Pharmacogenetics is the study of genetic variations that influence individual responses to drugs. It aims to provide information to help doctors prescribe better and safer drugs at appropriate doses tailored to a patient's genetics. The study examines how genetic variations can affect drug metabolism and efficacy. Understanding a patient's genetic profile could help predict drug responses and prevent adverse reactions.

1. Pharmacogenetics
Larry Baum
Hong Kong

2. Tailoring Treatments To Patients' Genetics (Wendy
Kaufman, National Public Radio, 11 September
2008):
http://www.npr.org/templates/story/story.php?storyId=9
What is pharmacogenetics?

3.  Study or clinical testing of genetic variation that
gives rise to differing response to drugs.
 Pharmacogenetics provides information that may
help:
 You receive better and safer drugs the first time.
 Your doctor provide you with a more appropriate
dose.
 Improve disease screening.
 Prevent disease.
 What is genetic variation?
What is pharmacogenetics?

4.  Same as pharmacogenetics. The two words are
used interchangeably.
What is pharmacogenomics?

5. Talk Outline
 Genetics
• Theory
 Drug responses

6.  Selected terms from Human Molecular Genetics;
by Strachan, Tom and Read, Andrew P.; published
by Garland Science; c1999:
http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=hm
Reference for this part of the talk

7. Genes
• Gene -- section of DNA that makes one protein
• 3 billion nucleotides and ~20,000 genes in humans
• DNA mutation -- gene alteration that leads
to a defective gene product
• Allele -- each gene has two copies, one from
each parent

8. Genetic disease pathway
DNA Mutation
↓
• Expression level: Too much or too little
OR
• Altered protein: Gain or loss of function

9. Mutseqmorphism
 Sequence alteration, sequence change -- any
change in DNA sequence
 Polymorphism -- a common sequence alteration
 Mutation -- a sequence alteration that causes disease
Polymorphism
Sequence alteration
Mutation

10. Types of Sequence Alterations
Murphy’s Law: “Whatever can go wrong, will go
wrong.”
If you can imagine a type of alteration, it’s happened.
 Silent -- most common, and no effect on protein
 Missense -- substitutes one amino acid with
another
 Nonsense -- substitutes amino acid codon with
stop codon
 Splicing -- change of splicing signal at
intron/exon junction
 Insertion, deletion -- frameshift or add/remove
amino acids

11. Sequence Alteration Naming
 cDNA (only the nucleotides that will be translated)
 Numbering: +1 is the A in start codon
 Substitution: 2389C>T, -94G>A
 Deletion: 2033delA, 435-437del
 Insertion: 880-881insGT
 Introns: IVS4+2T>A, 552+2T>A, IVS1-1G>C
 Amino acid: Y220M, R46X

12. Types of Sequence Alterations:
Examples
 Silent – Y220Y, 679C>T
 Missense – Y220M
 Nonsense – R46X
 Splicing – IVS18+1G>A
 Insertion, deletion – 406-407insA,
3214del11, 406-407insACCTTG

13. SNP
 SNP: Single Nucleotide Polymorphism
 Most common kind of polymorphism

14. Genotype & Phenotype
• Genotype: the DNA sequence of an individual
• Phenotype: the properties of an individual
(appearance, disease symptoms, behavior,
etc.)
Genotype + Environment → Phenotype

15. Types of genetic disease
• Genetic: from DNA
• Familial: runs in a family
• Congenital: onset before birth
• Hereditary: from parent DNA
• Sporadic: not familial
• Late-onset: onset at older ages

16. Genetic Diseases
Alterations
Genes
Diseases
Phenotypes
One DNA sequence alteration can cause
several diseases
Different alterations, in different genes,
can cause one disease
DNA sequence alterations may not cause
disease. In fact, most do not make any
difference

17. Haplotypes
• Group of alleles that tend to be inherited together
• Usually close together, but could be distant
SNP1
A/T
SNP2
C/T
SNP3
A/T
SNP4
C/G
Haplotype A: 23% A T T C
Haplotype B: 15% A T A C
Haplotype C: 11% T T A G
Other haplotypes: 51%

