Biomedical Engineering Reference
In-Depth Information
function in vitro, including the 421C
A (Gln141Lys) polymorphism in
ABCG2
,
which encodes MXR. This polymorphism caused reduced MXR expression and trans-
port of the anticancer agent topotecan in vitro,
29
and in a small preliminary study, two
carriers of the 421A allele had increased topotecan bioavailability compared to per-
sons with the wild-type allele, indicating reduced intestinal MXR efflux activity.
164
Pharmacogenetic studies of other ABC transporters that are thought to be involved in
multidrug resistance are ongoing. High expression of several members of the ABCC
family of transporters has been demonstrated in numerous tissues and tumor types,
165
suggesting that polymorphisms in these genes may affect the development and degree
of multidrug resistance.
Although genetic variation in the vast majority of ABC transporters implicated
in multidrug resistance have been studied using a genotype-phenotype approach,
there are a few ABC transporters in which polymorphisms were identified through
a phenotype-genotype approach. One prominent example is
ABCC7
, which was
mapped in 1989 as the pathogenic locus of cystic fibrosis (OMIM 219700). A com-
mon
>
F508 amino acid deletion was discovered in the cystic fibrosis transmembrane
conductance regulator (CFTR) protein of patients with cystic fibrosis.
166
This three-
nucleotide deletion in
ABCC7
causes a defective chloride channel in approximately
70% of cystic fibrosis patients; other polymorphisms are responsible for the remain-
ing 30% of cases. Additional examples of phenotype-genotype studies include the
polymorphisms in
ABCC2
(MRP2) that lead to a rare liver disorder called
Dubin-
Johnson syndrome
(DJS) (OMIM 237500),
89
and polymorphisms in
ABCC6
(MRP6)
that have been associated with pseudoxanthoma elasticum (PXE) (OMIM 264800),
a disorder of the connective tissue.
167
21.5. CONCLUSIONS
To date, most of the polymorphisms in transporter genes that result in a clinical effect
have been identified through phenotype-to-genotype studies. These polymorphisms
generally result in a decrease in expression and/or function of the transporter, lead-
ing to an obvious and observable clinical phenotype. Genotype-to-phenotype studies
provide a wealth of information about genetic diversity but have been less successful
at identifying polymorphisms that result in substantial clinical effects. This is in part
because of the multiplicity built into the genome and the ability of one gene to compen-
sate for the altered function of another, and in part because most clinical phenomena,
including drug response and toxicity, are complex events that involve multiple genes.
The consideration of genetic variation in a group of genes implicated in the response
and toxicity to a given drug—a pathway approach—may assist in the elucidation of
the effects of transporter polymorphisms in more complex clinical phenotypes. An
increasing number of drug response pathways are available at www.pharmgkb.org
and serve as an important resource for the design of pharmacogenetic studies.
Appropriate study design is another important consideration for pharmacogenetics
studies. In many of the early transporter genotype-phenotype association studies,
sample sizes were small and sufficient power to detect meaningful differences was
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