Genetic variation in eleven phase I drug metabolism genes in an ethnically diverse population

Abstract

The extent of genetic variation found in drug metabolism genes and its contribution to interindividual variation in response to medication remains incompletely understood. To better determine the identity and frequency of variation in 11 phase I drug metabolism genes, the exons and flanking intronic regions of the cytochrome P450 (CYP) isoenzyme genes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5 were amplified from genomic DNA and sequenced. A total of 60 kb of bi-directional sequence was generated from each of 93 human DNAs, which included Caucasian, African-American and Asian samples. There were 388 different polymorphisms identified. These included 269 non-coding, 45 synonymous and 74 non-synonymous polymorphisms. Of these, 54% were novel and included 176 non-coding, 14 synonymous and 21 non-synonymous polymorphisms. Of the novel variants observed, 85 were represented by single occurrences of the minor allele in the sample set. Much of the variation observed was from low-frequency alleles. Comparatively, these genes are variation-rich. Calculations measuring genetic diversity revealed that while the values for the individual genes are widely variable, the overall nucleotide diversity of 7.7 x 10(-4) and polymorphism parameter of 11.5 x 10(-4) are higher than those previously reported for other gene sets. Several independent measurements indicate that these genes are under selective pressure, particularly for polymorphisms corresponding to non-synonymous amino acid changes. There is relatively little difference in measurements of diversity among the ethnic groups, but there are large differences among the genes and gene subfamilies themselves. Of the three CYP subfamilies involved in phase I drug metabolism (1, 2, and 3), subfamily 2 displays the highest levels of genetic diversity.

The high prevalence of the poor and ultrarapid metabolite alleles of CYP2D6, CYP2C9, CYP2C19, CYP3A4, and CYP3A5 in Taiwanese population

“…Individuals who have normal metabolic activity are called extensive metabolizers (EM) whereas individuals with defective metabolic activity are called poor metabolizers (PM;Meyer 1990). It has been reported that phenotypes associated with genetic variations often contribute to differences in drug metabolism and the dynamics of drug-drug interactions (Solus et al 2004).…”

Pharmacokinetics and Pharmacodynamics of Lomitapide in Japanese Subjects

“…Genetic polymorphisms have been reported to have variable frequency in different ethnic populations 13,14) . The pharmacogenetics of enzymes participating in drug metabolism is responsible for a significant portion of drug-induced toxicity as polymorphisms in these genes contribute to alterations in drug clearance and influence the efficacy and toxicity of drug therapy 15) .…”

Controlling Chemotherapy-Induced Nausea and Vomiting with Neurokinin-1 Receptor Antagonists in Patients on AC-Based Chemotherapy—Are We There Yet?

“…As CR comprises both parameters of "no vomiting" and "no rescue medication use", this may have contributed to the equivocal CR rates between arms. Since aprepitant is both a substrate and moderate inhibitor of CYP3A4 [29,30], genetic differences [29,31] may have accounted for the varying aprepitant efficacies between this study, which comprised of 100% ethnic Chinese patients, and similar studies which sampled a large proportion of Caucasians [22].…”