Pharmacogenetic research has revolutionized precision medicine, yet disparities persist in the representation of underserved populations, resulting in inequitable healthcare outcomes. This study aimed to identify population-specific genetic variations influencing drug metabolism in African American, Hispanic/Latino, and Native American cohorts. Using next-generation sequencing and bioinformatics analyses, we investigated polymorphisms in key pharmacogenetic genes, including CYP2D6 and CYP3A5. A total of 1,500 participants were enrolled, with allele frequencies and haplotype structures analyzed using multivariate logistic regression and principal component analysis.

Results revealed significant disparities, with African Americans exhibiting a 20% frequency of the CYP2D6 *4 allele, compared to 15% in Hispanics and 10% in Native Americans (p<0.01). Similarly, the CYP3A5 *3 allele was present in 70% of African Americans, 50% of Hispanics, and 40% of Native Americans (p<0.001). These genetic differences were associated with altered drug response and increased risk of adverse drug reactions, underscoring the need for population-specific pharmacogenetic profiling. Community engagement strategies enhanced trust and participation, with 90% of participants expressing interest in future studies.