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Current Pharmacogenomics
ISSN: 1570-1603
Current Pharmacogenomics
Volume 4, Number 4, December 2006
Contents
Pharmacogenomic Approaches to Osteoporosis: 2005
Update Pp. 271-276
Yuan Chen, Dong-Hai Xiong, Hui Jiang and Hong-Wen Deng
[Abstract]
Pharmacogenomics of 5-Fluorouracil/Oxaliplatin
in Colorectal Cancer Pp. 277-283
Michael A. Gordon, Wu Zhang and Heinz-Josef Lenz
[Abstract]
Thiopurines in Inflammatory Bowel Disease –
The Role of Pharmacogenetics and Therapeutic Drug Monitoring
Pp. 285-300
Malin Lindqvist, Ulf Hindorf, Sven Almer and Curt Peterson
[Abstract]
Evolution in the Pharmacogenetics and Pharmacogenomics
of Inflammatory Bowel Disease–Order Slowly Rises from
the Chaos Pp. 301-306
D.M. Poppers and E.J. Scherl
[Abstract]
Will Pharmacogenetics Predict Response to Therapies
in Rheumatoid Arthritis? Pp. 307-319
Happy Chan and Prabha Ranganathan
[Abstract]
Pharmacogenomics and Severe Infections: The Role of
the Genomes of Both the Host and the Pathogen Pp.
321-329
G. Sirgo, J. Rello and G. Waterer
[Abstract]
Pharmacogenomics of the Human ATP-Binding Cassette
Transporter ABCG2 Pp. 331-344
Erin R. Gardner, William D. Figg and Alex Sparreboom
[Abstract]
Polymorphisms of Genes Encoding Phase I Enzymes in
Mexican Americans – An Ethnic Comparison Study
Pp. 345-353
Huai-Rong Luo and Yu-Jui Yvonne Wan
[Abstract]
Abstracts
[Back to top]
Pharmacogenomic Approaches to Osteoporosis: 2005 Update
Yuan Chen, Dong-Hai Xiong, Hui Jiang and Hong-Wen Deng
Osteoporosis is a skeletal disorder characterized by
compromised bone strength predisposing a person to an increased
risk of fracture. The overall rate of osteoporosis is increasing
annually around the world, especially among the elderly people,
resulting in heavier social-economic burden. Till now, certain
anti-osteoporosis medications have been applied to prevent
and/or treat osteoporosis by the mechanism of either decreasing
excessive bone resorption or promoting bone formation. However,
the efficacy of those therapies varies among people, sometimes
causing unnecessary medical cost or even unwanted side-effects.
Therefore, more cost-effective and subject-specific prevention
and treatment of osteoporosis is needed. In such context,
pharmacogenomic studies of osteoporosis are of particular
importance since it has been widely shown that genetic factors
play a role in the efficacy of osteoporosis treatment. The
goal of osteoporosis pharmacogenomics is to optimize drug
development and customize personalized treatment according
to the specific genetic background. Herein, we discussed the
application of genetic and genomic approaches to osteoporosis
clinics, which held the promise to revolutionize the way we
understand, prevent and treat osteoporosis.
[Back to top]
Pharmacogenomics of 5-Fluorouracil/Oxaliplatin
in Colorectal Cancer
Michael A. Gordon, Wu Zhang and Heinz-Josef Lenz
Pharmacogenomic studies in the field of colorectal cancer
have recently emerged as tools to benefit patients in receiving
tailored chemotherapy and potentially improved therapeutic
benefit. 5-fluorouracil/oxalplatin combination chemotherapy
has been approved in the United States and Europe for the
treatment of advanced colorectal cancer. However, overall
efficacy may be compromised by dose-limiting toxicity and
varying inter-individual responses to treatment. Determining
who is most likely to benefit from 5-FU/oxaliplatin is of
great importance, and may be determined in part by pharmacogenomic
studies. Genes involved in the cytotoxic and metabolic pathways
of 5FU and oxaliplatin may be predictive and prognostic markers
for colorectal cancer. Examining polymorphic variants leading
to altered function of these relevant genes offers an approach
to further individualize chemotherapeutic treatment. A number
of studies have implicated significant genes in altered clinical
outcome, indicating the need for an established comprehensive
genetic profile to predict efficacy of 5-FU/oxaliplatin. In
addition to polymorphic studies, array-based technology has
recently emerged as a tool to examine global gene expression
in predicting outcome to chemotherapy. The ultimate goal of
pharmacogenomic studies in colorectal cancer is to develop
a genetic profile to tailor chemotherapeutics to the individual
patient. With an increased knowledge of why patients have
altered responses to 5-FU/oxaliplatin, there can be greater
accuracy in selecting the most appropriate therapy.
