Evaluating the clinical implications for ACKR1/DARC associated neutropenia

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Abstract: White blood cell (WBC) counts and neutrophil counts are among the most commonly used medical tests. WBC counts and absolute neutrophil counts (ANC) are monitored closely in the setting of myelosuppressive therapy, and neutropenia is often the dose limiting toxicity when dosing chemotherapy. An elevated WBC count is also used in helping to diagnose and infection and risk stratifying patients with acute bacterial infections. Therefore, accurate interpretation of the WBC and neutrophil count is crucial in many branches of medicine. WBC and neutrophil counts vary substantially by race and ethnicity. African Americans, Latinos with African ancestry and some Middle Eastern populations have lower WBC and lower ANC. We have previously mapped the genetic variant underlying this difference. The variant maps to the promoter region of the Duffy Antigen Receptor Chemokine (DARC/ACKR1) locus and results in lack of expression of the DARC antigen on the surface of red blood cells. The allele which leads to loss of expression (Fya-/b- or Fy-) is the predominant allele in West Africa, but rare outside of Africa and the Middle East. Individuals with Fy-/- genotype have WBC and ANC that is > 1 standard deviation lower than individuals with the other genotype. Despite over a decade of knowledge about this effect, there has been little progress on incorporating this into clinical care. As a result, patients with this genotype who are predominantly African American in the U.S. may receive lower doses of myelosuppressive therapies and may be more likely to have reduced relative dose intensity of chemotherapy which may lead to disparities in outcomes. Since WBC and ANC are used to diagnose and make prognostic inferences among patients with infection, their care in the setting of severe infections may suffer. Therefore, large studies with outcomes are needed to help guide clinicians on how to treat these patients. We propose to leverage large biobanks tied to electronic health records to determine outcomes of patients on myelosuppressive therapies with this genotype and to determine how to use WBC and ANC in the setting of infection. (1) We will examine outcomes of patients on chronic myelosuppressive therapies by genotype. We will determine whether Fy-/- genotype is associated with high incidence of neutropenia on myelosuppressive therapies and whether this leads to dose reductions. We will examine the risk of infectious complications among patients with Fy-/- on myelosuppressive therapies. (2) We will examine outcomes of patients on chemotherapy according to genotype. We will determine if genotype is associated with relative dose intensity of chemotherapy and whether this is associated with differences in overall survival among these patients. We will determine if infectious complications are associated with genotype among patients on chemotherapy. (3) We will examine how WBC and neutrophil to lymphocyte count ratios vary in the setting of acute infections and how this affects diagnostic and prognostic use of these parameters. Our project will help clinicians optimize myelosuppressive therapy and diagnosis of infection among the large number of individuals with this genotype.