PMID- 35814780
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220716
IS  - 2296-858X (Print)
IS  - 2296-858X (Electronic)
IS  - 2296-858X (Linking)
VI  - 9
DP  - 2022
TI  - Genome-Wide Association Study and Gene-Based Analysis of Participants With 
      Hemophilia A and Inhibitors in the My Life, Our Future Research Repository.
PG  - 903838
LID - 10.3389/fmed.2022.903838 [doi]
LID - 903838
AB  - INTRODUCTION: 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. AIM AND METHODS: 
      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. RESULTS: 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. CONCLUSION: 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.
CI  - Copyright (c) 2022 Lessard, He, Rajpal, Klinger, Loh, Harris and Dumont.
FAU - Lessard, Samuel
AU  - Lessard S
AD  - Sanofi S.A., Framingham, MA, United States.
FAU - He, Chunla
AU  - He C
AD  - American Thrombosis and Hemostasis Network, Rochester, NY, United States.
FAU - Rajpal, Deepak K
AU  - Rajpal DK
AD  - Sanofi S.A., Framingham, MA, United States.
FAU - Klinger, Katherine
AU  - Klinger K
AD  - Sanofi S.A., Framingham, MA, United States.
FAU - Loh, Christine
AU  - Loh C
AD  - Bioverativ, a Sanofi Company, Waltham, MA, United States.
FAU - Harris, Tim
AU  - Harris T
AD  - Bioverativ, a Sanofi Company, Waltham, MA, United States.
FAU - Dumont, Jennifer
AU  - Dumont J
AD  - Sanofi S.A., Cambridge, MA, United States.
LA  - eng
PT  - Journal Article
DEP - 20220623
PL  - Switzerland
TA  - Front Med (Lausanne)
JT  - Frontiers in medicine
JID - 101648047
PMC - PMC9260508
OTO - NOTNLM
OT  - genome-wide association study
OT  - hemophilia A
OT  - humans
OT  - inhibitors
OT  - major histocompatibility complex
OT  - whole-genome sequencing
COIS- SL, DR, KK, and JD were employed by Sanofi, DR, KK, and JD hold shares and/or 
      stock options in the company. CL was employed by Nimbus Therapeutics. TH was 
      employed by Repertoire Immune Medicines. The remaining author declares that the 
      research was conducted in the absence of any commercial or financial 
      relationships that could be construed as a potential conflict of interest. This 
      study was funded by Sanofi (Cambridge, MA, United States). The funder had the 
      following involvement with the study: Sanofi (and Sobi) reviewed the manuscript 
      and Sanofi funded editorial support, provided by Ashleigh Pulkoski-Gross, Ph.D., 
      CMPP, and Sheila Longo, Ph.D., of JK Associates Inc., part of Fishawack Health. 
      All authors declare no other competing interests. CL and TH are former employees 
      of Sanofi.
EDAT- 2022/07/12 06:00
MHDA- 2022/07/12 06:01
PMCR- 2022/06/23
CRDT- 2022/07/11 04:22
PHST- 2022/03/24 00:00 [received]
PHST- 2022/05/17 00:00 [accepted]
PHST- 2022/07/11 04:22 [entrez]
PHST- 2022/07/12 06:00 [pubmed]
PHST- 2022/07/12 06:01 [medline]
PHST- 2022/06/23 00:00 [pmc-release]
AID - 10.3389/fmed.2022.903838 [doi]
PST - epublish
SO  - Front Med (Lausanne). 2022 Jun 23;9:903838. doi: 10.3389/fmed.2022.903838. 
      eCollection 2022.