[Back to top]
Thiopurines in Inflammatory Bowel Disease –
The Role of Pharmacogenetics and Therapeutic Drug Monitoring
Malin Lindqvist, Ulf Hindorf, Sven Almer and Curt Peterson
Pharmacogenetics represents the study of variability in drug
response due to genetic variations. Inflammatory bowel disease
(IBD, i.e. primarily Crohn’s disease and ulcerative
colitis) is characterized by a chronic or relapsing inflammation
of the digestive tract. The thiopurines 6-mercaptopurine (6-MP)
and azathioprine (AZA), an imidazol derivative and pro-drug
of 6-MP, are widely used in IBD, particularly in Crohn’s
disease. The metabolism of thiopurines is complex and individually
variable. Thiopurine methyltransferase (TPMT) is a key enzyme
in this metabolism and exhibits a genetic variability due
to a number of variant alleles coding for a defective enzyme.
The formation of biologically active thioguanine nucleotides
(TGN) and methylated metabolites may vary considerably due
to the TPMT activity. Patients with decreased TPMT activity
are at increased risk of developing severe side effects if
treated with conventional thiopurine doses, due to the accumulation
of toxic metabolites. Determination of the TPMT phenotype
or genotype is often used to identify individuals with increased
risk for adverse events. Twenty-one variant TPMT
alleles have been described, of which three are more common
than the others. An association between inosine triphosphate
pyrophosphatase polymorphisms and adverse events during thiopurine
treatment has also been proposed. In this review, the clinical
value of TPMT status determination and pharmacological monitoring
of thiopurine metabolites are discussed as well as the increased
interest in the use of 6-thioguanine, a thiopurine with a
less complex metabolism, as an alternative for patients who
do not tolerate AZA or 6-MP. It can be concluded that TPMT
determination before start of thiopurine therapy is of value
to identify individuals with increased risk for adverse reactions
due to genetic enzyme deficiency. However, large prospective
studies are still needed to evaluate the true benefit of monitoring
thiopurine metabolites during thiopurine treatment.
[Back to top]
Evolution in the Pharmacogenetics and Pharmacogenomics
of Inflammatory Bowel Disease–Order Slowly Rises from
the Chaos
D.M. Poppers and E.J. Scherl
The management of inflammatory bowel disease (IBD) remains
challenging due to the varied clinical manifestations of Crohn’s
disease (CD) and ulcerative colitis (UC). The development
of new modalities in therapy is promising, with immunomodulator-based
approaches rising to a more prominent position in our armamentarium.
Mutations in a variety of genes have been shown to be associated
with IBD and specific phenotypes of disease. The CARD15/NOD2
protein has been associated with the sensing of, and tolerance
to, intraluminal bacteria. Patients with specific NOD2 mutations
have an increased risk for the development of CD, and certain
mutations have been associated with specific disease subtypes,
including fibrostenotic and penetrating disease, and the likelihood
of surgical intervention. Mutations in the Toll-like receptor
4 (TLR4) gene have been associated with inflammatory or stenotic
disease. Other susceptibility loci, including OCTN and the
IBD loci, are associated with increased severity and early
onset of disease. The elucidation of mutations in enzymatic
pathways might predict who will respond to specific pharmacotherapies,
and those at risk for treatment-associated adverse effects.
Single nucleotide polymorphisms in the thiopurine methyltransferase
(TPMT) gene, with lowered enzymatic activities, may predict
patients who require lower doses of immunomodulatory therapies
and those who are at increased risk for myelosuppression and
hepatitis. Patients with mutations in the N-acetyltransferases
may be at increased risk for adverse effects of aminosalicylates.
Overall, our understanding of the genetics of susceptibility,
and of the likelihood of response to specific therapies, may
be beneficial in refining the medical approach to the complex
management of IBD.
[Back to top]
Will Pharmacogenetics Predict Response to Therapies
in Rheumatoid Arthritis?
Happy Chan and Prabha Ranganathan
Rheumatoid arthritis (RA) is a systemic inflammatory disorder
that mainly affects the joints. When left untreated, the disease
can be aggressive resulting in irreversible joint damage with
high morbidity and mortality. Disease modifying anti-rheumatic
drugs (DMARDS) are the cornerstones of treatment in RA. In
recent times, a new class of disease-modifying medications,
the biologics, has been added to the therapeutic armamentarium
in RA. DMARDs not only ameliorate the clinical signs and symptoms
of disease, but also prevent the radiographic progression
of joint damage. However, there is significant variability
in patients’ response to these agents, both in terms
of efficacy and toxicity. At the present time, there are no
reliable means of predicting, a priori, an individual patient’s
response to a given DMARD. In this review, the current published
literature on the pharmacogenetics of traditional DMARDS and
the newer biological DMARDs is highlighted. Pharmacogenetics
may be a powerful tool for optimizing drug therapy in patients
with rheumatoid arthritis.
