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Br J Haematol. 2019 Jun 5. doi: 10.1111/bjh.15998. [Epub ahead of print]

Identification of genetic biomarkers for alloimmunization in sickle cell disease.

Author information

1
Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
2
Department of Paediatric Haematology, Immunology and Infectious Diseases, Emma Children's Hospital, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
3
Department of Plasma Proteins, Sanquin Research and Landsteiner Laboratory, Academic Medical Centre, Univsersity of Amsterdam, Amsterdam, the Netherlands.
4
Department of Haematology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
5
Department of Haematology, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands.
6
Department of Haematology, Haga Hospital, the Hague, the Netherlands.
7
Reference Centre for Sickle Cell Disease, Hôpital Henri Mondor, Créteil, France.
8
Department of Experimental Immunohaematology, Sanquin Research and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
9
Etablissement Français Du Sang Ile de France, INSERM U955, University of Paris Est-Créteil, Hôpital Henri Mondor, Créteil, France.
10
Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
11
Department of Molecular Cell Biology, VU Medical Centre, Amsterdam, the Netherlands.

Abstract

Most sickle cell disease (SCD) patients rely on blood transfusion as their main treatment strategy. However, frequent blood transfusion poses the risk of alloimmunization. On average, 30% of SCD patients will alloimmunize while other patient groups form antibodies less frequently. Identification of genetic markers may help to predict which patients are at risk to form alloantibodies. The aim of this study was to evaluate whether genetic variations in the Toll-like receptor pathway or in genes previously associated with antibody-mediated conditions are associated with red blood cell (RBC) alloimmunization in a cohort of SCD patients. In this case-control study, cases had a documented history of alloimmunization while controls had received ≥20 RBC units without alloantibody formation. We used a customized single nucleotide polymorphism (SNP) panel to genotype 690 SNPs in 275 (130 controls, 145 cases) patients. Frequencies were compared using multiple logistic regression analysis. In our primary analysis, no SNPs were found to be significantly associated with alloimmunization after correction for multiple testing. However, in a secondary analysis with a less stringent threshold for significance we found 19 moderately associated SNPs. Among others, SNPs in TLR1/TANK and MALT1 were associated with a higher alloimmunization risk, while SNPs in STAM/IFNAR1 and STAT4 conferred a lower alloimmunization risk.

KEYWORDS:

TOLL-like receptors; alloimmunization; gene polymorphisms; responder; sickle cell disease

PMID:
31168801
DOI:
10.1111/bjh.15998

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