ADMIXTURE MAPPING IDENTIFIES AN AFRICAN ANCESTRY-ASSOCIATED ACKR1 EFFECT ON LEUKOCYTE COUNTS IN BRAZILIAN SICKLE CELL DISEASE PATIENTS

@article{passos2026admixture,
  title = {{ADMIXTURE MAPPING IDENTIFIES AN AFRICAN ANCESTRY-ASSOCIATED ACKR1 EFFECT ON LEUKOCYTE COUNTS IN BRAZILIAN SICKLE CELL DISEASE PATIENTS}},
  author = {Carlos Henrique PASSOS and Kelly NUNES and Carla Luana DINARDO and Andréa Roseli Vançan Russo HORIMOTO and Mina Cintho OZAHATA and Ester Cerdeira SABINO and Luiz AMORIM and Alessandra FERRAZ and André Rolim BELISáRIO and Brian CUSTER and Shannon KELLY and Thamy Caroline de Souza SILVA and Diogo MEYER},
  journal = {Hematology, Transfusion and Cell Therapy},
  year = {2026},
  month = oct,
  doi = {10.1016/j.htct.2026.106608},
  url = {https://doi.org/10.1016/j.htct.2026.106608},
  note = {CC BY},
}

TY  - JOUR
TI  - ADMIXTURE MAPPING IDENTIFIES AN AFRICAN ANCESTRY-ASSOCIATED ACKR1 EFFECT ON LEUKOCYTE COUNTS IN BRAZILIAN SICKLE CELL DISEASE PATIENTS
AU  - Carlos Henrique PASSOS
AU  - Kelly NUNES
AU  - Carla Luana DINARDO
AU  - Andréa Roseli Vançan Russo HORIMOTO
AU  - Mina Cintho OZAHATA
AU  - Ester Cerdeira SABINO
AU  - Luiz AMORIM
AU  - Alessandra FERRAZ
AU  - André Rolim BELISáRIO
AU  - Brian CUSTER
AU  - Shannon KELLY
AU  - Thamy Caroline de Souza SILVA
AU  - Diogo MEYER
PY  - 2026
DA  - 2026/10/23
JO  - Hematology, Transfusion and Cell Therapy
DO  - 10.1016/j.htct.2026.106608
UR  - https://doi.org/10.1016/j.htct.2026.106608
AB  - 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.
SN  - 2531-1379
SN  - 2531-1387
ER  -