■高达30%的A型血友病个体会产生替代因子VIII(FVIII)的抑制剂,使治疗无效。抑制剂开发的潜在机制仍然知之甚少。我的生活,我们的未来研究存储库(MLOFRR)收集了F8和F9突变信息,表型数据,以及来自超过11,000名血友病A(HA)和B参与者以及在美国血友病治疗中心注册的携带者的生物材料,包括超过5000个全基因组序列.识别与抑制剂相关的基因可能有助于我们理解为什么某些患者会产生这些中和抗体。
■这里,我们进行了全基因组关联研究和基于基因的分析,以鉴定来自MLOFRR的HA参与者中与抑制剂相关的基因.
■我们在具有F8内含子倒置的HA的参与者中,在人类白细胞抗原(HLA)基因座内发现了全基因组的显着关联。HLA分型显示与HLA等位基因主要组织相容性复合体的独立关联,二级,DRβ1(HLADRB1*15:01)和主要组织相容性复合体,二级,DQβ1(DQB1*03:03)。变体聚集测试进一步鉴定了GRID2IP(谷氨酸受体,离子型,δ2[GRID2]相互作用蛋白1)与抑制剂显著相关。
■总的来说,我们的研究证实了DRB1*15:01与FVIII抑制剂的相关性,并在携带F8内含子倒置的HA患者中发现了DQB1*03:03的新相关性.此外,我们的结果暗示GRID2IP,编码GRID2相互作用蛋白,随着抑制剂的发展,并暗示了该基因在自身免疫中的作用。
UNASSIGNED: Up to 30% of individuals with hemophilia A develop inhibitors to replacement factor VIII (FVIII), rendering the treatment ineffective. The underlying mechanism of inhibitor development remains poorly understood. The My Life, Our Future Research Repository (MLOF RR) has gathered F8 and F9 mutational information, phenotypic data, and biological material from over 11,000 participants with hemophilia A (HA) and B as well as carriers enrolled across US hemophilia treatment centers, including over 5,000 whole-genome sequences. Identifying genes associated with inhibitors may contribute to our understanding of why certain patients develop those neutralizing antibodies.
UNASSIGNED: Here, we performed a genome-wide association
study and gene-based analyses to identify genes associated with inhibitors in participants with HA from the MLOF RR.
UNASSIGNED: We identify a genome-wide significant association within the human leukocyte antigen (HLA) locus in participants with HA with F8 intronic inversions. HLA typing revealed independent associations with the HLA alleles major histocompatibility complex, class II, DR beta 1 (HLA DRB1*15:01) and major histocompatibility complex, class II, DQ beta 1 (DQB1*03:03). Variant aggregation tests further identified low-frequency variants within GRID2IP (glutamate receptor, ionotropic, delta 2 [GRID2] interacting protein 1) significantly associated with inhibitors.
UNASSIGNED: Overall, our
study confirms the association of DRB1*15:01 with FVIII inhibitors and identifies a novel association of DQB1*03:03 in individuals with HA carrying intronic inversions of F8. In addition, our results implicate GRID2IP, encoding GRID2-interacting protein, with the development of inhibitors, and suggest an unrecognized role of this gene in autoimmunity.