18. Haplotypes
• HapMap project identified haplotypes: hapmap.org
• Genotyped Chinese, Japanese, European, and
African individuals
• Tagging SNPs can represent haplotypes
• HapMap can select tagging SNPs

19. Talk Outline
 Genetics
• Theory
• Techniques
 Drug responses

20. How to genotype genetic
variations
• Novel variants
• Sequencing
• Known variants
• Variety of methods
• Choice depends on scale
• # of variants
• # of subjects

21. How to genotype novel variants
• Choose gene to examine, based
on:
• Function
• Location (linkage)
• Subjects
• Recruit subjects
• Collect from each subject:
• Drug response data
• Blood
• Sequence
• Extract DNA from blood
• Perform sequencing

22. Genotyping Troubleshooting
Hardy-Weinberg distribution deviation example:
Wild-type Heterozygotes Homozygotes
1 99 0
Wild-type Polymorphic
101 (50.5%) 99 (49.5%)
Observed
Genotypes:
Observed Alleles:
Wild-type Heterozygotes Homozygotes
100x.5052
=
25 (25.5%)
100x2x.505x.495=
50 (50.0%)
100x.4952
=
25 (24.5%)
Expected
Genotypes:
Observed vs. Expected Genotypes: chi square=63,
p<0.00000001, therefore significant deviation from Hardy-
Weinberg distribution

23. Discovering pharmacogenetic association with known
polymorphisms
 Choose subjects with drug response
data
 Choose polymorphisms
 Choose genotyping method
 Perform genotyping
 Analyze results

24. Choose polymorphisms
 Polymorphisms already reported to
associate with drug response
 Or polymorphisms near those
 Physically close: within several hundred
bases
 Linked: Use HapMap.org (Browse data) Tag
SNP picker with CHB subjects to find SNPs
representing haplotype blocks in a gene
 Or polymorphisms in suspect genes

25. Choose genotyping method
 If you only want to genotype a few SNPs, use:
 PCR-RFLP
1. Amplify region containing SNP
2. Apply restriction endonuclease that cuts only
one of the two possible sequences
3. Distinguish different length fragments on gel
4. Cost of material+labor ~US$1.5/genotype
 TaqMan or similar commercial assays
1. Need real-time PCR machine
2. Reagents cost much more than PCR-RFLP
3. But labor costs less than PCR-RFLP
4. Cost of material+labor ~US$1.2/genotype

26. Choose genotyping method
 More SNPs (~4-~200)
 Sequenom mass spectrometry
1. Companies can do for a fee
2. Does groups of ~30 SNPs & 356 samples
3. Cost of material+labor ~US$1.2/genotype

27. Choose genotyping method
 Many SNPs (~200-1,000,000)
 Illumina Bead Array
o Illumina can do for a fee
o Cost for 1000 samples:
 200 SNPs: ~US$0.25/genotype
 1000 SNPs: ~US$0.1/genotype
 100,000 SNPs: ~US$0.02/genotype
 Affymetrix or Illumina
o Companies can do for a fee
o Mass-produced chips with SNPs covering
the whole genome
o Cost for 1000 samples:
 1,000,000 SNPs: <US$0.001/genotype

28. Analyze results
 Hardy-Weinberg analysis to detect
genotyping errors
 Choose test
 T test for continuous variable
 χ2
test for categorical variable
 Genotypes and alleles
 P value
 Odds ratio & 95% confidence interval for χ2
 Correct for multiple comparisons
 Interpret results

29. Talk Outline
 Genetics
 Drug responses

30.  The Pharmacogenetics and Pharmacogenomics
Knowledge Base: http://www.pharmgkb.org
 T.E. Klein, J.T. Chang, M.K. Cho, K.L. Easton, R.
Fergerson, M. Hewett, Z. Lin, Y. Liu, S. Liu, D.E.
Oliver, D.L. Rubin, F. Shafa, J.M. Stuart and R.B.
Altman, "Integrating Genotype and Phenotype
Information: An Overview of the PharmGKB
Project", The Pharmacogenomics Journal (2001) 1, 167-
170.
Reference for this part of the talk

31.  Study or clinical testing of genetic variation that
gives rise to differing response to drugs.
 A drug may help most patients, but some
people might not respond at all to that drug.
 A drug may cause side effects in some patients
but not others.
What is pharmacogenetics?

