A genome-wide association study of alloimmunization in the TOPMed OMG-SCD cohort identifies a locus on chromosome 12.
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2024-09
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Abstract
Background
Red cell alloimmunization after exposure to donor red cells is a very common complication of transfusion for patients with sickle cell disease (SCD), resulting frequently in accelerated donor red blood cell destruction. Patients show substantial differences in their predisposition to alloimmunization, and genetic variability is one proposed component. Although several genetic association studies have been conducted for alloimmunization, the results have been inconsistent, and the genetic determinants of alloimmunization remain largely unknown.Study design and methods
We performed a genome-wide association study (GWAS) in 236 African American (AA) SCD patients from the Outcome Modifying Genes in Sickle Cell Disease (OMG-SCD) cohort, which is part of Trans-Omics for Precision Medicine (TOPMed), with whole-genome sequencing data available. We also performed sensitivity analyses adjusting for different sets of covariates and applied different sample grouping strategies based on the number of alloantibodies patients developed.Results
We identified one genome-wide significant locus on chr12 (p = 3.1e-9) with no evidence of genomic inflation (lambda = 1.003). Further leveraging QTL evidence from GTEx whole blood and/or Jackson Heart Study PBMC RNA-Seq data, we identified a number of potential genes, such as ARHGAP9, STAT6, and ATP23, that may be driving the association signal. We also discovered some suggestive loci using different analysis strategies.Discussion
We call for the community to collect additional alloantibody information within SCD cohorts to further the understanding of the genetic basis of alloimmunization in order to improve transfusion outcomes.Type
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Sun, Quan, Matthew S Karafin, Melanie E Garrett, Yun Li, Allison Ashley-Koch and Marilyn J Telen (2024). A genome-wide association study of alloimmunization in the TOPMed OMG-SCD cohort identifies a locus on chromosome 12. Transfusion, 64(9). pp. 1772–1783. 10.1111/trf.17944 Retrieved from https://hdl.handle.net/10161/33596.
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Scholars@Duke
Allison Elizabeth Ashley-Koch
My work focuses on the dissection of human traits using multi-omic technologies (genetics, epigenetics, metabolomics and proteomics). I am investigating the basis of several neurological and psychiatric conditions such as neural tube defects and post-traumatic stress disorder. I also study modifiers of sickle cell disease.
Marilyn Jo Telen
Dr. Telen is recognized as an expert in the biochemistry and molecular genetics of blood group antigens and the pathophysiological mechanisms of vaso-occlusion in sickle cell disease. She is the Director of the Duke Comprehensive Sickle Cell Center.
Dr. Telen's laboratory focuses on structure/function analysis of membrane proteins expressed by erythroid cells, as well as the role of these proteins in non-erythroid cells. Proteins are also studied in transfectant systems, and research focuses especially on adhesion receptors. The goals of this work are (1) to understand the mechanism and role of red cell adhesion to leukocytes and endothelium in sickle cell disease; (2) to understand the signaling mechanisms leading to activation (and inactivation) of red cell adhesion molecules; (3) to understand the molecular basis of blood group antigen expression, and (4) to understand the interactions of erythroid membrane proteins with other cells and with extracellular matrix..
Recent investigations have focused on the role of signaling pathways in the upregulation of sickle red cell adhesion. Present studies include (1) investigation of beta-adrenergic signaling pathway responsible for activation of B-CAM/LU and LW adhesion receptors; (2) understanding how nitric oxide and ATP downregulate sickle red cell adhesion; (3) studying the effect of these processes in animal models.
Dr. Telen is also involved in a large multicenter study looking for genetic polymorphisms that affect clinical outcomes in sickle cell disease, as well as a multi-center study investigating the mechanisms and treatment of pulmonary hypertension in sickle cell disease.
Key Words:
Adhesion molecules
Erythrocyte membrane
Sickle cell disease
Transfusion medicine
Immunohematology
CD44
B-CAM/LU
Genetic polymorphisms
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