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V8 Pharmacogenomics
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Biological Sequence Analysis
SS 2008
lecture 8
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Pharmacogenomics
Pharmacogenomics is the branch of pharmacology which deals with the
influence of genetic variation on drug response in patients by correlating gene
expression or single-nucleotide polymorphisms with a drug's efficacy or toxicity.
By doing so, pharmacogenomics aims to develop rational means to optimise
drug therapy, with respect to the patients' genotype, to ensure maximum
efficacy with minimal adverse effects.
Such approaches promise the advent of "personalized medicine", in which
drugs and drug combinations are optimised for each individual's unique genetic
makeup.
Pharmacogenomics is the whole genome application of pharmacogenetics,
which examines the single gene interactions with drugs.
www.wikipedia.org
Biological Sequence Analysis
SS 2008
lecture 8
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Expected benefits from pharmacogenomics
Biological Sequence Analysis
SS 2008
lecture 8
Pharmacogenomics
Licinio, Wang (Eds)
Wiley (2002)
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SNPs that influence drug metabolism
Biological Sequence Analysis
SS 2008
lecture 8
Pharmacogenomics
Licinio, Wang (Eds)
Wiley (2002)
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Mutation in TMD4 of 2-adrenergic receptor
Well characterized drug target for
anti-asthma medication.
Thr164Ile mutation occurs at low
Frequency. According to homology
model mutant Ile interacts with
Ser165.
This affects ligand binding constant.
Biological Sequence Analysis
SS 2008
lecture 8
Pharmacogenomics
Licinio, Wang (Eds)
Wiley (2002)
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Mutation in TMD4 of 2-adrenergic receptor
Biological Sequence Analysis
SS 2008
lecture 8
Green et al.
J. Biol. Chem.
268, 23116 (1993)
6
Mutations on HIV protease surface
Boden & Markowitz,
(1998)
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Pharmacogenomics of cigarette smoking
WHO: tobacco smoking is responsible for death of ca. 5 million people/year.
approximately 22% of adults in the United States are smokers.
Although the majority (~80%) of smokers express a desire to quit smoking,
less than 5% are able to do so unaided owing to the highly addictive properties
of nicotine, the primary psychoactive substance in tobacco smoke.
FDA-approved pharmacotherapies to aid smoking cessation include nicotine
replacement therapies and the antidepressant bupropion (Zyban).
There is large interindividual variability in response and few maintain long-term
abstinence.
 need to better understand the biological determinants of nicotine
dependence (ND) and cessation.
What genetic factors determine response to nicotine replacement therapies?
Ho & Tyndale, Pharmacogenomics J. 7, 81 (2007)
Biological Sequence Analysis
SS 2008
lecture 8
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Pharmacogenomics of cigarette smoking
Cigarette smoking is a complex behavior that includes a number of stages such
as initiation, experimentation, regular use, dependence, cessation and relapse.
Although environmental factors such as the influence of family members, peers and
culture undoubtedly affects one’s smoking behaviors at these stages, genetics also has a
substantial role.
Numerous twin, adoption and family studies have been performed on the
heritability of ‘ever’ smoking.
Once smoking is initiated, the heritability for persistence to regular smoking has been
estimated at 28–84%, for number of cigarettes smoked at 45–86% and for diagnosed ND
at 31– 75%.
A genetic influence on nicotine withdrawal symptoms and smoking cessation has also
been identified with heritability estimated at 26–48 and 50–58%, respectively.
Taken together, these studies suggest a substantial genetic contribution to most aspects
of smoking.
Ho & Tyndale, Pharmacogenomics J. 7, 81 (2007)
Biological Sequence Analysis
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Genome-wide linkage studies
Genome-wide linkage studies have become more feasible with the availability of
denser markers, higher throughput and cost-effective genotyping methods.
Some of the loci associated with ND are near genes of known biological
relevance, including the
- 1-opioid receptor (OPRM1) on chromosome 6,
- serotonin receptor 5A on chromosome 7
- 2-nicotinic acetylcholine receptor (CHRNA2) and
- 1A-adrenergic receptor (ADRA1A) on chromosome 8.
Loci identified with other smoking phenotypes also contain some biologically
interesting candidates, such as a region on chromosome 5q located near the
dopamine receptor (D1) gene.
