Jose Ordovas PhD

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Apo E and pharmacogenetics tailoring cures to
the patient

• Jose Ordovas PhD
• Professor/Senior Scientist
• JM-USDA-Human Nutrition Research Center on Aging,
  Tufts University
• Boston, MA

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Pharmacogenetics

• If genetic make-up can be used to predict a
  patient's susceptibility to disease or their
  likely response to treatment, care could be
  tailored to individual patients.
• A major gene involved in cardiovascular disease
  and a focus of much study is the one coding for
  apolipoprotein ? (apo E).
• Apo E is one of the first genes being used to
  predict risk and response to treatment.

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Apolipoprotein E
Marker for cardiovascular risk

• Carriers of the e4 allele (1213 of the white
  population) have risk factors associated with
  cardiovascular disease
• higher cholesterol levels
• higher LDL cholesterol levels
• in some instances higher triglyceride levels
• Carriers of the e4 allele are at higher risk for
  cardiovascular disease.

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4S study
e4 carriers risk and response

• Scandinavian Simvastatin Survival Study
• The original 4S study convinced people of the
  importance of cholesterol as a risk factor and
  the fact that real benefit is achieved by
  decreasing cholesterol.
• 4S showed that carriers of the e4 allele are at
  greater risk for cardiovascular disease.
• However, carriers of the e4 allele also get more
  benefit in terms of cardiovascular events from
  statin treatment than those who are not carriers.

Lancet 1994344(8934)1383-1389
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4S substudy
e4 allele carriers

• Carriers of the e4 allele of the apo E gene are
  at a higher risk of coronary heart disease than
  people with other genotypes.
• The 4S substudy examined whether the risk of
  death or major coronary event in survivors of
  myocardial infarction depended on apo E genotype
  and whether response to simvastatin treatment
  differed between genotypes.
• 5.5 years of follow-up data from 966 Danish and
  Finnish myocardial infarction survivors enrolled
  in the Scandinavian Simvastatin Survival Study
  were analyzed.

Gerdes LU, et al. Circulation 2000101(12)1366-13
71
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4S substudy
Results 5.5 year follow-up

• Apo E genotype did not predict the risk of a
  major coronary event.
• Myocardial infarction survivors with the e4
  allele were at nearly twice the risk of dying
  than non-carriers, and the excess mortality can
  be abolished by treatment with simvastatin.
• e4 is a common genetic marker that identifies a
  subgroup of coronary patients that is
  simultaneously at a higher risk of death and
  particularly prone to benefit from preventive
  treatment.

Gerdes LU, et al. Circulation 2000101(12)1366-13
71
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CETP and atherosclerosis
Study design

• This study was designed to determine if the
  presence of a common DNA variant predicts whether
  treatment with pravastatin will delay the
  progression of coronary atherosclerosis in men
  with coronary artery disease (the presence of
  this DNA variation was referred to as B1, and its
  absence as B2).
• The DNA of 807 men with angiographically
  documented coronary atherosclerosis was analyzed
  for the presence of a polymorphism in the gene
  coding for CETP.
• All patients participated in a cholesterol-lowerin
  g trial designed to induce the regression of
  coronary atherosclerosis and were randomly
  assigned to either pravastatin or placebo for 2
  years.

Kuivenhoven JA, et al. N Engl J Med 1998 338(2)
86-93
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CETP and atherosclerosis
Polymorphism in the CETP gene
Kuivenhoven JA, et al. N Engl J Med 1998 338(2)
86-93
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CETP and atherosclerosis
Results

• The significant association observed between the
  B1 allele and the progression of coronary
  atherosclerosis was abolished by pravastatin.
• Pravastatin therapy slowed the progression of
  coronary atherosclerosis in B1B1 carriers but not
  in B2B2 carriers.
• There is a significant relation between variation
  at the CETP gene locus and the progression of
  coronary atherosclerosis that is independent of
  plasma HDL cholesterol levels and the activities
  of lipolytic plasma enzymes.
• This common DNA variant appears to predict
  whether treatment with pravastatin will delay the
  progression of coronary atherosclerosis in men
  with coronary artery disease.

Kuivenhoven JA, et al. N Engl J Med 1998
338(2)86-93
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Gene chips
Chip technology can be used to identify DNA
polymorphisms in the human genome, which may
prove useful for large-scale linkage analysis.

• Small synthetic pieces of DNA are annealed in
  arrays on a silicon chip or another matrix.
• Human template DNA is hybridized to the chip,
  indicating the presence or absence of a DNA
  sequence polymorphism.
• Chips may prove useful for studies of the genetic
  factors that contribute to complex multifactorial
  disease.

The intensity and color of each spot encode
information on a specific gene from the tested
sample.
Courtesy of DOE Human Genome Program(http//www.o
rnl.gov/hgmis)

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Genegene interaction
Practical application

• Gene chips will be used to determine
• genetic predisposition
• response to treatment
• In some cases the same gene that predispose to
  risk will also be a determinant of response.
• If you know you are at high risk for
  cardiovascular disease because of lifestyle or
  genetics primary or secondary preventive measures
  can be taken.

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Genetic screening

• The same gene variant that predisposes people to
  higher risk of cardiovascular disease also
  predispose them to Alzheimer's disease.
• Some commercial ventures are already testing
  people for apo E in relation to dementia and
  Alzheimer's, but not yet in relation to
  cardiovascular disease.
• Cardiovascular disease is multifactorial with
  both the genetic and the environmental
  components.
• Assessing risk on the basis of a genetic test
  alone may be misleading.
• Clinical application of genetic screening will
  probably become more routine within 5 years.

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Human genome project
A first step

• A coordinated effort is being made to
  characterize all human genetic material by
  determining the complete sequence of the DNA in
  the human genome.

The ultimate goal is to discover all of the more
than 100 000 human genes. Once the genome
sequence is known, the meaningful mutations must
then be separated from the hundreds of thousands
of mutations that are not meaningful. Then
identification can begin of the 500 genes with
different mutations involved in cardiovascular
disease. The problem that will arise is
bio-informatics how to analyze so much complex
information.
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Gene mapping

• More than 250 genes have already been mapped to
  chromosome 19.
• The positions of the genes listed on the lower
  half of this illustration are known with far
  greater accuracy than shown here.
• The genes listed above the chromosome have been
  mapped to larger regions of the chromosome -- or
  merely localized to chromosome 19 generally.

apo E
Courtesy of DOE Human Genome Program(http//www.o
rnl.gov/hgmis)
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Unraveling the complexity

• Gene chips with bio-informatics databases will
  help overcome the complexity of gene variability.
• With current work, a statistically significant
  (2 and 10) component of gene variability may be
  explained.
• In the future, up to 50 of the variability may
  be explained.
• We will never explain 100 of the variability.
• With 50 of the variability explained, therapy
  will become more individualized and, in the long
  term, more economical.

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Risk scales
Complementary information

• Genetic information and risk scales provide
  complementary information.
• Even relatively good scales are based on
  probability they cannot assess every aspect of
  risk.
• The genetic information will increase the utility
  of algorithms to individuals, not just certain
  populations or groups.
• Genetics information will add the individuality
  to those equations.