{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Instituto de Biociências da Universidade de São Paulo (USP), São Paulo, SP, Brazil",
    "Fundação Pró-Sangue Hemocentro de São Paulo, São Paulo, SP, Brazil",
    "Department of Genetics of University of North Carolina, United States",
    "Departamento de Ciência da Computação da Universidade de São Paulo (USP), São Paulo, SP, Brazil",
    "Instituto de Medicina Tropical da Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brazil",
    "Hemorio, Rio de Janeiro, RJ, Brazil",
    "Fundação de Hematologia e Hemoterapia de Pernambuco (Hemope), Recife, PE, Brazil",
    "Fundação Hemominas (FH), Juiz de Fora, MG, Brazil",
    "Vitalant Research Institute, United States",
    "Benioff Children's Hospital Oakland, United States",
    "Department of Pharmaceutical Sciences of the Universidade de São Paulo (USP), São Paulo, SP, Brazil"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 13,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Carlos Henrique PASSOS"
    },
    {
      "affs": [
        0
      ],
      "name": "Kelly NUNES"
    },
    {
      "affs": [
        1
      ],
      "name": "Carla Luana DINARDO"
    },
    {
      "affs": [
        2
      ],
      "name": "Andréa Roseli Vançan Russo HORIMOTO"
    },
    {
      "affs": [
        3
      ],
      "name": "Mina Cintho OZAHATA"
    },
    {
      "affs": [
        4
      ],
      "name": "Ester Cerdeira SABINO"
    },
    {
      "affs": [
        5
      ],
      "name": "Luiz AMORIM"
    },
    {
      "affs": [
        6
      ],
      "name": "Alessandra FERRAZ"
    },
    {
      "affs": [
        7
      ],
      "name": "André Rolim BELISáRIO"
    },
    {
      "affs": [
        8
      ],
      "name": "Brian CUSTER"
    },
    {
      "affs": [
        9
      ],
      "name": "Shannon KELLY"
    },
    {
      "affs": [
        10
      ],
      "name": "Thamy Caroline de Souza SILVA"
    },
    {
      "affs": [
        0
      ],
      "name": "Diogo MEYER"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/d827zdzqpp8nn.bib",
  "cited_by": 0,
  "doi": "10.1016/j.htct.2026.106608",
  "fulltext_url": "http://www.sciencedirect.com/science/article/pii/S253113792600355X",
  "id": "d827zdzqpp8nn",
  "issns": [
    "2531-1379",
    "2531-1387"
  ],
  "landing_url": "https://doi.org/10.1016/j.htct.2026.106608",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "lcc",
      "RC633-647.5"
    ],
    [
      "openalex",
      "2716|Hemoglobinopathies and Related Disorders"
    ]
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  "openalex": "W7223147656",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-23",
  "publisher": "Elsevier",
  "ris": "https://research.draconitic.com/paper/d827zdzqpp8nn.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T13:43:19Z",
      "native_id": "637e567dde7e4f74afdb2dcb1de512b7",
      "source": "doaj",
      "url": "https://doi.org/10.1016/j.htct.2026.106608"
    }
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  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2716|Hemoglobinopathies and Related Disorders",
      "subfield": "human-genetics"
    }
  ],
  "title": "ADMIXTURE MAPPING IDENTIFIES AN AFRICAN ANCESTRY-ASSOCIATED ACKR1 EFFECT ON LEUKOCYTE COUNTS IN BRAZILIAN SICKLE CELL DISEASE PATIENTS",
  "title_text": "ADMIXTURE MAPPING IDENTIFIES AN AFRICAN ANCESTRY-ASSOCIATED ACKR1 EFFECT ON LEUKOCYTE COUNTS IN BRAZILIAN SICKLE CELL DISEASE PATIENTS",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T13:43:19Z",
  "url": "https://research.draconitic.com/paper/d827zdzqpp8nn",
  "venue": "Hematology, Transfusion and Cell Therapy",
  "versions": []
}