to new therapies. Nat Rev Genet. 2005;6:488–501. - PubMed - DOI

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions

Grants and funding

C06 RR020547/RR/NCRR NIH HHS/United States

LinkOut - more resources

Full Text Sources
- Nature Publishing Group
Medical
- MedlinePlus Health Information
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

Update of

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous