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Current Pharmacogenomics
ISSN: 1570-1603
Current Pharmacogenomics
Volume 4, Number 3, September 2006
Contents
Molecular Methods for Individualization of Psychotropic
Drug Treatment Pp. 177-189
B. Bondy and P. Zill
[Abstract]
Pharmacogenetics in Affective Disorders: A Drug
Response Approach Pp. 191-208
R. Lefebvre and J. Del-Favero
[Abstract]
Microarray Data Analysis: Current Practices and
Future Directions Pp. 209-218
F. Vaince, J. Bona and H.M. Fathallah-Shaykh
[Abstract]
Essential Hypertension: Translating Pathophysiology
into Pharmacogenomics Pp. 219-229
F. Filigheddu, G. Argiolas, C. Troffa and N. Glorioso
[Abstract]
An Overview of the Pharmacogenetics and Molecular
Genetics of ADHD Pp. 231-243
N. Lowe, E. Barry, M. Gill and Z. Hawi
[Abstract]
Focused Microarray Analysis: Characterization
of Phenomes by Gene Expression Profiling Pp. 245-260
A. Inoue, M. Tanji and R. Kiyama
[Abstract]
Ethical Implications of Pharmacogenetics: Shaping
the Future of the Field Pp. 261-269
L. Marx-Stölting
[Abstract]
Abstracts
[Back to top]
Molecular Methods for Individualization of Psychotropic
Drug Treatment
B. Bondy and P. Zill
Genetic factors are supposed to play a major role for
the differences in response to treatment or the incidence
of adverse drug effects in psychopharmacotherapy. The aim
of pharmacogenetics is to elucidate this variability due to
hereditary differences. According to the currently known hypotheses
on the mechanisms of drug action, several mutations in genes
coding for neurotransmitter-receptors, -degrading enzymes,
transport proteins or enzymes of the drug metabolizing system
have been identified and investigated in terms of efficacy
and adverse drug effects. Although there exists considerable
controversy among the results, many studies are supportive
for the hypothesis, that psychopharmacogenetics will be helpful
in predicting an individual’s drug response and identify
persons at risk for serious side effects on the basis of the
genetic make up. The introduction and inclusion of pharmacogenomics,
which is a powerful tool to identify genes affected by drugs,
will most likely help to delineate so far unknown drug targets,
predict drug responsiveness and adverse reactions and finally
propose new hypotheses for both the pathophysiological basis
of psychiatric disorders and the mechanisms of psychotropic
drug action. This paper briefly overviews the present status
of pharmacokinetic and pharmacodynamic aspects in the pharmacogenetics
of antipsychotics, antidepressants and lithium ions. Further,
a summary on the work investigating genes of the signal transduction
cascade, neuronal plasticity and stress response is given.
[Back to top]
Pharmacogenetics in Affective Disorders: A Drug
Response Approach
R. Lefebvre and J. Del-Favero
Affective disorders, including unipolar (UP) disorder
and bipolar (BP) disorder are among the most important causes
of death and disability worldwide and result in high costs
in terms of morbidity as well as mortality. Although the etiology
and pathophysiology is widely unknown, family-, twin- and
adoption studies argue for a strong genetic determination
of these disorders.
These studies indicate that there is between 40-85% heritability
for these disorders but point also to the importance of environmental
factors. Despite the availability of a wide range of different
drugs, about 30–50% of patients do not respond properly
to acute treatment.
Here we provide an overview of genetic drug response markers
for affective disorder. Central in review is the question
if individual therapeutic outcome for a given treatment can
be predicted using genetic markers? An overview of pharmacogenetic
and pharmacogenomic approaches is described for selective
serotonin reuptake inhibitors (SSRIs), tricyclic anti-depressants
(TCAs), and mood stabilizing drugs in relation to each of
the major candidate genes for affective disorders.
[Back to top]
Microarray Data Analysis: Current Practices and
Future Directions
F. Vaince, J. Bona and H.M. Fathallah-Shaykh
Microarrays have become one of the leading technologies
used for gene expression analysis and functional genomics
in many biological fields. Potential applications of microarrays
can facilitate advances in molecular biology, systems biology,
functional genomics, clinical medicine, and pharmacogenomics.
However, microarray data can also lead to inaccurate and irreproducible
conclusions. Here, we present a critical review of current
computational tools used for normalization, statistical analysis,
cluster analysis, and mathematical modeling-based analysis.
Despite the pitfalls and challenges that still encompass the
computational analysis of microarray data, the use of this
technology remains very promising. In our opinion, achieving
the full potential of microarray technology requires additional
theoretical advances.
[Back to top]
Essential Hypertension: Translating Pathophysiology
into Pharmacogenomics
F. Filigheddu, G. Argiolas, C. Troffa and N. Glorioso
This paper will review the literature on the most recent
advances of pharmacogenomics of essential hypertension. Specifically,
the hypotheses regarding the responsibility of gene polymorphisms
in hypertension and whether the pathophysiological mechanisms
underlying hypertension can be translated in pharmacogenomic
evidence will be analyzed. In particular, the present review
will cover the role of genes in blood pressure regulation
(mostly, sodium-sensitivity and vasoconstriction) as well
as in the antihypertensive response to drugs: associations,
lack of associations and contradictory results will be evaluated,
and the reasons for discrepancies examined. Emphasis will
be placed on the methodologies used so far to conceive and
develop pharmacogenomic hypotheses to improve our capability
to achieve solid, unequivocal results to be translated in
the day-by-day clinical practice.
[Back to top]
An Overview of the Pharmacogenetics and Molecular
Genetics of ADHD
N. Lowe, E. Barry, M. Gill and Z. Hawi
Attention deficit hyperactivity disorder (ADHD) is a
common childhood disorder, symptoms of which include inattentiveness,
impulsiveness, distractibility and hyperactivity. Although
the etiology of ADHD is not known, high heritability estimates
(ranging from 60-90%) have been reported. The mode of inheritance
is also unknown, however, it is widely believed that multiple
susceptibility genes (each of small effect) are contributing
to the liability of the disorder. Animal, pharmacological
and molecular studies have implicated disruption in catecholamine
neurotransmission (dopaminergic, serotonergic, and noradrenergic)
in the etiology of ADHD. Recent genetic studies have identified
ADHD susceptibility genes including DAT1, DRD4 and
DRD5. In addition, there is evidence that DNA variation
at the serotonin transporter (5-HTT), serotonin receptor 1B
(5-HT1B) and the synaptosomal associated protein–25
(SNAP-25) genes contribute to susceptibility for ADHD. Genetic
variants at these and other candidate genes have been examined
for their potential to predict medication response in ADHD.
Preliminary results are conflicting with no clear pattern
emerging. However, the numbers of pharmacogenetic studies
to date are limited and are mainly focused on methylphenidate
and variants at the dopaminergic system genes. A more focused
approach is required, examining genetic variation in genes
involved kinetically and dynamically in medications used to
treat ADHD. In this context, studies should be extended to
include atomoxetine, a selective inhibitor of the noradrenergic
transporter used in the treatment of ADHD. These studies might
include a range a noradrenergic system genes.
[Back to top]
Focused Microarray Analysis: Characterization
of Phenomes by Gene Expression Profiling
A. Inoue, M. Tanji and R. Kiyama
Although microarray analysis is a highly promising technology
in the genome era, its application for gene expression profiling
to characterize various phenomes, including genetic phenotypes,
diseases, responses to chemicals and clinical annotations,
is far from being a real use. One of the obstacles is the
quality of the data, which needs to be enough to be able to
solely use microarrays for these purposes. For this, selecting
a set of genes as a molecular signature, based on transcriptomics,
proteomics or metabolomics, and the use of the selected set
of genes in focused microarrays has great merits. Here, we
summarize how sets of genes were selected, what types of genes
were used and what kind of statistics will be needed for focused
microarrays, to distinguish them from genome-wide microarrays
and to explain why focused microarray analysis is advantageous
in gene expression profiling.
[Back to top]
Ethical Implications of Pharmacogenetics: Shaping
the Future of the Field
L. Marx-Stölting
Pharmacogenetics is a rapidly expanding area of research
focussed on the relationship between drug response and genetic
variation. Due to the broad range of potential applications
its influence on the process of drug development and on the
practice of medicine, but also on society could be enormous.
Therefore, the ethical, social and legal issues connected
to the field are the subject of a number of recent publications.
This review summarizes the key ethical implications of pharmacogenetics
concerning both research and potential clinical applications,
such as the stratification of patients and research participants,
the establishment and use of biobanks, the use of racial identifiers
in research, the problem of secondary information, informed
consent issues, the potential for discrimination and stigmatisation,
possible changes to the doctor-patient relationship and issues
of access to and allocation of pharmacogenetic services. The
study of the literature shows that there is no fundamental
opposition to the field, even though a large number of potential
problems have been identified. Most discussions are aimed
to partake in the shaping of the field and its implementation
into clinical practice, pointing at potential pitfalls. Ethical
evaluations of putative future developments and their consequences
are based on the anticipation of different future scenarios
and thus tied to actual developments in the field. Thus, specifications
and possibly revisions will be necessary as the field progresses.
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