A locus on chromosome 5 shows African ancestry–limited association with alloimmunization in sickle cell disease

Abstract

Red blood cell (RBC) transfusion remains a critical therapeutic intervention in sickle cell disease (SCD); however, the apparent propensity of some patients to regularly develop RBC alloantibodies after transfusion presents a significant challenge to finding compatible blood for so-called alloimmunization responders. Predisposing genetic loci have long been thought to contribute to the responder phenomenon, but to date, no definitive loci have been identified. We undertook a genome-wide association study of alloimmunization responder status in 267 SCD multiple transfusion recipients, using genetic estimates of ancestral admixture to bolster our findings. Analyses revealed single nucleotide polymorphisms (SNPs) on chromosomes 2 and 5 approaching genome-wide significance (minimum P = 2.0 × 10−8 and 8.4 × 10−8, respectively), with local ancestry analysis demonstrating similar levels of admixture in responders and nonresponders at implicated loci. Association at chromosome 5 was nominally replicated in an independent cohort of 130 SCD transfusion recipients, with meta-analysis surpassing genome-wide significance (rs75853687, Pmeta = 6.6 × 10−9), and this extended to individuals forming multiple (>3) alloantibodies (Pmeta = 9.4 × 10−5). The associated variant is rare outside of African populations, and orthogonal genome-wide haplotype analyses, contingent on local ancestry, revealed genome-wide significant sharing of a ∼60-kb haplotype of African ancestry at the chromosome 5 locus (Bayes Factor = 4.95). This locus overlaps a putative cis-acting enhancer predicted to regulate transcription of ADRA1B and the lncRNA LINC01847, both members of larger ontologies associated with immune regulation. Our findings provide potential insights to the pathophysiology underlying the development of alloantibodies and implicate non-RBC ancestry-limited loci in the susceptibility to alloimmunization.

Human leukocyte antigen (HLA) class I antibodies and transfusion support in paediatric HLA‐matched haematopoietic cell transplant for sickle cell disease

“…A question raised by this secondary analysis is why pre‐HCT HLA class I antibodies are associated with acute GVHD in our patients undergoing solely HLA‐matched HCT. It is possible that “responders,” who form HLA alloantibodies in the first place, are immunologically distinct from “non‐responders” (Bao et al , ; Tatari‐Calderone et al , ; Zhong et al , ; Nickel et al , ; Vingert et al , ; Godefroy et al , ; Verduin et al , ; Maluskova et al , ; Sippert et al , ; Williams et al , ). We and others have previously shown that patients with HLA alloantibodies are more likely to form other types of antibodies (specifically RBC antibodies), independent of transfusion burden (Brantley & Ramsey, ; van de Watering et al , ; McPherson et al , ; Nickel et al , ; Belizaire et al , ).…”

Red cell transfusion and alloimmunization in sickle cell disease

“…65,66 Efforts to identify genetic markers for alloimmunization in patients with SCD have demonstrated moderate associations but no strong predictors. 67,68 Patients with high baseline levels of inflammation, such as those with autoimmune disease, have higher rates of alloimmunization. 40 SCD is a chronic inflammatory state in which hemolysis results in elevated levels of circulating hemoglobin and free heme, activating neutrophils and macrophages and causing secretion of pro-inflammatory cytokines.…”

“… 65 , 66 Efforts to identify genetic markers for alloimmunization in patients with SCD have demonstrated moderate associations but no strong predictors. 67 , 68 …”

Red blood cell alloimmunization and sickle cell disease: a narrative review on antibody induction

“…SNPs found to be associated with alloimmunization prevention included those in STAM (encoding a protein involved in downstream signaling of cytokine receptors including IL-2 and GM-CSF), STAT4, and IFNAR ( 112 ). A different group reported a regulatory locus on Chromosome 5 to be associated with RBC alloantibody formation ( 113 ), with the same group reporting no large-effect SNPs in a smaller study of alloimmunized and non-alloimmunized people with SCD ( 114 ).…”