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CHAPTER 5 Pharmacogenomics 75

GLOSSARY

Term Definition
Allele One of two or more alternative forms of a gene that arise by mutation and are found at the same genetic
locus. Example: CYP2D6*3 is an important variant allele for a drug-metabolizing enzyme, CYP2D6.
Allele frequency The fraction or percentage of times a specific allele is observed in proportion to the total of all possible
alleles that could occur at a specific location on a chromosome.
Coding single nucleotide A single base-pair substitution that occurs in the coding region.
polymorphisms (cSNPs)
Copy number variations (CNVs) A segment of DNA in which a variable number of that segment has been found.
Haplotype A series of alleles found in a linked locus on a chromosome.
Hardy-Weinberg equilibrium The principle that allele frequencies will remain constant from generation to generation in the absence of
evolutionary influences.
Insertions/deletion (indel) Insertion or deletion of base pairs, which may occur in coding and noncoding regions.
Linkage disequilibrium The nonrandom association of alleles at two or more loci that descend from a single ancestral chromosome.
Noncoding region polymorphism Polymorphisms that occur in the 3′ and 5′ untranslated regions, intronic regions, or intergenic regions.
Nonsynonymous SNPs (nsSNPs) A single base-pair substitution in the coding region that results in an amino acid change.
Polymorphism or variant Any genetic variation in the DNA sequence; the terms can be used interchangeably.
PM, IM, EM, or UM Poor, intermediate, extensive, or ultra-rapid metabolizer phenotype.
SNPs Single nucleotide polymorphisms: base-pair substitutions that occur in the genome.
Synonymous SNPs Base-pair substitutions in the coding region that do not result in an amino acid change.

■ GENETIC VARIATIONS IN copy of the gene is detected, the activity score is then multiplied
ENZYMES by the number of copies observed. Enzyme activity is generally a
co-dominant or additive trait. For example, if an individual car-
ries one normal function allele and one nonfunctional allele, he
PHASE I ENZYMES will have an intermediate metabolic activity or be considered an

intermediate metabolizer (IM). The sum of allelic activity scores
As described in Chapter 4, biotransformation reactions mediated typically ranges between 0 and ≥ 3.0 and is most often used to
by P450 phase I enzymes typically modify functional groups define phenotypes as follows: 0 = PM (poor metabolizer), 0.5 =
(−OH, −SH, −NH , −OCH ) of endogenous and xenobiotic com- IM, 1.0–2.0 = EM, and ≥ 2.0 = UM (ultra-rapid metabolizer).
3
2
pounds, resulting in an alteration of the biological activity of the
compound. Phase I enzymes are involved in the biotransforma- CYP2D6
tion of over 75% of prescription drugs; therefore, polymorphisms
in these enzymes may significantly affect blood levels, which in As described in Chapter 4, cytochrome P450 2D6 is involved in
turn may alter response to many drugs. Polymorphisms in drug- the metabolism of up to one quarter of all drugs used clinically,
metabolizing enzymes dominated the field of pharmacogenom- including predominantly basic compounds such as β blockers,
ics for many years, and for some years, metabolic phenotypes antidepressants, antipsychotics, and opioid analgesics. Among
such as extensive metabolizer (EM), reflecting an individual’s the CYP enzymes, CYP2D6 is responsible for metabolism of
metabolic rate of a particular drug that is a known substrate of about 20% of clinically used drugs. Similar to other polymorphic
a specific enzyme, were used to describe genetic effects on drug enzymes, four clinically defined metabolic phenotypes, ie, PMs,
metabolism. After genotypic information became available, a new IMs, EMs, and UMs, are used to predict therapeutic and adverse
nomenclature was used to characterize an individual’s metabolic responses following the administration of CYP2D6 substrates.
rate. In particular, diplotypes, consisting of one maternal and one The gene encoding CYP2D6 is highly polymorphic, with over
paternal allele, using star (*) allele nomenclature, have been used. 100 alleles defined (www.cypalleles.ki.se/cyp2d6.htm); however,
Each star (*) allele is defined by specific sequence variation(s) greater than 95% of phenotypes can be accounted for with just
within the gene locus, eg, single nucleotide polymorphisms nine alleles, ie, CYP2D6 alleles *3, *4, *5, and *6 are nonfunc-
(SNPs), and may be assigned a functional activity score when the tional; alleles *10, *17, and *41 have reduced function; and alleles
functional characterization is known, eg, 0 for nonfunctional, *1 and *2 are fully functional. As with many polymorphisms,
0.5 for reduced function, and 1.0 for fully functional. Some allele frequencies vary across populations (Table 5–1). Some
genes, such as CYP2D6, are subject to whole gene deletions, eg, genetic variants are shared among populations at similar allele
CYP2D6*5, and whole gene duplications or multiplications, eg, frequencies, whereas others vary considerably. For example, the
*1xN, *2xN, where N is the number of copies. If more than one most common nonfunctional allele, CYP2D6*4, is observed at