Apolipoprotein E gene & PSA levels in Black men

Background/Significance: Prostate cancer (Pca) is more prevalent among African American (AA) men compared to men of other racial and ethnic groups. Apolipoprotein E (APOE) plays a critical role in lipid metabolism and facilitates cholesterol and lipid transport, with its isoforms potentially impacting cancer progression. Prostate-specific antigen (PSA) is a biomarker of Pca and elevated PSA levels may predict the presence of Pca in patients. Our study investigates the genetic factors underlying this disparity, with a specific focus on the APOE gene and its role in prostate cancer cell proliferation. In this study, we aim to conduct an in-depth analysis of the APOE gene locus, examining isoform differentiation and its relationship to PSA elevation in African American men. Methods: APOE SNP-level (rs429358, rs7412, rs440446) and haplotype-level analyses were performed using linear and logistic regression and haplotype-based modeling (R package haplostats). Models adjusted for age, West African genetic ancestry (WAA), vitamin D, case-control status, and PSA when applicable. Analyses were conducted separately after quality control in 1,370 men of west African ancestry from Washington DC (N=648), Columbia, SC (N=632) and Cameroon west Africa (Bamileke, N=90). Results: Among AA men, PSA levels were strongly predicted by age (beta = 0.050, p = 1.39 × 10⁻⁵) and case status (beta = 0.52, p < 1 × 10⁻¹²). APOE haplotypes demonstrated no association with PSA (E4: p = 0.80; E2: p = 0.36) or prostate cancer status (logistic regression: E4 p = 0.71, E2 p = 0.58). Vitamin D (p = 0.12) and WAA (p = 0.25) were also non-significant predictors. Among men from Cameroon west Africa, we observed a nominal association suggesting higher PSA in E2 haplotype carriers (beta = 1.03, p = 0.045), but this was not observed among AAs. No significant associations were detected for E4 (p = 0.69) or E3. In the combined analysis, APOE SNPs and haplotypes were not significantly associated with PSA (E4: p = 0.93; E2: p = 0.67) or case-control status (allelic tests: p > 0.50 for all SNPs). Across all models, age (p < 2 × 10⁻⁹) and PSA (p < 6 × 10⁻¹⁵) remained the strongest predictors of prostate cancer status. Conclusion and Implications: Across three groups totaling more than 1,300 Black men, APOE genetic variation including the E2, E3, and E4 haplotypes did not significantly predict PSA levels or prostate cancer risk. Associations observed in the stratified analyses were not replicated and did not withstand combined analysis. More studies are needed to confirm if APOE plays a biologically meaningful role in prostate cancer etiology or PSA regulation in these populations. Acknowledgment of Funding: This research is supported by the Health Equity Research Career Advancement Program funded by the American Cancer Society's Diversity in Cancer Research Institutional Development Grant 885016.