Personalized Medicine - UCLA · • A meta-analysis of other studies showed that the ......
Transcript of Personalized Medicine - UCLA · • A meta-analysis of other studies showed that the ......
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Personalized Medicine
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Population-Based Screening for Genetic Risk
• Principles of population-based screening: - Public health importance of the
disorder - Quality of tests and interventions - Policy development and intervention
• The goal of population-based screening – identify those with higher levels of genetic risk
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Population-Based Screening for Genetic Risk
• Adult-onset disorders that meet these criteria and have significant genetic risk are the “single gene” Mendelian disorders
• Common disorders (cancer, diabetes, heart disease) have higher frequency, but we don’t begin to understand them
• Studies of the “single gene” Mendelian disorders require large numbers of participants because they are rare
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Liver section stained with trichome for fibrosis (blue).
Higher power of liver showing macrophages containing intracellular hemosiderin particles
(brown) within fibrotic bands
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Population-Based Screening for Genetic Risk
• Hemochromatosis is an autosomal recessive disorder of iron overload that leads to liver disease, diabetes, heart disease, bronzing of the skin, arthritis, and fatigue
• Treatment is regular blood collection
• 1 in 200 individuals of Northern European descent has a mutation in the HFE gene
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• The HFE protein consists of extracellular domains and a transmembrane domain that spans the cell membrane and binds to the beta-2-microglobulin protein • The extracellular domains interact with the transferrin receptor • The transferrin receptor is another transmembrane protein important for iron regulation
M. J. Bennett et al. Nature 403:46-53, 2000
Two views of the HFE (blue and green) and beta-2 microglobulin (aqua and gold) proteins.
Cysteine 282 is shown in purple.
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Population-Based Screening for Genetic Risk
• 80-90% of those with hemochromatosis were C282Y homozygotes
• Most of the others were C282Y/H63D compound heterozygotes – H63D: Histidine-63-Aspartic acid
• The C282Y homozygotes were 1 in 150-200 Northern Europeans
• Hemochromatosis – On a genetic basis, the most common autosomal
recessive disorder in Northern Europeans – But this is a significant overestimate
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Population-Based Screening for Genetic Risk
• The NIH-funded Hemochromatosis and Iron Overload Screening Study (HEIRS) had 99,711 participants
• C282Y and H63D were the most common mutations in Whites
• Majority of C282Y/C282Y homozygotes had increased levels of iron saturation in the blood
• Male C282Y homozygotes were 3.3 times more likely to report liver disease
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Population-Based Screening for Genetic Risk
• Male C282Y/H63D heterozygotes were 1.7 times more likley to report liver disease
• No increase in diabetes was found • Other studies have shown that the
penetrance of these alleles is quite low • A study in South Wales showed only 1%
of C282Y homozygotes had symptoms of clinical hemochromatosis
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Population-Based Screening for Genetic Risk
• A meta-analysis of other studies showed that the penetrance of the C282Y/C282Y genotype is very low – Homozygosity for the mutation is a necessary, but not
sufficient, condition for the disease • Other nuclear and mitochondrial genes, and
environmental factors are involved • Let’s consider alcohol consumption,
known to be associated with increased iron saturation
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Population-Based Screening for Genetic Risk
• C282Y homozygotes had significantly elevated iron saturation without increased clinical symptomatology, if they drank more than four bottles of beer, four glasses of wine or six ounces of 80-proof spirits daily
• Among C282Y homozygotes identified clinically, who had a liver biopsy, the rate of serious liver disease identified microscopically was – 9-fold higher among the higher consumption group – 66% of higher consumption group versus 7% of those
who consumed less alcohol
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Population-Based Screening for Genetic Risk
• Hemochromatosis teaches us that large population studies are required before broad-based genetic testing should be recommended
• Screening should not be based on preliminary data from a population defined by clinical symptomatology
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Population-Based Screening for Genetic Risk
• When a disorder is defined prospectively by a laboratory test, it has more clinical variation
• Hemochromatosis shows us that we should not rush to population screening simply because we have identified a gene
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Pharmacogenomics
• In 2000, the Institute of Medicine estimated that adverse drug reactions (ADRs) cause 7,000 patient deaths each year
• Other studies have placed the rate of ADRs much higher
• In nursing homes, 350,000 ADRs are estimated annually
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Pharmacogenomics
• Among hospitalized patients: - 2million serious ADRs each year - 6.7% will have a serious ADR
• The estimated fatality rate from ADRs is 0.32%
• More than 100,000 deaths annually are due to ADRs
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Pharmacogenomics
• The FDA states, “If true, then ADRs are the 4th leading cause of death – ahead of pulmonary disease, diabetes, AIDS, pneumonia, accidents and automobile deaths.”
