Evaluating the clinical implications for ACKR1/DARC associated neutropenia

评估 ACKR1/DARC 相关中性粒细胞减少症的临床意义

• 批准号: 10754130
• 负责人: Elad Ziv
• 金额: $ 69.29万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10754130
• 关键词: Acute; Address; Affect; Africa; African; African American; African American population; African ancestry; Alleles; Antigen Receptors; Antigens; Asian ancestry; Bacterial Infections; Caring; Chromosome Mapping; Chronic; Clinical; Diagnosis; Diagnostic; Disparity; Dose; Dose Limiting; East Asian; Electronic Health Record; Erythrocytes; Ethnic Origin; European; European ancestry; Fever; Frequencies; Genotype; Incidence; Individual; Infection; Inflammatory; Knowledge; Latino Population; Leukocytes; Link; Lymphocyte Count; Maps; Medical; Medicine; Middle East; Middle Eastern; Monitor; Myelosuppressive Therapy; Neutropenia; Outcome; Patient-Focused Outcomes; Patients; Persons; Pharmaceutical Preparations; Pneumonia; Population; Process; Prognosis; Prognostic Factor; Promoter Regions; Race; Recurrent Malignant Neoplasm; Research; Risk; Sepsis; Severities; Surface; Testing; Toxic effect; Variant; White Blood Cell Count procedure; accurate diagnosis; acute infection; biobank; cancer recurrence; chemokine receptor; chemotherapy; clinical care; cohort; data integration; electronic health database; genetic variant; improved; infection risk; large datasets; neutrophil; outcome prediction; patient stratification; prognostic; prognostication; risk stratification

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.

抽象的： 白细胞 (WBC) 计数和中性粒细胞计数是最常用的医学测试之一。白细胞 在骨髓抑制治疗中密切监测计数和绝对中性粒细胞计数（ANC）， 中性粒细胞减少症通常是化疗时的剂量限制性毒性。白细胞计数也升高 用于帮助诊断、感染和对急性细菌感染患者进行风险分层。所以， 在许多医学分支中，准确解读白细胞和中性粒细胞计数至关重要。白细胞和 中性粒细胞计数因种族和民族的不同而有很大差异。非裔美国人、具有非洲血统的拉丁裔和 一些中东人群的 WBC 和 ANC 较低。我们之前已经绘制了遗传图谱 这种差异背后的变体。该变体映射到达菲抗原受体的启动子区域 趋化因子（DARC/ACKR1）位点并导致红色表面缺乏 DARC 抗原表达 血细胞。导致表达丧失的等位基因（Fya-/b-或Fy-）是西非的主要等位基因， 但在非洲和中东以外地区很少见。具有 Fy-/- 基因型的个体的 WBC 和 ANC > 1 标准差低于具有其他基因型的个体。尽管了解了十多年 尽管存在这种影响，但将其纳入临床护理方面进展甚微。结果，患有这种疾病的患者 在美国以非裔美国人为主的基因型可能会接受较低剂量的骨髓抑制药物 疗法，并且可能更有可能降低化疗的相对剂量强度，这可能导致 结果的差异。由于 WBC 和 ANC 用于诊断和做出预后推断 感染患者，他们在严重感染情况下的护理可能会受到影响。因此，大型研究 需要结果来帮助指导临床医生如何治疗这些患者。我们建议利用大 生物库与电子健康记录相关联，以确定患者接受骨髓抑制治疗的结果 该基因型并确定如何在感染情况下使用 WBC 和 ANC。 (1) 我们将审查 按基因型划分的慢性骨髓抑制治疗患者的结果。我们将确定是否Fy-/- 基因型与骨髓抑制治疗中中性粒细胞减少症的高发生率相关，以及这是否导致 以减少剂量。我们将检查 Fy-/- 患者发生感染并发症的风险 骨髓抑制疗法。 (2)我们将根据基因型检查患者的化疗结果。 我们将确定基因型是否与化疗的相对剂量强度相关，以及这是否与 与这些患者的总生存率差异相关。我们将确定是否有感染性并发症 与化疗患者的基因型相关。 (3) 我们将检查白细胞和中性粒细胞如何 与淋巴细胞计数的比率在急性感染的情况下有所不同，以及这如何影响诊断和预后 使用这些参数。我们的项目将帮助临床医生优化骨髓抑制治疗和诊断 大量具有该基因型的个体中的感染。