Personalized Medicine - UCLA · • A meta-analysis of other studies showed that the ......

Personalized Medicine

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


•  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

Liver section stained with trichome for fibrosis (blue).

Higher power of liver showing macrophages containing intracellular hemosiderin particles

(brown) within fibrotic bands


•  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

•  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.


•  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


•  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


•  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


•  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


•  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


•  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


•  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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Genes Possibly Involved in Function and Metabolism of Vitamin K and its Antagonist, Warfarin

Wadelius and Pirmohamed, Pharmacogen J 7:99-111,

2007

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

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

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)

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

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

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

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)

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

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

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

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

Personalized Medicine - UCLA · • A meta-analysis of other studies showed that the ......

Documents

Transcript of Personalized Medicine - UCLA · • A meta-analysis of other studies showed that the ......