2270: ACKR1 and Leukopenia in Patients with Rheumatoid Arthritis Treated with Disease Modifying Antirheumatic Drugs

Background/Purpose: Disease-modifying antirheumatic drugs (DMARDs) such as methotrexate, sulfasalazine, and leflunomide are
commonly prescribed for RA treatment but carry the risk of leukopenia. The ACKR1 promoter genotype
(rs2814778-CC) has been associated with leukopenia and is predominantly present among individuals of
African ancestry. This study aimed to examine whether leukopenia is more frequent among patients with RA
who carried the rs2814778-CC genotype compared to patients without the rs2814778-CC genotype when
using these DMARDs.

Methods: Retrospective cohort study using the All of Us research program data. We collected genetic and EHR data,
including reported race, as well as laboratory data including white blood cell (WBC) and platelet counts after
starting sulfasalazine, leflunomide, or methotrexate. Leukopenia was defined as a WBC count <3,000
cells/mm³, and thrombocytopenia as a platelet count <100,000 cells/mm³. We utilized short-read whole-
genome sequencing (srWGS) data from the All of Us Curated Data Release (v7), with direct genotyping of the
ACKR1 SNP rs2814778 (C/T). We compared patients of EHR reported Black race with the CC genotype to those
with TT/TC genotypes, as well as to patients of EHR reported White race, because of the known association of
the CC genotype with lower WBC counts among patients of Black race.

Results: Among RA patients, 463 individuals who were prescribed sulfasalazine, leflunomide, or methotrexate and had
recorded WBC counts after diagnosis were included in the study. The median age at RA diagnosis was 66 years
[IQR: 58.0,73.0], and more than 80% of patients were female. Notably, the rs2814778-CC genotype was absent
in the patients of EHR reported White race but found in 68% of the patients of EHR reported Black race. The
overall leukopenia rate was 36.0% in patients of Black race and 30.9% in patients of White race (p= 0.39).
patients of Black race with the CC genotype had the highest leukopenia risk (45.6%), followed by patients of
White race with the TT/TC genotypes (30.9%), while patients of Black race with the TT/TC genotypes had the
lowest risk (15.6%) (P = 0.01), indicating a significant correlation between genotype and leukopenia risk. The
rates of thrombocytopenia were statistically similar across
all groups (P = 1.00).

Conclusion: Our findings emphasize that individuals of black race with the CC genotype had the highest rates of
leukopenia; highlighting the potential impact of the ACKR1 rs2814778-CC genotype on the risk of leukopenia
in patients with RA treated with sulfasalazine, leflunomide, or methotrexate.