final Flashcards
The individual above has 3 copies of the CYP2D6 gene, assuming that all 3 copies code for normal function enzymes, the CYP2D6 phenotype assignment would be an –
UM
– is one of the rare pharmacogenes where people can inherit more than
two copies of the gene
CYP2D6
(COPY NUMBER VARIATION)
Some individuals may carry just one copy of the CYP2D6 gene,
Commonly reported as –* allele, which means the allele is —
*5 allele
deleted
The function of CYP2D6 / 2D7 hybrids depends on the — variants present in the hybrid gene and is for the most part still under investigation
-CYP2D6
-this is called the Hybridization of the CYP2D6 gene with the CYP2D7 pseudogene, where parts of the CYP2D6 gene are often deleted.
-CYP2D6 / 2D7 hybrids can also be on the same chromosome strand with a normal copy of the CYP2D6 gene.
-It is important to know whether the genetic testing laboratories can identify CYP2D6 hybrids
1/2 duplication
means
Means the patient has a *2 variant and more than 2 copies of the CYP2D6 gene, but it is not known how many extra copies the patient has
1xN/2
Means the patient has more than 2 copies of the CYP2D6 gene, and that the *1 allele is duplicated, but it is unknown how many duplicated copies exist
(1/2)xN
Means the patient has three or more copies of the CYP2D6 gene but it is unknown which allele is duplicated and how many copies the patient actually has
what are the values of the activity score system used to assign CYP2D6 phenotypes (from UM to PM)
-UM >2.25
-NM 1.25<x<2.25
-IM 0 <x<1.25
-PM 0
what are the values of the activity value system used to assign CYP2D6 enzyme functional status
-Increased function: >1
-Normal function: 1
-Decreased function: 0.25 and 0.5
-No function: 0
The CYP2C19*17 allele is characterized by — CYP2C19 enzyme function
increased
-Unlike CYP2D6, the CYP2C19 RM and UM phenotypes are assigned in the presence of increased function alleles instead of having multiple copies of a gene.
Polymorphism in the promoter region of the CYP2C19 gene increases —
transcription
what are genotype definitions of UM compared to RM for CYP2C19
-UM: increased act compared to RM and have 2 increased fucn alleles.
-RM: inc act compared to NM but less than UM: has combinations of normal func and increased func alleles.
— allele frequencies are dependent on race and ethnicity
-which are the most common variants
-CYP2C19
- *2 and *3 alleles (principal nonfunctional alleles
)
CYP2C19 are present in the following races:
-*2 allele:
–% of Asians
–% of Caucasians and African Americans
-*3 allele:
–% of Asians
–% of Caucasians and African Americans
-PM phenotype
–% of Asians
–% of Caucasians and African Americans
-*2 allele:
30% of Asians
15% of Caucasians and African Americans
-*3 allele:
8% of Asians
less than 1% of Caucasians and African Americans
-PM phenotype
25% of Asians
~5% of Caucasians and African Americans
The CYP2C19 —— allele shares the same promoter region SNP as the increased function CYP2C19*17 allele (-806C>T)
no function *4B
It is important to test for — in addition to – to make an accurate CYP2C19 allele assignment
-1A>G (in *4B)
- -806C>T
the activity score system is used to assign CYP2C9 phenotypes
-NM: 2
-IM: 1 or 1.5
-PM: 0 or 0.5
Each CYP2C9 allele is assigned an activity value that will contribute to the final activity score number
-normal function 1
-decreased function 0.5
-no function 0
— enzymes are located both in the gut and the liver
-Patients who express the CYP3A5 gene are CYP3A5 – and – metabolizers.
-Patients who do not express the CYP3A5 gene are CYP3A5 – metabolizers
CYP3A5
-normal and intermediate
-poor
-It is common for individuals of – descent to express CYP3A5
enzymes.
-It is common for individuals of – descent NOT to have any
CYP3A5 enzymes (PM)
-African
-European
— phenotype is the low-risk phenotype: no dosage adjustments are required for patients with this phenotype.