[Back to top]
Pharmacogenomics and Severe Infections: The Role of
the Genomes of Both the Host and the Pathogen
G. Sirgo, J. Rello and G. Waterer
Pharmacogenomics holds the promise that drugs might one day
be tailor-made for individuals and adapted to each person´s
own genetic makeup. The field of pharmacogenomics in regards
to severe infections is a growing and important field in modern
medicine. Severe infections, like severe community acquired
pneumonia (CAP) or sepsis have a great impact in morbidity
and mortality and consume a great amount of sanitary resources.
Those infections have not been analyzed properly under the
point of view of pharmacogenomics. The genomes of both the
host and the pathogen are key points in this field. There
are specific mutations in the host genome associated with
adverse outcomes (genes of antigen recognition molecules,
pro-inflammatory cytokines, anti-inflammatory cytokines, and
effectors molecules). Those mutations could define a genetic
profile of high risk patient in whom a specific treatment
should be added urgently. In addition, some adverse effects
to antibiotics can be predicted performing genetic testing.
As the concept one-drug-fits-all approach is no longer appropriate
in medicine, the genetic profile is discussed like useful
tool to make important clinical decisions regarding treatment
and to design clinical trials. Moreover, the genome of the
host could help us to know if nonresponding patients to vaccine
are genetically pre-programmed to be nonresponders or whether
failure to respond is a random event.
On the other hand, genome of pathogen could have advantages
in the clinical management establishing a definitive diagnosis,
determining antimicrobial resistance and/or following the
response to treatment.
[Back to top]
Pharmacogenomics of the Human ATP-Binding Cassette
Transporter ABCG2
Erin R. Gardner, William D. Figg and Alex Sparreboom
Members of the ATP binding cassette transporter family are
responsible for the cellular efflux of a broad range of endogenous
compounds and xenobiotics in multiple tissues. The ABCG2 (ABCP,
BCRP, MXR) protein, which is highly expressed in the gastrointestinal
tract and liver as well as numerous multi-drug resistant cancer
cells, is considered to be of particular importance in governing
drug absorption, elimination and cellular sensitivity to a
wide variety of clinically important drugs. A wealth of recent
literature has also indicated that inhibition of this transporter
may result in drug-drug interactions. Furthermore, genetic
polymorphisms in the gene encoding ABCG2 have been described,
which can significantly affect expression, cellular localization,
and/or substrate recognition in vitro and in
vivo. Alteration of ABCG2 transporter function by either
of these mechanisms has been demonstrated to contribute to
interindividual variability in drug disposition and treatment
outcome (toxicity or response) with certain, but not all,
substrates for ABCG2. In this report, we provide an update
on this rapidly emerging field.
[Back to top]
Polymorphisms of Genes Encoding Phase I Enzymes in
Mexican Americans – An Ethnic Comparison Study
Huai-Rong Luo and Yu-Jui Yvonne Wan
The inter-individual and inter-ethnic variations in phase
I enzyme activity is largely attributed to gene polymorphisms.
The distribution and clinical consequences of these variations
have been extensively studied in Africans, Asians, and Caucasians.
However, information is still lacking regarding the frequency
and the impact of these variations on xenobiotic metabolism
and disease processes in Mexican Americans. Therefore, this
review addresses the polymorphisms of genes encoding phase
I enzymes in Mexican Americans; these include: cytochrome
P450 (CYP) 2C19, CYP2D6, CYP2E1, alcohol dehydrogenase
(ADH), and aldehyde dehydrogenase (ALDH).
This review article summarizes the association between phenotype
(drug metabolism) and genotype for CYP2C19 and CYP2D6 as well
as the role of genetic variations in CYP2E1, ADH,
and ALDH as potential risk factors for alcoholism
in the Mexican American population. The major findings are
as follows: (1) Mexican Americans have unique genetic patterns
compared with other ethnic groups; (2) In general, Mexican
Americans tend to be extensive metabolizers of substrates
for CYP2C19 and CYP2D6; (3) Genotypes of CYP2D6 can
be used to predict phenotypes in Mexican Americans; and (4)
Variations in alcohol metabolizing genes contribute to alcoholism
in the Mexican American population.
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