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

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.