Ho & Tyndale, Pharmacogenomics J. 7, 81 (2007)
Biological Sequence Analysis
SS 2008
lecture 8
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Ho & Tyndale, Pharmacogenomics J. 7, 81 (2007)
Biological Sequence Analysis
SS 2008
lecture 8
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Dopaminergic system
The dopaminergic system has received considerable attention because its role
in the rewarding properties of nicotine is well established.
Dopamine receptors are a class of G-protein-coupled receptors with five
different subtypes (D1–D5) encoded by the genes DRD1–5.
Genome-wide linkage analyses have implicated a region near DRD2 on
chromosome 11q23 with cigarette consumption.
Genetic variation in DRD2 has been investigated; the TaqI A1 variant is a 32806
CT substitution at 10 kb downstream of DRD2 and lies within a novel, as yet
uncharacterized, kinase gene ANKK1.
Some studies, but not all, found the TaqI A1 allele resulted in a lower density of
D2 receptors in the human striatum in vitro and in vivo.
Ho & Tyndale, Pharmacogenomics J. 7, 81 (2007)
Biological Sequence Analysis
SS 2008
lecture 8
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Dopamine receptor
Dopamine receptors are prominent in the vertebrate central nervous system.
The neurotransmitter dopamine is the primary endogenous ligand for dopamine
receptors.
dopamine
Dopamine receptors have key roles in many processes, including
- the control of motivation,
- learning, and
- fine motor movement, as well as
- modulation of neuroendocrine signaling.
Abnormal dopamine receptor signaling and dopaminergic nerve function is
implicated in several neuropsychiatric disorders.
www.wikipedia.org
Biological Sequence Analysis
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Dopaminergic system
The Taq1 B1 allele is a second RFLP that lies 913 bp upstream of the start codon
in exon 2 of DRD2, suggesting that it may be a better marker for association
studies of substance abuse.
It is in significant linkage disequilibrium with the Taq1 A1 allele.
In population genetics, linkage disequilibrium is the non-random association of alleles at two or more loci,
not necessarily on the same chromosome. Linkage disequilibrium describes a situation in which some
combinations of alleles or genetic markers occur more or less frequently in a population than would be
expected from a random formation of haplotypes from alleles based on their frequencies. Non-random
associations between polymorphisms at different loci are measured by the degree of linkage disequilibrium
(LD). Linkage disequilibrium is generally caused by genetic linkage and the rate of recombination; rate of
mutation; random drift or non-random mating; and population structure.
Similar to the Taq1 A1 allele, individuals with the Taq1 B1 allele were more
likely to have ever smoked and started smoking at an earlier age.
A 48-bp variable number tandem repeat in exon 3 of DRD4 has also been of
interest; genome-wide linkage analyses have implicated a region on chromosome
11p15.5 near DRD4 with habitual smoking.
Ho & Tyndale, Pharmacogenomics J. 7, 81 (2007)
Biological Sequence Analysis
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Dopaminergic system
In African Americans, but not Caucasians, the long (L) allele (containing 6–10
repeats) has been associated with a greater risk of current smoking, and a shorter
time before the first cigarette in the morning compared to the short (S) allele
(containing 2–5 repeats).
Individuals with the L-allele also experienced greater craving, more arousal, less
positive affect and more attention to smoking cues than individuals with the
S-allele.
In adolescents, the L-allele (seven-repeat) increased the risk of smoking and
novelty seeking in males; however, another study failed to replicate these findings.
Ho & Tyndale, Pharmacogenomics J. 7, 81 (2007)
Biological Sequence Analysis
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Drug transporters and their cellular localizations
OAT: organic anion transporter
OCT: organic cation transporter
PepTs: peptide transporters
MDRs: multi-drug resistant proteins
MRPs: multidrug resistance-related
proteins
BCRP: breast cancer resistance
protein
Biological Sequence Analysis
SS 2008
lecture 8
Pharmacogenomics
Licinio, Wang (Eds)
Wiley (2002)
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V9: pharmacogenomics of efflux pump P-glycoprotein
Biological Sequence Analysis
SS 2008
lecture 8
Pharmacogenomics
Licinio, Wang (Eds)
Wiley (2002)
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