Association Between a Common, Benign Genotype and Unnecessary Bone Marrow Biopsies Among African American Patients

Abstract

he observation of lower mean white blood cell (WBC) counts among individuals of African ancestry compared with those of European ancestry is well established. [1][2][3][4] The clinical finding of low WBC counts among healthy individuals of African ancestry is variably designated benign ethnic neutropenia and is not associated with an increased risk of infection. [5][6][7] This phenomenon is attributed, in large part, to homozygosity for the rs2814778-C variant in the promoter of ACKR1 (OMIM 613665) gene. Loss of expression of ACKR1 on cell surfaces may lead to relative neutropenia attributable to sequestration of neutrophils in peripheral tissues, including the spleen. 8 This variant is common (allele frequency, 0.96) among populations in sub-Saharan Africa but uncommon (allele frequency, 0.006) among White populations of European ancestry. [9][10][11][12][13] Approximately 63% of African American individuals, who are of mixed European and African ancestries, have the CC genotype and would be anticipated to have benign ethnic neutropenia. 9 Because reference ranges of normal values for WBC counts do not account for genotype, persons with the rs2814778-CC genotype are more likely to have a WBC count that falls below the reference range. Although many practitioners are aware of IMPORTANCE Up to two-thirds of African American individuals carry the benign rs2814778-CC genotype that lowers total white blood cell (WBC) count.OBJECTIVE To examine whether the rs2814778-CC genotype is associated with an increased likelihood of receiving a bone marrow biopsy (BMB) for an isolated low WBC count. DESIGN, SETTING, AND PARTICIPANTSThis retrospective genetic association study assessed African American patients younger than 90 years who underwent a BMB at

Frequency of benign neutropenia among Black versus White individuals undergoing a bone marrow assessment

“…These data suggest that Black individuals are more susceptible to an unnecessary, invasive, and painful procedure than White individuals due to frequent carriage of a benign genotype. Furthermore, the cost of a bone marrow biopsy at our medical centre is approximately $6000, significantly less than Duffy antigen testing, which costs less than $200 when performed in most laboratories and blood banks 12 . Omission of an unnecessary BMB would decrease health care utilization costs.…”

“…Knowing whether an individual carried the Duffy Null phenotype would indicate whether a lower ANC value may reflect a benign predisposition. In support of a role for genotyping/phenotyping, a retrospective study of individuals of Black race treated at three medical centres who had a BMB to investigate an isolated low white blood cell count, 97% of individuals carried the rs2814778‐CC (Duffy Null) genotype 12 . Furthermore, 97% of the biopsies among genotype carriers demonstrated benign findings.…”

“…Lower baseline neutrophil counts could predispose Black individuals to undergo clinical evaluations, including invasive diagnostic procedures such as bone marrow biopsy (BMB), to identify a pathological cause contributing to the lower counts. Since the lower neutrophil counts among rs2814778‐CC genotype carriers are not associated with underlying disease or other clinically meaningful sequelae, these investigations would not be expected to identify underlying pathology 12 …”

“…Since the lower neutrophil counts among rs2814778‐CC genotype carriers are not associated with underlying disease or other clinically meaningful sequelae, these investigations would not be expected to identify underlying pathology. 12 We hypothesized that, because of the high frequency of the rs2814778‐CC genotype among individuals of Black race, this predisposition to lower neutrophils could result in a measurable race‐related healthcare disparity. To test this hypothesis, we analysed a clinical data set to determine whether Black individuals who underwent an evaluation by a haematologist that included a BMB to investigate a finding of neutropenia were more likely than White individuals to be diagnosed with a clinically insignificant neutropenia.…”

Leveraging genomic diversity for discovery in an EHR-linked biobank: the UCLA ATLAS Community Health Initiative

“…For example, Benign Ethnic Neutropenia (BEN) is observed predominantly in African Americans, but specifically is strongly associated with the variant at rs2814778 [65], [66]. Recent studies have suggested that genotype screening at rs2814778 could aid in the interpretation of neutropenia in African Americans and avoid unnecessary invasive procedures as well as lead to an increase of the inclusion of these individuals to various treatments [67]. Additionally, the Kidney Donor Risk Index (KDRI) equation uses race as a risk factor [68], but it has been recently proposed to use the presence of APOL1 variants as a factor instead [69].…”