• By applying genomic concepts, informatics and tehcnologies to improve the safety of drugs, pharmacogenomics will reduce ADRs
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Pharmacogenomics • The role of differential gene expression on
drug activity or the influence of drugs on gene expression involves the measurement of RNA
• The evaluation of proteins and structural biology (physical structure of proteins), and the influence of drugs on these structures are critical in drug design and discovery – “Rational drug discovery” vs.
random testing of hundreds of thousands of molecules
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Pharmacogenomics
• Genetic variations responsible for an ADR to a specific drug may be quite rare
• Large population studies are required to consider correlations between drug responses, toxic side effects, and genetic variation
• One approach is to use single nucleotide polymorphisms (SNPs) to correlate with drug responses and toxicities
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Pharmacogenomics • SNPs may alter an amino acid that affects
activity or stability of a drug metabolizing enzyme or a drug receptor, and therefore alter responses to the drug
• Pharmaceutical companies have been collecting SNP data since the mid 1990s
• In 1999, a consortium of pharmaceutical companies and other researchers published 1million SNPs on the internet
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Pharmacogenomics
• Many clinical trials require DNA samples for compilation of SNPs
• The FDA may require DNA data and association studies with every new drug application
• Banked DNA specimens may be valuable if problems arise with a drug after its release for use in the community
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Pharmacogenomics
• Side effects are not purely probabilistic • Each one of us does not have the same
probability of having a side effect • Certain individuals are at increased risk of a side
effect because of their genomic sequence • If the pharmaceutical industry and
the FDA could move toward a more personalized approach to medicine, we could decrease ADRs
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Pharmacogenomics
• Drugs that are extremely effective and have a low incidence of ADRs could still be available to those for whom they work
• Testing before starting on the drug would prevent ADRs in those who are susceptible
• This is better than taking a drug off the market when there is an increase in ADRs
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Pharmacogenomics
• Kathryn Phillips and Stephanie Van Bebber, health economists at UCSF, studied SNP testing for the drug metabolizing enzyme, CYP2D6
• The cytochrome P450 (CYP) enzyme superfamily is a group of enzymes involved in metabolizing drugs and toxins, particularly CYP2 and CYP3
Cytochrome P450 protein model
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Pharmacogenomics
• In December 2004, the FDA approved the Roche AmpliChip, a DNA microarray that is designed to test for SNP variations in two CYP enzymes: - 29 polymorphisms and mutations
in the CYP2D6 gene - 2 polymorphisms in the
CYP2C19 gene
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Pharmacogenomics
• CYP2D6 metabolizers are poor, intermediate, extensive, or ultra-rapid
• CYP2D19 metabolizers are poor or extensive
• CYP2D6 ultra-rapid metabolizers have 3-13 copies of the allele, so they make much more enzyme, and metabolize the drug much more rapidly
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Pharmacogenomics • A. Antihypertensive medication, debrisoquine, is metabolized by CYP2D to 4-hydroxy (OH)-debrisoquine, and therefore the urinary ratio of debrisoquine/4-OH-debrisoquine is a measure of the CYP2D activity; the lower the ratio the higher the CYP2D activity. – Horizontal boxes above the bars
represent genotype. – Ratio increases as number of
normal alleles decreases – Filled bars (right) represent poor
metabolizers, and individual (extreme left) with 12 additional normal CYP2D alleles represents an ultra-rapid metabolizer.
http://www.blackwell-synergy.com/doi/full/10.1046/j.0306-5251.2001.01548.x
A
B
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Pharmacogenomics • B. The doses of the antidepressant drug, nortriptyline, are shown that would be required to treat individuals with those genotypes effectively and safely. – It is impressive that the dose
can vary by a factor of 25 or more.
– Peak plasma concentration of nortriptyline after a single dose of 25 mg varies by a factor of more than four.
