Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

102 Applying Pharmacogenomics in Therapeutics
TABLE 5.2
CYP2D6 Metabolizer Group
Phenotyping Group Ethnic Group Frequency Main Alleles
Poor metabolizer Whites (5–10%) Null alleles *3, *4, *6, and gene
deletion *5
East Asian (rare) *4 (splice defect) 1–2%
Africans (highly variable) *4 (splice defect) 1–2%
Intermediate metabolizers Whites (10–15%)
East Asian (up to 50%) High prevalence of *10
African (up to 30%) High prevalence of *17
Ultrarapid metabolizers Whites (1–10%) Gene duplications or multiduplications
Extensive metabolizers Whites (60–85%)
have a narrow therapeutic window (Eichelbaum et al. 2006; Evans and Relling 1999;
nomenclature; Zanger et al. 2004). The CYP2D6 gene is located at chromosome
band 22q13 and is highly polymorphic with more than 70 alleles and 130 genetic
variations (nomenclature). The phenotypic distribution for CYP2D6 is multimodal
with four metabolizer groups by the predicted number of functional alleles: poor
metabolizer (PM), intermediate metabolizer (IM), extensive metabolizer (EM), and
ultrarapid metabolizer (UM) (see Table 5.2). The frequency of various alleles is significantly
distinct among different ethnic groups (Ingelman-Sundberg et al. 2007;
Zanger et al. 2004). The PMs have no CYP2D6 enzymatic activity due to carrying
two null alleles. PM is more common in the white population with a frequency of
5–10%. It is rare in Asians and highly variable in those of African ancestry (Bradford
2002; McGraw and Waller 2012).
The IMs have reduced CYP2D6 enzymatic activity because they carry a combination
of either a null allele or two deficient alleles. The common deficient alleles
are CYP2D6*9, *10, *17, and *41 (Bradford 2002). In contrast to PMs, IMs are
more frequent in Asians (up to 50%) than whites (10–15%) because of the high prevalence
of the defective allele CYP2D6*10. The frequency of IMs in Africans (up to 30%)
is also higher than that in whites and the allele *17 is more frequent in this ethnic group.
The UMs have increased CYP2D6 enzymatic activity due to gene duplications
or multiduplications and are found in 1–10% of whites (Ingelman-Sundberg
et al. 1999). Gene duplications are described in 20% of Saudi Arabians and 29% of
Ethiopians. The EMs have normal enzymatic activity and represent 60–85% of the
white populations.
CYP2C9
CYP2C9 is another gene of the CYP superfamily exhibiting a genetic polymorphism
with more than 35 allelic variants. The two most common allelic variants are
CYP2C9*2 (Rettie et al. 1994) and CYP2C9*3 (Sullivan-Klose et al. 1996). Both lead
to reduced activity of CYP2C9. Patients with the CYP2C9*2 and CYP2C9*3 alleles
required a low dose of warfarin to reduce the risk of bleeding because CYP2C9 is