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<p>Hemophilia-A (HA) is the X-linked bleeding disorder caused by heterogeneous factor (F)VIII gene (<i>F8</i>)-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-<i>F8</i>-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 <i>NOS2A</i> (rs117382854; <i>p</i> = 3.2 × 10<sup>−6</sup>) and <i>B3GNT2</i> (rs10176009; <i>p</i> = 5.1 × 10<sup>−6</sup>)—pleiotropic-IMD-genes known previously to function in anti-microbial-/-tumoral-immunity but not in the development of FEIs—and confirmed associations with <i>CTLA4</i> (rs231780; <i>p</i> = 2.2 × 10<sup>−5</sup>). We also found that baseline-FEI-status has a substantial heritability (~55%) that involves (i) a <i>F8</i>-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 <i>F8</i>-mutation-types and non-<i>F8</i>-genetics.</p>

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

  • 期刊论文

  • 发表日期：

    2025年4月22日

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  • Marcio A. Almeida,
  • Vincent P. Diego,
  • Kevin R. Viel,
  • Bernadette W. Luu,
  • Karin Haack,
  • Raja Rajalingam,
  • Afshin Ameri,
  • Meera Chitlur,
  • Natalia Rydz,
  • David Lillicrap,
  • Raymond G. Watts,
  • Craig M. Kessler,
  • Christopher Ramsey,
  • Long V. Dinh,
  • Benjamin Kim,
  • Jerry S. Powell,
  • Eron G. Manusov,
  • Juan M. Peralta,
  • Ruayda Bouls,
  • Shirley M. Abraham,
  • Yu-Min Shen,
  • Carlos M. Murillo,
  • Henry Mead,
  • Paul V. Lehmann,
  • Eli J. Fine,
  • Miguel A. Escobar,
  • Satish Kumar,
  • Barbara A. Konkle,
  • Sarah Williams-Blangero,
  • Carol K. Kasper,
  • Laura Almasy,
  • Shelley A. Cole,
  • John Blangero,
  • Tom E. Howard

摘要

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.