– Duration of the drug’s effect is also influenced by the rate of metabolism.
http://www.blackwell-synergy.com/doi/full/10.1046/j.0306-5251.2001.01548.x
A
B
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Pharmacogenomics • Knowledge of an individual’s drug
metabolizing status will determine their dose
• 100 drugs are substrates for CYP2D6, including treatments for – Depression – Psychoses – Heart arrhythmias – High blood pressure – Cough
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Pharmacogenomics
• Phillips and Van Bebber concluded that drugs that metabolize CYP2D6 account for 5-10% of outpatient drugs – 189M prescriptions and US$12.8B annually
• Large prospective clinical trials will be required to provide the evidence-base necessary to change clinical practice and to understand genetic variation
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Pharmacogenomics
• Phillips and Van Bebber noted an economic disincentive for pharmaceutical companies to use pharmacogenomics to stratify the population into subgroups based on genetics
• This will decrease the number of blockbuster drugs and lead to boutique drug manufacturers with a different business plan
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Pharmacogenomics
• Warfarin is an anticoagulant (blood thinner) that is used to prevent life threatening blood clots in the lungs or brain
• Therapeutic dosing of warfarin is difficult, so it is underused, even though for every one bleeding episode caused by warfarin, 20 strokes are prevented by warfarin
Wisconsin Alumni Research Foundation
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Genes Possibly Involved in Function and Metabolism of Vitamin K and its Antagonist, Warfarin
Wadelius and Pirmohamed, Pharmacogen J 7:99-111,
2007
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Pharmacogenomics
• Warfarin is metabolized by CYP2C9 • More than 30% of Caucasians have one of
two variant alleles: – CYP2C9*2 reduces
warfarin metabolism by 30-50%
– CYP2C9*3 reduces warfarin metabolism by 90%
Williams et al. Nature 424:464-468, 2003
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Pharmacogenomics
• Simon Sanderson and colleagues from the UK and Australia, showed that patients with one of these two variants had daily warfarin doses that were up to 37% lower and a bleeding risk that was ≥2X higher compared to those with the normal CYP2C9* alleles
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Pharmacogenomics • Y.T. Chen, Taiwan and Duke University,
and collaborators, studied the interaction between CYP2C9 variants and polymorphisms in VKOR (the enzyme inhibited by warfarin – vitamin K epoxide reductase complex I)
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Pharmacogenomics
• Missense mutations in VKOR are associated with blood clotting disorders: - Deficiency of vitamin K dependent
clotting factors that causes life threatening bleeding episodes, treated with vitamin K
- Resistance to the anticoagulant effects of warfarin
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Pharmacogenomics
• Chen and colleagues wanted to understand why Chinese patients were more sensitive to warfarin
• They identified CYP2C9*3 and two other sequence variants in their Chinese patients
• The allele variants were present in some warfarin sensitive patients
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Pharmacogenomics
• Chen and colleagues sequenced the VKOR gene and found allelic variants that correlated with warfarin resistance or sensitivity
• They explained that the sensitive patients had only the normal CYP2C9*1 allele
• Based on these data, the FDA recommended a two year study of sequence variants in the CYP2C9 and VKOR genes
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Pharmacogenomics • Even better data more recently
from YT Chen’s group • Correlation after 12 wks
between predicted and maintenance doses.
• White area indicates predicted matching maintenance doses.
• Number on each bar indicates the number of patients.
• Note high correlation especially in the most challenging low and high dose groups.
Wen et al. Clin Pharm Ther. Jan 2008 (epub ahead of print)
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The SEARCH Collaborative Group, 2009
• Statins are used to lower LDL • Side effect of muscle pain or weakness • Studied 85 patients on 80 mg simvastatin
who had side effect and 90 who did not • Genomewide association study found one
SNP in SLCO1B1 (metabolizes statins) • One C 4.5 fold increased risk • CC 16.9 fold increased risk
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The SEARCH Collaborative Group, 2009
• Replicated this study in patients taking 40mg simvastatin
• Relative risk of 2.6 per copy of the C allele • Patients also taking cyclosporine and/or
amiodarone had further increased risk • Results suggest that patients should be
genotyped for the C allele before statins are prescribed
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Pharmacogenomics
• As the cost of DNA sequencing decreases, sequence based pharmacogenomics will lead us toward genomic medicine for everyone
• Genomic medicine needs to be inclusive, not exclusive
• Personalized drug therapy will save lives and prevent ADRs
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Pharmacogenomics
• Large datasets will be required to understand genomic variation
• Relatively rare sequence variations can cause severe problems
• Each of us has a unique sequence • All of us may have to enroll in ongoing
population based genomic studies • Those who don’t participate may be excluding
themselves from the benefits of genomic medicine
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