In Vivo Functional Effects of a Novel and Common Variant in the Yup'ik Alaska Native Population.

Alaska Native people are under-represented in genetic research but have unique gene variation that may critically impact their response to pharmacotherapy. Full resequencing of in a cross-section of this population identified () a novel, relatively common single nucleotide polymorphism hypothesized to confer CYP2C9 poor metabolizer phenotype by disrupting the start codon. is present at a minor allele frequency of 6.3% in Yup'ik Alaska Native people and thus can contribute to the risk of an adverse drug response from narrow-therapeutic-index CYP2C9 substrates such as ()warfarin. This study's objective was to characterize the catalytic efficiency of the Leu1 variant enzyme in vivo by evaluating the pharmacokinetic behavior of naproxen, a probe substrate for CYP2C9 activity, in genotyped Yup'ik participants. We first confirmed the selectivity of ()-naproxen -demethylation by CYP2C9 using activity-phenotyped human liver microsomes and selective cytochrome P450 inhibitors and then developed and validated a novel liquid chromatography mass spectrometry method for simultaneous quantification of ()naproxen, ()-desmethylnaproxen, and naproxen acyl glucuronide in human urine. The average ratio of ()-desmethylnaproxen to unchanged ()naproxen in urine was 18.0 ± 8.0 ( = 11) for the homozygous reference group and 10.3 ± 6.6 ( = 11) for the variant carrier group ( = 0.011). The effect of variation on CYP2C9 function and its potential to alter the pharmacokinetics of drugs metabolized by the enzyme has clinical implications and should be included in a variant screening panel when pharmacogenetic testing in the Alaska Native population is warranted. SIGNIFICANCE STATEMENT: The novel variant in Alaska Native people was recently identified. This study validated ()naproxen as a CYP2C9 probe substrate to characterize the in vivo functional activity of the variant. The results of this pharmacogenetic-pharmacokinetic study suggest that the variant exhibits loss of enzyme activity. This finding may be important to consider when administering narrow-therapeutic-index medications metabolized by CYP2C9 and also compels further investigation to characterize novel genetic variation in understudied populations.