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

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Solus JF, Arietta BJ, Harris JR, Sexton DP, Steward JQ, McMunn C, Ihrie P, Mehall JM, Edwards TL, Dawson EP

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

Pharmacogenomics. 2004 Oct;5(7):895-931.

PubMed ID
15469410 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
Cytochrome P450 3A5P20815Details
Cytochrome P450 2D6P10635Details
Cytochrome P450 1A2P05177Details
Cytochrome P450 3A4P08684Details
Cytochrome P450 2C9P11712Details
Cytochrome P450 2C8P10632Details
Cytochrome P450 2A6P11509Details
Cytochrome P450 2E1P05181Details
Cytochrome P450 2C19P33261Details
Cytochrome P450 1A1P04798Details
Cytochrome P450 2B6P20813Details