Howard Tom, Almieda Marcio, Diego Vincent, Viel Kevin, Luu Bernadette, Haack Karin, Raja Rajalingam, Ameri Afshin, Chitlur Meera, Rydz Natalia, Lillicrap David, Watts Raymond, Kessler Craig, Ramsey Christopher, Dinh Long, Kim Benjamin, Powell Jerry, Peralta Juan, Bouls Ruayda, Abraham Shirley, Shen Yu-Min, Murillo Carlos, Mead Henry, Lehmann Paul, Fine Eli, Escobar Miguel, Kumar Satish, Williams-Blangero Sarah, Kasper Carol, Almasy Laura, Cole Shelley, Blangero John, Konkle Barbara
University of Texas Rio Grande Valley School of Medicine.
University of California, San Francisco.
Res Sq. 2023 Oct 18:rs.3.rs-3371095. doi: 10.21203/rs.3.rs-3371095/v1.
Hemophilia-A (HA) is caused by heterogeneous loss-of-function factor (F)VIII gene ()-mutations and deficiencies in plasma-FVIII-activity that impair intrinsic-pathway-mediated coagulation-amplification. The standard-of-care for severe-HA-patients is regular infusions of therapeutic-FVIII-proteins (tFVIIIs) but ~30% develop neutralizing-tFVIII-antibodies called "FVIII-inhibitors (FEIs)" and become refractory. We used the PATH study and ImmunoChip to scan immune-mediated-disease (IMD)-genes for novel and/or replicated genomic-sequence-variations associated with baseline-FEI-status while accounting for non-independence of data due to genetic-relatedness and -mutational-heterogeneity. The baseline-FEI-status of 450 North American PATH subjects-206 with black-African-ancestry and 244 with white-European-ancestry-was the dependent variable. The -mutation-data and a genetic-relatedness matrix were incorporated into a binary linear-mixed model of genetic association with baseline-FEI-status. We adopted a gene-centric-association-strategy to scan, as candidates, pleiotropic-IMD-genes implicated in the development of either ³2 autoimmune-/autoinflammatory-disorders (AADs) or ³1 AAD and FEIs. Baseline-FEI-status was significantly associated with SNPs assigned to (rs117382854; p=3.2E-6) and (rs10176009; p=5.1E-6), which have functions in anti-microbial-/-tumoral-immunity. Among IMD-genes implicated in FEI-risk previously, we identified strong associations with assigned SNPs (p=2.2E-5). The -mutation-effect underlies ~15% of the total heritability for baseline-FEI-status. Additive genetic heritability and SNPs in IMD-genes account for >50% of the patient-specific variability in baseline-FEI-status. Race is a significant determinant independent of -mutation-effects and non--genetics.
血友病A（HA）由功能丧失的异质性因子（F）VIII基因（）突变以及血浆FVIII活性缺乏引起，这些会损害内源性途径介导的凝血放大作用。重度HA患者的标准治疗方法是定期输注治疗性FVIII蛋白（tFVIII），但约30%的患者会产生称为“FVIII抑制剂（FEI）”的中和性tFVIII抗体并变得难治。我们利用PATH研究和免疫芯片扫描免疫介导疾病（IMD）基因，以寻找与基线FEI状态相关的新的和/或重复的基因组序列变异，同时考虑到由于遗传相关性和突变异质性导致的数据非独立性。450名北美PATH受试者（206名有非洲黑人血统，244名有欧洲白人血统）的基线FEI状态是因变量。将突变数据和遗传相关性矩阵纳入与基线FEI状态的遗传关联二元线性混合模型。我们采用以基因为中心的关联策略，扫描与至少2种自身免疫/自身炎症性疾病（AAD）或至少1种AAD和FEI发生相关的多效性IMD基因作为候选基因。基线FEI状态与分配给（rs117382854；p = 3.2E - 6）和（rs10176009；p = 5.1E - 6）的单核苷酸多态性（SNP）显著相关，这些SNP在抗微生物/抗肿瘤免疫中发挥作用。在先前涉及FEI风险的IMD基因中，我们发现与分配的SNP有强关联（p = 2.2E - 5）。突变效应约占基线FEI状态总遗传力的15%。IMD基因中的加性遗传力和SNP占基线FEI状态患者特异性变异性的50%以上。种族是一个独立于突变效应和非遗传学的重要决定因素。