32. A case study: (Joanne Silberner, “Gene Test
Promises to Find Right Drug, Right Dose,”
National Public Radio, 20 July 2006)
http://www.npr.org/templates/story/story.php?storyId=
What is pharmacogenetics?

33.  Let’s guess his
phenotypes
AmpliChip CYP450 Test
genotypes for
cytochrome P450 2D6
(CYP2D6) and 2C19
(CYP2C19) genes to
identify slow or fast
metabolizers.
Jacob

34.  CYP2D6 phenotypes
 Poor metabolizers
 Intermediate metabolizers
 Extensive metabolizers
 Ultrarapid metabolizers: multiple gene copies
 CYP2C19 phenotypes
 Normal
 Poor metabolizers
 Jacob’s phenotype
 Intermediate for one gene: CYP2D6
 Slow for another: CYP2C19
Jacob

35.  He took risperidone
 Metabolized by CYP2D6, not CYP2C19
 But 9-hydroxy-risperidone also has activity (and is
now sold as a drug!)
 Thus, not clear why CYP2D6 affects risperidone
Jacob
risperidone 9-hydroxy-risperidone
CYP2D6

36. Another CYP2D6 example: codeine
 CYP2D6
haplotypes affect
conversion to
morphine
 What would
response to codeine
be for:
 Ultrarapid
metabolizer?
 Poor
metabolizer?

37. Drug responses

38. Drug responses
codeine

39. Drug responses
Next example:
AEDs

40. Example of pharmacogenetic
research: anti-epileptic drugs
 Anti-epileptic drugs (AEDs)
 Many, with different mechanisms
 May be combined
 Different drugs, at different doses, work on
different patients.
 20-40% of patients aren’t helped by any drug,
and are called resistant or refractory. If drugs do
suppress seizures, the patient is responsive or in
remission.
 If drug treatment fails, surgery may be used to
remove tumor or epileptic focus

41. Mechanisms of AEDs
 Mechanism is not fully known for all AEDs
 Some may limit sustained, repetitive, neuronal
action potentials by blocking voltage-gated
sodium channels:
 Carbamazepine
 Phenytoin
 Some block other channels

42. Causes of pharmacoresistance
 Type or cause of epilepsy?
 Decreased (or increased) level or
function of AED target?
 Faster metabolism of AED?
 Increased transport of AED out of brain?

43. Causes of pharmacoresistance
 Type or cause of epilepsy?
 Decreased (or increased) level or
function of AED target?
 Faster metabolism of AED?
 Increased transport of AED out of brain?

44. AED export
 Some proteins pump drugs out of brain
across the blood-brain barrier.
 One is multi-drug resistance protein 1
(MDR1), also called P-glycoprotein (Pgp)
or ABCB1.
 Mixed evidence for Pgp action on AEDs
 It is overexpressed in neurons and
astrocytes in epileptic foci.

45. ABCB1
 ABCB1 SNPs were associated with AED
responsiveness.
 3435C>T: T frequency significantly
increased (or decreased!) in refractory
epilepsy.
 2677G/T/A and 1236 SNPs also
associated inconsistently with drug
responsiveness.
 Thus we performed case-control study.

46. ABCB1
 Used a haplotype-tagging strategy to
select SNPs to cover:
 SNPs in Chinese, based on HapMap
data of genotype frequencies and the
Tagger function of the Haploview program
 + 4 interesting SNPs
 Genotyped 12 SNPs

47. ABCB1 haplotype analysis
• Numbers in diamonds indicate linkage disequilibrium (r2
x100)
between pairs of SNPs.
• Which pair of SNPs has strongest LD?
• Which pair of SNPs are closest?

48. ABCB1 and drug resistance
rs3789243C and 2677A/T, or alleles in linkage disequilibrium with
them, may independently increase AED resistance.

