Diversity of variant alleles encoding Kidd, Duffy, and Kell antigens in individuals with sickle cell disease using whole genome sequencing data from the NHLBI TOPMed Program

Abstract

Background Genetic variants in the SLC14A1, ACKR1, and KEL genes, which encode Kidd, Duffy, and Kell red blood cell antigens, respectively, may result in weakened expression of antigens or a null phenotype. These variants are of particular interest to individuals with sickle cell disease (SCD), who frequently undergo chronic transfusion therapy with antigen‐matched units. The goal was to describe the diversity and the frequency of variants in SLC14A1, ACKR1, and KEL genes among individuals with SCD using whole genome sequencing (WGS) data. Study Design and Methods Two large SCD cohorts were studied: the Recipient Epidemiology and Donor Evaluation Study III (REDS‐III) (n = 2634) and the Outcome Modifying Gene in SCD (OMG) (n = 640). Most of the studied individuals were of mixed origin. WGS was performed as part of the National Heart, Lung, and Blood Institute's Trans‐Omics for Precision Medicine (TOPMed) program. Results In SLC14A1, variants included four encoding a weak Jka phenotype and five null alleles (JKnull). JKA*01N.09 was the most common JKnull. One possible JKnull mutation was novel: c.812G>T. In ACKR1, identified variants included two that predicted Fyx (FY*X) and one corresponding to the c.‐67T>C GATA mutation. The c.‐67T>C mutation was associated with FY*A (FY*01N.01) in four participants. FY*X was identified in 49 individuals. In KEL, identified variants included three null alleles (KEL*02N.17, KEL*02N.26, and KEL*02N.04) and one allele predicting Kmod phenotype, all in heterozygosity. Conclusions We described the diversity and distribution of SLC14A1, ACKR1, and KEL variants in two large SCD cohorts, comprising mostly individuals of mixed ancestry. This information may be useful for planning the transfusion support of patients with SCD.

The Recipient Epidemiology and Donor Evaluation Study‐IV‐Pediatric (REDS‐IV‐P): A research program striving to improve blood donor safety and optimize transfusion outcomes across the lifespan

“…Another study objective is to optimize RBC unit characteristics that patients with SCD and thalassemia receive (beyond RBC phenotype matching for Rh C, E and K antigens), so as to minimize iron loading and iron toxicity. 40 Thus, aim 2 will measure markers of hemolysis and iron parameters before and two hours after single-unit transfusion in simply transfused patients with SCD (in both the US and Brazil), thalassemia (US only), or in pediatric patients with a hematologic/oncologic diagnosis and a hypo-proliferative bone marrow (US only). Since anemia in these patient populations is due to differing pathophysiology, it is hypothesized that the relationship between blood donor, manufacturing, and recipient factors and change in serum iron after transfusion will differ by disease.…”

“…Iron‐related tissue toxicity is a major cause of morbidity and mortality in regularly transfused patients. Another study objective is to optimize RBC unit characteristics that patients with SCD and thalassemia receive (beyond RBC phenotype matching for Rh C, E and K antigens), so as to minimize iron loading and iron toxicity 40 . Thus, aim 2 will measure markers of hemolysis and iron parameters before and two hours after single‐unit transfusion in simply transfused patients with SCD (in both the US and Brazil), thalassemia (US only), or in pediatric patients with a hematologic/oncologic diagnosis and a hypo‐proliferative bone marrow (US only).…”

Proceedings of the 2022 NHLBI and OASH state of the science in transfusion medicine symposium

“…Patients from different population groups experience higher rates of transfusion‐associated non‐infectious adverse events, in part due to genetic differences between donors and recipients in red blood cell groups (Rh), platelet and human leukocyte antigens (HLA) 52,72,73 . Adverse events include alloimmunization, delayed hemolytic transfusion reactions (DHTR), and poor stem cell engraftment which are associated with significant morbidity and mortality 74 .…”

Current advances in transfusion medicine 2021: A critical review of selected topics by the AABB Clinical Transfusion Medicine Committee

“…Rh variants in SCD patients have been extensively studied, but variant alleles of Kell, Kidd, and Duffy blood group systems are less characterized. Dinardo et al performed WGS on 3274 patients to assess diversity and frequency of variant alleles in these systems 40 . Investigators identified variant alleles conferring null phenotypes or weakened expression, while also identifying several novel alleles.…”

“…Dinardo et al performed WGS on 3274 patients to assess diversity and frequency of variant alleles in these systems. 40 Investigators identified variant alleles conferring null phenotypes or weakened expression, while also identifying several novel alleles.…”