Abstract:
Hemophilia-A (HA) is caused by heterogeneous loss-of-function factor (F)VIII gene (F8)-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 F8-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 F8-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 NOS2A (rs117382854; p=3.2E-6) and B3GNT2 (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 CTLA4 assigned SNPs (p=2.2E-5). The F8-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 F8-mutation-effects and non-F8-genetics.
摘要:
血友病A(HA)是由异质性功能丧失因子(F)VIII基因(F8)突变和血浆FVIII活性缺乏引起的,这损害了内在途径介导的凝血扩增。重度HA患者的标准护理是定期输注治疗性FVIII蛋白(tFVIIIs),但约30%的患者会产生称为“FVIII抑制剂(FEIs)”的中和tFVIII抗体并变得难治性。我们使用PATH研究和Immunochip扫描免疫介导的疾病(IMD)基因,寻找与基线FEI状态相关的新的和/或复制的基因组序列变异,同时考虑由于遗传相关性和F8突变异质性导致的数据不独立。450名北美PATH受试者的基线FEI状态-206名具有非洲黑人血统和244名具有欧洲白人血统-是因变量。将F8突变数据和遗传相关性矩阵并入具有基线FEI状态的遗传关联的二元线性混合模型中。我们采用了以基因为中心的关联策略进行扫描,作为候选人,多效性-IMD-基因牵涉于2种自身免疫/自身炎症性疾病(AAD)或1种AAD和FEI的发展。基线FEI状态与分配给NOS2A(rs117382854;p=3.2E-6)和B3GNT2(rs10176009;p=5.1E-6)的SNP显着相关,具有抗微生物/肿瘤免疫功能。在以前与FEI风险有关的IMD基因中,我们确定了与CTLA4分配的SNP的强关联(p=2.2E-5)。F8突变效应是基线FEI状态总遗传力的约15%的基础。IMD基因中的加性遗传遗传性和SNP占基线FEI状态中>50%的患者特异性变异性。种族是独立于F8突变效应和非F8遗传学的重要决定因素。