Abstract 4342014: Association of ACKR1 Genotype with Cancer Risk in Participants with African Ancestry in the ARIC study

Background: Individuals of African ancestry typically express a null variant in the Duffy antigen receptor for chemokines (DARC), encoded by the ACKR1 gene, which is associated with protection against malaria but enhanced inflammation, a common risk factor for both cardiovascular disease (CVD) and cancer. CVD rates are higher in individuals of African ancestry. We assessed the hypothesis that DARC-null African Americans had higher cancer risk and examined the potential modification by CVD. Methods: We included 3,192 African Americans from the Atherosclerosis Risk in Communities (ARIC) study without prior cancer and followed them from visit 1 (1987-1989) until end of 2015, for cancer diagnosis, death, or loss to follow-up. DARC status (Duffy-null [GG] or positive [AG/AA]) was imputed from rs2814778 SNP genotyping. We used Cox proportional hazards models to estimate hazard ratios (HR) for cancer incidence, adjusted for age, sex, and study center. We tested for interaction with demographic, social and CVD risk factors. We also stratified by baseline CVD status. Results: Participants (median age 53.6 years, 61% females, 69% DARC-null) were followed for a median of 22.4 years (62,120 person-years), during which 966 (30%) were diagnosed with cancer. DARC-positive status was not significantly associated with total cancer (aHR 0.95, 95%CI 0.83-1.09, P=0.49). Similar null associations were observed for smoking-related cancer and obesity-related cancers. However, a significant interaction (P=0.002) between DARC and sex was observed, where DARC-positive males, but not DARC-positive females, had a lower risk of smoking-related cancers (aHR 0.65, 95%CI 0.47-0.90, p=0.009). Among participants who developed incident CVD during follow-up, sensitivity analysis indicated that DARC-positive status was significantly associated with a lower risk of smoking-related cancers (aHR 0.44, 95%CI 0.27-0.71), solid cancers (aHR 0.73, 95%CI 0.55-0.97), and lung cancer (aHR 0.39, 95%CI 0.17-0.88). Conclusion: Among African Americans in the ARIC study, Duffy genotype was not associated with overall cancer risk, irrespective of baseline CVD status. A significant association was observed in men and in those with incident CVD. Together, these data suggest that specific factors might modify the association between DARC and the risk for specific cancers, which warrants further investigation with a larger sample size. Funding: NHLBI, NCI, NPCR, AHA