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Admixture Mapping Identifies an African Ancestry-associated Ackr1 Effect on Leukocyte Counts in Brazilian Sickle Cell Disease Patients

Year: 2026

Type: article

Abstract: Introduction Sickle-cell disease (SCD) is a monogenic disorder caused by mutations in the HBB gene and is characterized by substantial clinical heterogeneity, with leukocyte counts contributing to inflammation, vaso-occlusive complications, and disease severity. The sickle HBB mutations and the Duffy-null (ACKR1) variant are common in populations with African ancestry due to malaria-driven selection. Although ACKR1 has been associated with leukocyte counts in healthy, non-admixed populations, the contribution of local ancestry to leukocyte variability in individuals with SCD, particularly in highly admixed populations, remains largely unexplored. Objectives To investigate associations between local ancestry and leukocyte counts in a Brazilian SCD cohort using admixture mapping. Identifying ancestry-specific genetic modifiers of leukocyte counts may improve our understanding of the biological mechanisms underlying interindividual variability in inflammatory and clinical phenotypes in highly admixed populations. Material and Methods We analyzed whole-genome sequencing data from 2,533 Brazilian individuals with SCD from the REDS-III cohort. Mean leukocyte counts were quantile normalized. Global and local ancestry were inferred using ADMIXTURE and G-Nomix, respectively. Associations between local ancestry and leukocyte counts were evaluated by admixture mapping using linear mixed models adjusted for demographic, clinical, population structure, and relatedness covariates. Results We identified a significant ancestry-associated region on chromosome 1 (158.7‒160.1 Mb), where African local ancestry was associated with lower leukocyte counts (p=2.12×10 -7 ). The association was driven by rs2814778 (-67T>C) in the ACKR1 gene, which defines the Duffy-null allele. Although Duffy-null genotypes were more frequent among individuals with higher African ancestry, substantial overlap in genome-wide ancestry distributions was observed across genotype groups, reflecting the heterogeneous ancestry backgrounds of this admixture cohort. Discussion and Conclusions Local ancestry and the Duffy-null (ACKR1) variant remain important determinants of leukocyte counts in individuals with SCD despite chronic inflammation, highlighting the value of integrating local ancestry and functional genetic variation to understand hematological variability in admixed populations. Since Duffy-null status is only partially explained by genome-wide ancestry, locus-specific genetic information complements ancestry estimates in admixed populations.

Source: Hematology Transfusion and Cell Therapy

DOI: 10.1016/j.htct.2026.106608