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Genotyping
Genotyping also predicts metabolic capacity but involves identifi cation of defi ned
genetic mutations that give rise to the specifi c drug metabolism phenotype. These
mutations include genetic alterations that lead to overexpression (gene duplication),
absence of an active protein (null allele), or production of a mutant protein with
diminished catalytic capacity (inactivating allele). Genetic mutations can be
screened by molecular diagnostic methods. Advantages of genotyping are:
- Not affected by coadministered medications
- Only one blood sample is needed
- Information acquired has life-long validity
Genotyping vs Phenotyping
Genotyping has 100 % specifi city for detection of impaired metabolizers of CYP2D6
due to genetic reasons but with respect to sensitivity phenotyping is still the pre-
ferred method. Phenotype (sensitivity 98 %) provides information on CYP2D6
function, whether it is infl uenced by either genotype or acquired hepatic disease.
Genotyping, on the other hand, provides time invariant information on the individ-
ual’s metabolizing capacity and it is applied in clinical and epidemiological studies.
If therapeutic decisions are based on this information, 10–20 % of poor metabolizes
may be wrongly classifi ed as extensive metabolizes. Genotyping is valuable both
for individual cases, particularly when a phenotype cannot be established due to
concomitant therapy, and for screening of populations in clinical studies.
Phenotype tests have applied successfully in some pharmacogenetics conditions
such as malignant hyperthermia, porphyries and glucose-6-phosphate dehydroge-
nase defi ciency. It is likely that more practical genotyping tests would be used in the
future and phenotypes would be predicted via genotyping. The traditional
phenotype- to-genotype pharmacogenetic research paradigm is reversing direction
to create a complementary genotype-to-phenotype fl ow of information. Examples
of genotyping and phenotyping are shown in Table 4.8.
Phenomics
Phenomics is the study of genomics information to better understand the complex
relationship between genotype and phenotype. This relationship is frequently non-
linear in nature, which poses a problem for traditional means of genetic study. These
traditional methods are not well suited to accommodate the effect of quantitative
trait loci or multi-dimensional genetic interactions at work in the determination of
most human phenotypes.
4 Pharmacogenetics