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Sequence Polymorphisms   & Personalized Medicine Unit 6. BIOL221T : Advanced Bioinformatics for Biotechnology. Irene Gabashvili, PhD [email protected] Pharmacogenomics - Study of genetic variation underlying differential response to drugs.

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Sequence polymorphisms personalized medicine unit 6

Sequence Polymorphisms   & Personalized MedicineUnit 6

BIOL221T: Advanced Bioinformatics for Biotechnology

Irene Gabashvili, PhD

[email protected]


Pharmacogenomics study of genetic variation underlying differential response to drugs
Pharmacogenomics - Study of genetic variation underlying differential response to drugs


Complexity of finding gene variations that affect drug responses
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.


Limited drug benefits
Limited Drug Benefits responses

  • 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 Alzheimer’s 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.


Genetic variation
Genetic Variation responses

  • 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)


Environmental factors
Environmental factors responses

  • 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……?


False or false
False (+) or False (-) responses

  • 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


Gene gene interaction
Gene-Gene Interaction responses

  • 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 don’t

  • Hard to base therapy…


Research in large populations
Research in large populations responses

  • 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 !!!!


Www pharmgkb org
www.pharmgkb.org responses


Pgx flow
PGx Flow responses


Pharmgkb in brief
PharmGKB, in brief. responses

  • Mission: aggregate, integrate & annotate PGxdata 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%)


Core contents
Core contents responses



Literature annotations publication links
Literature annotations & Publication Links responses

  • 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


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