49. ABCB1 and drug resistance
2677G was associated with drug resistance after
adjustment by logistic regression for sex, age, onset
age, etiology, and all polymorphisms: OR=0.69, p=0.02.

50. ABCB1 and drug resistance
Haplotypes were associated with resistance.

51. ABCB1 SNPs
• Functional effects reported for these SNPs, but
confusing and contradictory
 3435T is non-coding SNP associated with lower expression of
ABCB1 in Europeans, but higher in Asians! Is discrepancy due
to different LD with other SNPs that affect expression? Also
associated with altered protein conformation and activity.
 2677T (Ser) associated with lower level but higher activity of
ABCB1, and higher CYP3A4 activity.
 rs3789243 was reportedly associated with ulcerative colitis.
• Since ABCB1 expression varies many fold among
tissues and individuals, subtle interactions of SNPs
may greatly affect activity.

52. Drug responses
next example:
AEDs

53. Causes of pharmacoresistance
 Type or cause of epilepsy?
 Decreased (or increased) level or
function of AED target?
 Faster metabolism of AED?
 Increased transport of AED out of brain?

54. Sodium channels
 SCN1A, 2A, and 3A are the genes for voltage-
gated sodium channels type 1α, 2α, and 3α.
 The 3 genes are in a cluster on chromosome 2.
 A polymorphism in SCN1A was associated with
the effective AED dose.
 We examined SCN1A, 2A, and 3A for
association with AED responsiveness in 494
epilepsy patients: 279 responsive, 215 resistant.

55. Sodium channels
 Used a haplotype-tagging strategy to
select SNPs to cover: HapMap data of
SNP genotype frequencies from Chinese
and the Tagger function of the Haploview
program + 3 interesting SNPs
 5 SCN1A SNPs
 14 SCN2A SNPs
 4 SCN3A SNPs
 Captured 257 of 299 alleles with r2
>0.8

56. Sodium channels: haplotypes

57. SCN
 None of the SNPs in SCN1A or 3A were
associated with AED responsiveness.
 3 SNPs in SCN2A were associated with AED
responsiveness.
SNP rs# Gene Alteration Minor Allele Frequency P
Remission Refractory
1965757 SCN2A A>G 0.312 0.244 0.02
2304016 SCN2A IVS7-32A>G 0.100 0.051 0.005
935403 SCN2A A>G 0.297 0.224 0.03

58. SCN2A
Affected * rs2304016 code Crosstabulation
1 53 225 279
.4% 19.0% 80.6% 100.0%
3 16 198 217
1.4% 7.4% 91.2% 100.0%
4 69 423 496
.8% 13.9% 85.3% 100.0%
Count
% within Affected
Count
% within Affected
Count
% within Affected
remission
refractory
Affected
Total
GG AG AA
rs2304016 code
Total
Chi-Square Tests
15.049a 2 .001
15.922 2 .000
7.583 1 .006
496
Pearson Chi-Square
Likelihood Ratio
Linear-by-Linear
Association
N of Valid Cases
Value df
Asymp. Sig.
(2-sided)
2 cells (33.3%) have expected count less than 5. The
minimum expected count is 1.75.
a.
Odds Ratio=0.49
for G allele

59. • rs2304016 (IVS7-32A>G) is only a tagging
SNP, presumably in linkage disequilibrium (LD)
with the functional SNP that directly affects drug
responsiveness by changing the level or
function of the protein.
• What is the functional SNP?
• Search of HapMap for SNPs in LD shows
none in exons, and none of the intronic SNPs
predicted to affect splicing.
SCN2A

60. • We measured SCN2A mRNA level and
number of exons but saw no change with IVS7-
32A>G
• Thus, IVS7-32A>G may have a subtle effect or
be in linkage disequilibrium with the functional
SNP(s).
SCN2A

61. The challenge of finding relevant polymorphisms in
pharmacogenetics

62. Future directions in AED pharmacogenetics
• Genotype studies of other AED targets,
transporters, and metabolizing enzymes.
• Genetic profile of epilepsy patients to
select effective drugs quickly, without
trial and error period.
• Design of new drugs to avoid refractory
mechanisms.

