Background: The Duffy Antigen Receptor for Chemokines (DARC/ACKR1) regulates inflammatory chemokine levels. The functional ACKR1 rs12075 G>A (p.Gly42Asp) polymorphism influences this activity and varies across populations, but studies on its association with human diseases such as coronary artery disease (CAD) are limited. The purpose of this study was to investigate the potential genetic link between this specific variation in the Duffy blood group gene ACKR1 and the risk of developing CAD within a Saudi Arabian population cohort.

Methods: A case-control study of 100 confirmed CAD patients and 100 matched healthy controls was conducted. Genomic DNA was extracted from peripheral blood and genotyped for the ACKR1 rs12075 variant using the Amplification Refractory Mutation System PCR (ARMS-PCR). Allelic and genotypic frequencies were compared using Chi-square tests, and associations with CAD risk were estimated via logistic regression, calculating odds ratios (ORs) with 95% confidence intervals (CI).

Results: The genotype distribution differed significantly between cases and controls (p = 0.0004). The AA genotype frequency was markedly higher in CAD patients (15%) versus controls (2%). In a recessive inheritance model, the AA genotype conferred a significantly increased risk of CAD (OR = 8.64, 95% CI: 1.92–38.90, p = 0.004). The GA genotype was also associated with elevated risk (OR = 2.06, 95% CI: 1.04–4.11, p = 0.037). Furthermore, the AA and GA genotypes showed significant associations with key CAD comorbidities, including hypertension, hyperlipidemia, diabetes mellitus, and a history of myocardial infarction (p < 0.05).

Conclusion: The ACKR1 rs12075 A allele, particularly in the homozygous state, is strongly associated with an increased risk of CAD in a Saudi Arabian cohort and is linked to a more severe clinical phenotype. These findings suggest that this genetic variant may serve as a potential biomarker for CAD susceptibility and severity in this population.