Pharmacogenetic study reveals increased CYP3A4*1G enzyme activity in American Indian and Alaska Native communities, suggesting faster drug metabolism for carriers.
Key Points
To characterize genetic variation in CYP3A4 and CYP3A5 and evaluate the functional impact of the CYP3A4*1G allele on enzyme activity in American Indian and Alaska Native populations.
Partnered with Yup'ik Alaska Native individuals from rural southwest Alaska and urban AIAN individuals receiving care in Anchorage, Alaska.
Assessed CYP3A4 and CYP3A5 genetic variation and evaluated CYP3A4*1G expression and activity using human lymphoblastoid cell lines and human liver microsomes.
Quantified in vivo CYP3A4-mediated 4β-vitamin D hydroxylation in Yup'ik participants carrying the CYP3A4*1G allele.
Identified low frequencies of novel and known CYP3A4 and CYP3A5 variants, including CYP3A4*1G and CYP3A5*1, with distinct linkage disequilibrium patterns compared to Montana cohorts.
Demonstrated that the CYP3A4*1G allele increases protein expression in lymphoblastoid cells as well as protein content and metabolic activity in human liver microsomes.
Confirmed enhanced in vivo 4β-vitamin D hydroxylation in Yup'ik individuals with the CYP3A4*1G allele, indicating accelerated clearance of CYP3A drug substrates.