63. Drug responses
next example:
carbamazepine

64. Highly effective
Serious
side effects
Ineffective
Epilepsy
Neuropathic
pain
Psychiatric illnesses
(e.g. mood disorders)
Carbamazepine

65. Drug Induced Severe Skin Allergies
SJS/TEN
Fauci AS et al, Harrison’s Principles of Internal Medicine, 17th
ed. www.accessmedicine.com

66. Fein and Hamann NEJM 2005;352:1696.
Stevens Johnson Syndrome (SJS)
<30% skin detachment

67. Hall JB, Schmidt GA, Wood LDH. Principles of Critical Care 3rd
Edition. www.accessmedicine.com
Toxic Epidermal Necrolysis (TEN)
>30% skin detachment
• Mortality up to 30%
• 1 in 1000 to 10000
• Occurs in first few
weeks of starting drug
• Unpredictable

68. Drug Induced Severe Skin Allergies
Stevens Johnson Syndrome/Toxic Epidermal Necrolysis
 Skin and mucosa (mouth, eyes) blistering, detachment, fever,
inflammation of lungs, liver
 Mortality up to 30%
 Induced by many drugs, incl. common antiepileptic drugs:
 Carbamazepine, phenobarbital, phenytoin, lamotrigine,
oxcarbazepine
 1 in 1000 to 10000 exposures
 Occurs in first few weeks of starting drug
 Difficult to predict who will develop the allergies
 Up to 10 times more common in Asians than Whites

69. Severe Skin Allergies and Immune Variant HLA-B*1502
 HLA
 Human leukocyte antigen
 Group of genes related to immunity
 Highly polymorphic
 HLA-B
 An HLA class I antigen
 Presents peptides inside cells
 Stimulates killer T cells
 Some variants associated with ankylosing spondylitis, AIDS, or malaria
 HLA-B*1502
 An allele of HLA-B
 Reported in several studies as associated with severe skin allergies and
carbamazepine

70. Severe Skin Allergies and Immune Variant HLA-B*1502

71. Patient Sex Age at onset
(yrs)
Drug HLA-B*1502
1 F 28 Carbamazepine Positive
2 M 23 Carbamazepine Positive
3 F 53 Carbamazepine Positive
4 M 10 Carbamazepine Positive
5 F 53 Phenytoin Positive
6 F 41 Lamotrigine Positive
Man CBL, Kwan P, Baum L, Yu E, Lau KM, Cheng ASH, Ng MHL. Association between
HLA–B*1502 allele and antiepileptic drugs-induced cutaneous reactions in Han Chinese.
Epilepsia 2007;48:1015-8
Presence of HLA-B*1502 increased risk 72x
Severe Skin Allergies and Immune Variant HLA-B*1502

72. Rates of HLA-B*1502 in Different Populations
Southern China
(including Hong Kong Chinese)
10 – 20%
India 12 – 16%
Taiwan 11 – 15%
Thailand 14 – 16%
Europeans <2%

74. FDA News Dec 12, 2007
 “Patients with ancestry from areas in which HLA-
B*1502 is present should be screened for the HLA-
B*1502 allele before starting treatment with
carbamazepine. If they test positive, carbamazepine
should not be started unless the expected benefit
clearly outweighs the increased risk of serious skin
reactions.”
 “In HLA-B*1502 positive patients, doctors should
consider avoiding use of other antiepileptic drugs
associated with SJS/TEN when alternative therapies
are equally acceptable.”

