Association of duffy antigen receptor for chemokines with clinical conditions: A scoping review Free

Introduction: The Duffy antigen receptor for chemokines (ACKR1) is found on erythrocytes and appears to function as a chemokine sink modulating inflammatory responses. A homozygous polymorphism leading to the lack of ACKR1 expression on erythrocytes, the Duffy-null phenotype, is linked with resistance to Plasmodium vivax which may explain its prevalence in people of African and Middle Eastern ancestry. The Duffy-null phenotype is associated with a lower circulating neutrophil count but preserved total body neutrophil count, an entity called Duffy null-associated neutrophil count (DANC). Thus, DANC is generally considered a normal variant without pathophysiological implications. However, there have been numerous in-vitro studies evaluating for association between ACKR1 presence/absence and inflammation or oncogenesis. Therefore, the aim of this study was to systematically evaluate the existing literature reporting on the association between ACKR1 status and clinical outcomes.

Methods: We conducted a systematic search on Pubmed, MEDLINE, EMBASE, CINAHL, Evidence-Based Medical Reviews, Scopus and Cochrane Central, for all published articles evaluating for association between ACKR1 and clinical outcomes until December 31, 2024. The protocol was registered on OSF Registries. For the purpose of this abstract, the acronym DANC refers to the phenotype or genotype. We included articles which focused on ACKR1 and it's associations with clinical outcomes. We excluded papers which looked at ACKR1 and delay in chemotherapy or treatments, clozapine use and ACKR1 with association with resistance to Plasmodium Vivax. Two independent reviewers screened the titles, abstracts, full texts and extracted data from selected studies with adjudication from a third reviewer as needed.

Results: 1310 article title/abstracts were screened and 144 proceeded to full text screening. 54 articles were included for data extraction. Fourty one studies had a sample size of greater than 100 people. Of the 54 included studies, 14 examined cancer associations (26%), Fourteen studies evaluated for association between ACKR1 and cancer, 12 for infection of which 7 focused on HIV, 3 for autoimmune disease, 3 for cardiovascular disease, 1 for mental illness, and 11 for sickle cell disease. Six (6) breast cancer studies demonstrated: increased incidence (n=2), relapse risk (n=2) and lymph node metastases (n= 2) associated with DANC; 1 did not find association between DANC and breast cancer outcomes. Two studies found association between greater lymph node involvement and DANC in patients with colorectal cancer, one reported decreased survival with DANC in endometrial cancer, 1 showed increased incidence of multiple myeloma and chronic lymphocytic leukemia with DANC, and 1 found worse outcomes in laryngeal squamous cell carcinoma with DANC. Two studies did not find association between prostate cancer outcomes and DANC. One study described less chemotherapy toxicity and longer progression free survival in patients with multiple myeloma and DANC. One study did not find association between DANC and viral or bacterial infection. Of the 7 papers looking at HIV outcomes, there was mixed data on mortality and survival outcomes. Two papers found an association between DANC and incidence of or hospitalization with COVID infection. One study found an association between DANC and Jorge Lobo disease. Three studies found no association between DANC and Behcet's disease, lupus or psoriasis. Of the 3 studies on DANC and cardiovascular disease, 1 found higher risk of cardiovascular events and mortality, 1 found association with malignant hypertension and 1 found no association between DANC and cardiovascular events. 9/11 studies on sickle cell disease did not find an association between DANC and disease severity or outcomes.

Conclusion: We found conflicting evidence on the association between ACKR1 and cancer, infection, cardiovascular and sickle cell disease outcomes. There is likely a complex relationship between the social identity of race, environmental exposures, African genetic ancestry and ACKR1. To our knowledge, this is the first scoping review on this topic. Large prospective and comparative population based studies are required to better understand the potential impacts of ACKR1 status on pathophysiology and access to care on clinical outcomes.