Investigation of Pharmacogenomic Variants in the CYP (P450) Family in Native American Populations of the Brazilian Amazon

The cytochrome P450 (CYP) enzyme superfamily is essential for xenobiotic metabolism, detoxification pathways, and the regulation of cellular homeostasis. Genetic variability in CYP genes, together with environmental factors, contributes substantially to interindividual and interethnic differences in drug metabolism and therapeutic response. However, Indigenous populations remain largely underrepresented in pharmacogenomic and population genomics studies, limiting the generalizability of current knowledge. This study is aimed at characterizing genetic variation within CYP genes in Native American populations from the Brazilian Amazon and comparing the observed patterns with those of the five continental populations represented in the 1000 Genomes Project. Whole-exome sequencing data were generated for 64 Indigenous individuals belonging to 12 distinct Amazonian ethnic groups. Variants were identified and annotated across CYP family genes, and their predicted functional impacts were assessed. A total of 506 genetic variants were detected across 63 <i>CYP</i> genes. Variants predicted to have modifying effects constituted the majority (<i>n</i> = 300), followed by variants of moderate (<i>n</i> = 90), low (<i>n</i> = 95), and high impact (<i>n</i> = 21). Importantly, 11 variants appear to be novel, with no previous annotation in dbSNP or other publicly available variant databases. Comparative analyses revealed distinct variant distributions relative to global reference populations. To our knowledge, this is the first comprehensive exome-based characterization of <i>CYP</i> gene variation in Indigenous populations from Northern Brazil. These findings provide an important genomic resource for an underrepresented population and offer a foundational framework for future pharmacogenomic research, with potential implications for the development of personalized and culturally appropriate precision medicine strategies in the Brazilian Amazon.