75. Drug intake Absorption Blood, immune
response
Effects in
brain
Metabolism Excretion
Effectiveness of Antiepileptic Drugs
Influenced by Genetic Differences
HLA-B*1502
Drug Transporter
P-glycoprotein gene
Sodium channel
genes
Research Goal: “Personalized” Medicine

76. Drug responses: summary
warfarin
warfarin

77. Warfarin pharmacogenetics
 Pharmacodynamics

78. Warfarin pharmacogenetics
 Pharmacodynamics
 VKORC1 is target of warfarin
o VKORC1 is subunit of vitamin K epoxide
reductase complex
o Reduces vitamin K
o S-warfarin is 3-5x more potent inhibitor than R
 GGCX
o Reduced vitamin K is needed for function
o Adds CO2 to Glu to form γ-
carboxyglutamic acid (Gla)
o Gla binds calcium
o Gla modification of clotting factors
activates them

79. Warfarin pharmacogenetics
 Pharmacodynamics
 Genetics
o VKORC1 -1639G>A
• A allele has lower expression
• Less VKORC1 means less warfarin needed
• A is 40-50% of alleles in Europeans
• A is ~90% of alleles in East Asians
• Remember that each person has 2 alleles
AA AG or GA GG
~90%x90% ~90%x10%+
10%x90%
~10%x10%
~81% ~18% ~1%

80. Warfarin pharmacogenetics
 Pharmacokinetics

81. Warfarin pharmacogenetics
 Pharmacokinetics
 CYP2C9
o Major metabolism of S-warfarin
o S-warfarin is 3-5x more potent inhibitor than R
o Genetic variants
 Less CYP2C9 means less warfarin needed
 CYP2C9*2 (Arg144Cys)
• Cys has lower activity
• Cys ~10% in Europeans
• Cys ~0% in East Asians
 CYP2C9*3 (Ile359Leu)
• Leu has lower activity
• Leu ~10% in Europeans
• Leu ~3% in East Asians

82. Warfarin pharmacogenetics
 Genome-wide association study
 VKORC1, CYP2C9 polymorphisms had
effects
 No other genes had major effect
 Will genotyping these help clinically?
 Try randomized trial

83. Warfarin pharmacogenetics

84. Warfarin pharmacogenetics
 Genome-wide association study
 VKORC1 polymorphisms had biggest effect
 CYP2C9 polymorphisms had smaller effect
 No other genes had major effect
 Will genotyping these help clinically?
 Try randomized trial
 Proportion of all patients with wrong dose (out-of-
range INRs) wasn’t reduced significantly…
 but was among patients with extreme genotypes
 Reduced number and size of dosing changes
 Thus, genotyping may help somewhat
 Planned study of 2000 patients should clarify
 Is it cost-effective?

85. Warfarin pharmacogenetics

86. Warfarin pharmacogenetics

87. Warfarin pharmacogenetics

88. Warfarin pharmacogenetics

89. Warfarin pharmacogenetics
 Example: myself
 VKORC -1639: GA
 CYP2C9: *2/*3
 How did I get my genotype?
 http://23andMe.com
 ~US$300 for 1 million SNPs

90. Warfarin pharmacogenetics

91. Warfarin pharmacogenetics

92. Warfarin pharmacogenetics

93. Cancer pharmacogenetics
Drug Gene
6-MP TPMT
Irinotecan UGT1A1
Tamoxifen CYP2D6

94. Drug responses: summary
6-MP

95. Metabolism of 6-Mercaptopurine
N
N
N
N
H
SH
N
N
N
N
H
SCH3
N
N
N
N
H
SH
HO
OH
N
N
N
N
H
SCH3
OH
OH
Xanthine Oxidase
(XO)
Thiopurine
Methyltransferase
(TPMT)
XO TPMT
2,8-Dihydroxy-6-Methylmercaptopurine
AdoHcy
AdoHcy
AdoMet
AdoMet
6-MP

96.  Treats acute lymphoblastic leukemia (ALL)
 TPMT inactivates
 TPMT alleles
 Wildtype
o *1
 Variants
o Reduced activity
o Thus more toxicity: heterozygotes need 6-MP dose cut in
half
o *2
 Ala80Pro
 <1% of alleles in East Asians
o *3C
 Cys240Tyr
 ~1% of alleles in East Asians
6-MP

