Abstract
Many medical treatments, from oncology to psychiatry, can lower white blood cell counts and thus access to these treatments can be restricted to individuals with normal levels of white blood cells, principally in order to minimize risk of serious infection. This adversely affects individuals of African or Middle Eastern ancestries who have on average a reduced number of circulating white blood cells, because of the Duffy-null (CC) genotype at rs2814778 in the ACKR1 gene. Here, we investigate whether the Duffy-null genotype is associated with the risk of infection using the UK Biobank sample and the iPSYCH Danish case-cohort study, two population-based samples from different countries and age ranges. We found that a high proportion of those with the Duffy-null genotype (21%) had a neutrophil count below the threshold often used as a cut-off for access to relevant treatments, compared with 1% of those with the TC/TT genotype. In addition we found that despite its strong association with lower average neutrophil counts, the Duffy-null genotype was not associated with an increased risk of infection, viral or bacterial. These results have widespread implications for the clinical treatment of individuals of African ancestry and indicate that neutrophil thresholds to access treatments could be lowered in individuals with the Duffy-null genotype without an increased risk of infection.
Highlights
It has long been recognized that individuals with an African or certain Middle Eastern ancestries often have reduced numbers of white blood cells, neutrophils, compared with those with European ancestries [1]
Analysis of genetic principal components supports the finding that the CC genotype is not completely congruent with self-reported Black African/Caribbean ethnicity or our definition of African ancestry (Supplementary Material, Fig. S1)
In two samples covering different countries and age ranges, we found that the CC (Duffy-null) genotype at rs2814778, which causes a reduction in the number of circulating neutrophils, does not increase the risk of serious infection
Summary
It has long been recognized that individuals with an African or certain Middle Eastern ancestries often have reduced numbers of white blood cells, neutrophils, compared with those with European ancestries [1]. The Duffy-null (CC) genotype at rs2814778, in the Atypical Chemokine Receptor 1 (ACKR1) gene, previously known as FY and DARC, has been robustly associated with reduced neutrophil counts in individuals of African ancestry [2,3] and is considered to be the cause of benign ethnic neutropenia [4]. Recent studies have indicated that the Duffy-null genotype causes an altered neutrophil morphology that leads to neutrophils egressing from circulating blood into tissues and causing neutropenia [7,8]. This mechanism is thought to be clinically benign because the production and functioning of neutrophils is not reduced and so their ability to fight infection remains unchanged [4]. There have only been a few studies assessing infection outcomes in small clinical cohorts (
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