Sequence Polymorphisms

1
Sequence Polymorphisms   Personalized
MedicineUnit 6

• BIOL221T Advanced Bioinformatics for
  Biotechnology

Irene Gabashvili, PhD igabashvili_at_yahoo.com
2
Pharmacogenomics - Study of genetic variation
underlying differential response to drugs
3
Complexity of Finding Gene Variations that affect
drug responses

• SNP (single nucleotide polymorphism) are common
  DNA sequence variations that occur when a single
  nucleotide (A,T,C,or G) in the genome sequence is
  altered, at 1 or higher frequency in the
  population.
• Millions of SNPs must be identified and analyzed
  to determine their involvement (if any) in drug
  response.
• Multi-gene interactions
• Gene-environment interactions
• Further complicating the process is our limited
  knowledge of which genes are involved with each
  drug response.

4
Limited Drug Benefits

• 5 to 10 percent of people from Mediterranean and
  African ancestry lack the glucose-6-phosphate
  dehydrogenase enzyme and thus risk breakdown of
  red blood cells from more than 200 drugs.
• Less than 5 percent of patients in breast cancer
  and Alzheimers are caused by genetic burden.
• Only 10 of NSC lung cancer patients (15-30)
  will benefit from NSCLC drugs Tarceva and IRESSA
• No population group is homogeneous.
• Even if drugs are developed, few people benefit.

5
Genetic Variation

• Few genotypes predict patients drug handling with
  high fidelity.
• Rare variants (frequency of less than 1) cannot
  account for high proportion of frequently
  occurring ADRs
• The presence of a polymorphism associated with
  altered drug handling is usually not a powerful
  predictor of the outcome.
• Example, the genetic test for exon 26 of the MDR
  gene is not a powerful predictor for low activity
  of the membrane p-glycoprotein. (Because
  sometimes these genes will give the same amino
  acid sequence)

6
Environmental factors

• Differences in the function of enzymes or
  proteins that affect drug handling may result
  from non genetic modification which might be
  influenced by other drugs or other exogenous
  factors
• Example, cholesterol level is affected by diet
  and exercise.
• Cholesterol is also high during pregnancy. Women
  should wait at least six weeks after the baby is
  born to have cholesterol measured.
• Genetic or environmental?

7
False () or False (-)

• Giving therapy when not needed based on genetic
  testing revealing false tests
• Unless genetic variant is highly predictive of
  altered drug handling, the test for variance will
  not have clinical significance
• Even for well established risk of polyneuritis in
  isoniazid users who are slow acetylators, the
  predictive value of testing is rather weak
• Breast cancer therapy, false positives and false
  negatives

8
Gene-Gene Interaction

• Some mutations will not alter drug handling
  unless mutations in genes at other loci are
  simultaneously present.
• Black or white
• No quality ranking, either have it or dont
• Hard to base therapy

9
Research in large populations

• Many of the trials would recruit only patients
  with favorable pharmacogentic profile in order to
  make the trials smaller and faster.
• Problem You do not get a full range of results
  for people who do not have ideal genetic
  profiles.
• In phase III testing there is even more reduction
  of sample size so less adverse reactions
  observed.
• Opposed to large populations where highly
  variable population so almost all adverse drug
  reactions observed
• BIG BIAS !!!!

10
www.pharmgkb.org
11
PGx Flow
12
PharmGKB, in brief.

• Mission aggregate, integrate annotate PGx
  data and knowledge
• Main resources (Statistics as of Fall-2006)
• 232 genes with detailed genotypes
• 1600 published gene-drug associations
• 37 Annotated PGx Pathways
• 16 VIP Gene variant summaries
• 44K unique IP visitors in 10/06
• Google referrals predominantly drugs (30)
• Referred from drug resources (15)
• Referred from gene resources (10)
• Direct links (30)
• Misc (15)

13
Core contents
14
(No Transcript)
15
(No Transcript)
16
(No Transcript)
17
(No Transcript)
18
Whole Genome Data
19
(No Transcript)
20
(No Transcript)
21
(No Transcript)
22
(No Transcript)
23
(No Transcript)
24
(No Transcript)
25
(No Transcript)
26
(No Transcript)
27
Literature annotations Publication Links

• Literature Annotations
• PharmGKB curators create data entries that
  associate genes with drugs and phenotypes, based
  on an interpretation of the literature. They
  encode with controlled vocabularies.
• Publication Links
• Scientists can upload phenotype files (all
  formats) at the time of submission of
  publications
• PharmGKB ID numbers provided in advance to cite
  in manuscripts

28
(No Transcript)
29
(No Transcript)
30
(No Transcript)
31
(No Transcript)
32
(No Transcript)
33
(No Transcript)
34
(No Transcript)
35
(No Transcript)