97. Drug responses: summary
Irinotecan

98. Irinotecan
 Cancer drug
 Kills cancer cells via action of its metabolite,
SN-38
 Metabolized by CYP450 3A4 to inactive
metabolites
 UGT1A1 inactivates the active form (SN-38)
 Side effects: diarrhea (“I-run-to-the-can!”),
nausea & vomiting, neutropenia, alopecia
 Rates of early treatment-related deaths
associated with irinotecan are 3X higher than
with control regimens

99. Irinotecan metabolism
Deficiencies in UGT1A1  accumulation of bilirubin & SN 38
(active metabolite that inhibits DNA topoisomerase) –
significant diarrhea & neutropenia observed in some patients
uridine diphosphate-glucuronyl transferase 1A1 (UGT1A1)uridine diphosphate-glucuronyl transferase 1A1 (UGT1A1)

100. Irinotecan

101. Pharmacogenetic test
 FDA approved a lab test for UGT1A1*28 genotyping in 2005
 Labeling change in product insert

102.  UGT1A1 alleles
 Promoter polymorphism: *28
 7 TA repeats (vs 6 TA repeats for wildtype)
 ~14% of alleles in East Asians
 Reduced transcription of UGT1A1
 Thus more SN-38 and toxicity: heterozygotes may
need irinotecan dose cut
 But no prospective study yet to determine dose
adjustment
Irinotecan

103. Drug responses: summary
Tamoxifen

104. Tamoxifen

105.  Treats breast cancer
 CYP2D6 activates to endoxifen
Tamoxifen

106.  CYP2D6
 1st
phase metabolism of many drugs
 Prototype pharmacogene
 Many haplotypes, grouping people into 4 phenotypes
o Ultrarapid metabolizers (UM): multiple CYP2D6 gene
copies
o Extensive metabolizers (EM): normal CYP2D6 function
o Intermediate metabolizers (IM)
o Poor metabolizers (PM)
 Highest functioning haplotype determines phenotype
Tamoxifen

107.  CYP2D6
 Haplotypes
o *10
 ~50% of haplotypes in Chinese
 Intermediate metabolizer
o *1
 ~25% of haplotypes in Chinese
 Extensive metabolizer
o *2
 ~10% of haplotypes in Chinese
 Extensive metabolizer
o *5
 ~5% of haplotypes in Chinese
 Whole gene deletion: Poor metabolizer
o *41
 ~3% of haplotypes in Chinese
 Intermediate metabolizer
o UM
 ~1% of haplotypes in Chinese
 Whole gene duplication: Ultrarapid metabolizer
Tamoxifen

108.  CYP2D6
 Try estimating frequencies of the 4 metabolizer phenotypes in
Chinese
 Some studies showed that poor metabolizers had higher
cancer relapse rates
 Other studies did not
 Thus, no consensus yet on value of CYP2D6 testing for
tamoxifen outcome
Tamoxifen

109. Drug responses: summary
AEDs
carbamazepine
Codeine
6-MP
Irinotecan
Tamoxifen
AEDs

110. Who offers tests?
 Genelex: http://www.genelex.com
 Gendia: http://www.gendia.eu/
 DNAvision: http://www.dnavision.com/pharmacogenetics.php
 Cincinnati Children’s Hospital:
http://www.cincinnatichildrens.org/service/g/genetic-pharmacology/default/
 Warfarin dosing: http://www.warfarindosing.org
 Many others

111. “Pharmacogenomics will undoubtedly become a very compelling part of medical practice. The
limiting factor right now is that oftentimes, if you are ready to write a prescription, you do not want to
wait a week to find out the genotype before you decide whether you’ve got the right dose and the
right drug. But if everybody’s DNA sequence is already in their medical record and it is simply a click
of the mouse to found out all the information you need, then there is going to be a much lower barrier
to beginning to incorporate that information into drug prescribing. If you have the evidence, it will be
hard, I think to say that this is not a good thing. And once you’ve got the sequence, it’s not going to
be terribly expensive. And it should improve outcomes and reduce adverse events.” – Francis Collins
Pharmacogenomics

112.  “Be careful about reading health books. You may
die of a misprint.” – Mark Twain
Health education
 “I have never let my schooling interfere with my
education.” – Mark Twain

113. Thank you
The End