— are the high-risk phenotypes
Dosing modifications may be necessary for certain medications for patients with these phenotypes
-CYP3A5 PM
-CYP3A5 IM and NM phenotypes
– polymorphisms have been associated with reduced glucuronidation in patients who have inherited decreased or no function variants
UGT1A1
— genotyping is used o diagnose Gilbert and Crigler-Najjar syndromes
UGT1A1
-– Gilbert syndrome
Decreased — activity (~30% of normal)
Patients who have – function variants (-,-,-)
– Crigler-Najjar syndrome (types 1 and 2)
Type 1: — of UGT1A1 activity
Type 2: — enzyme activity
– Gilbert syndrome
Decreased hepatic UGT1A1 activity (~30% of normal)
Patients who have two decreased function variants (*6, *28, *37)
– Crigler-Najjar syndrome (types 1 and 2)
Type 1: almost complete absence of UGT1A1 activity
Type 2: severely decreased but detectable UGT1A1 enzyme activity
UGT1A1 expression is regulated by the number of — repeats in the promoter region of the gene
thymine-adenine (TA)
UGT1A1
– Normal function alleles carry – TA repeats
– The decreased function variants are characterized by – TA repeats
– The increased function variant *– is characterized by – TA repeats (this condition is typically benign)
-6 (28)
-7
-36 - 5
UGT *6 allele is more common in – decent
28 is less common in –
-36 and 37 are more common in africants
-60 allele is – function more common in —
-asians
-asians
-africans
-normal function: african americans
DPYD activity score
-NM: 2
-IM: 1 or 1.5
PM: 0 or 0.5
DPYD activity value
-N fucntion: 1
-dec func: 0.5
-no func: 0
Each DPYD allele is assigned an activity — that will contribute to the final activity — number
value that will contribute to –score.
— starting doses of warfarin are recommended in individuals carrying a decreased function allele (CYP4F2*3)
higher
CYP4F2 is not involved in the metabolism of —, and it plays a role in —- which explains why patients need altered doses of –
-warfarin
-vitamin K oxidation
-warfarin
the —- gene belongs to solute carrier organic anion transporter
family
SLCO1B1 member 1B1
which is the membrane-bound transporter expressed in the
liver to remove many substrates from blood
- these substrates include
SLCO1B1 or OATP1B1
- Substrates include
many endogenous and
xenobiotic compounds including HMG-CoA reductase inhibitors (statins), bilirubin, and methotrexate
rs4149056 is
-encoded by: — gene
-on chromosome
— kilobases
— exons
-confers — function for several substrates
- associated with —
-encoded by: SLCO1B1 gene
-on chromosome 12
- 109 kilobases
- 15 exons
-confers REDUCED function for several substrates
- associated with simvastatin-induced myopathy
associated with simvastatin-induced myopathy
rs4149056 encoded by SLCO4149056 *5 and *15: NO FUNCTION ALLELES
due to low elimination of statin leading to muscle weakness
— is merging and renaming
alleles
PharmVar
— is merging and renaming
alleles
PharmVar
-SLCO1B11 (or 1A) allele: common in —-
-SLCO1B11B allele: common in —
-SLCO1B15 & SLCO1B115 alleles: — function alleles containing the rs4149056 variant associated with simvastatin-induced myopathy
-SLCO1B12 & 3: — function alleles
-SLCO1B114 & *35: — function alleles
SLCO1B11 (or 1A) allele: common in Caucasians
SLCO1B11B allele: common in Africans
SLCO1B15 & SLCO1B115 alleles: no function alleles containing the rs4149056 variant associated with simvastatin-induced myopathy
SLCO1B12 & 3: no function alleles
SLCO1B114 & *35: increased function alleles
what are genotypes for the following SLCO1B1 phenotypes:
-IF:
-NF:
-DF:
-PF:
-IF: 1 or more inc func alleles
-NF: 2 norm func alleles
-DF: 1 norm func and 1 no func alleles
-PF: 2 no func alleles
—— occur commonly for drug target proteins,
including receptors, enzymes, and ion channels
Genetic polymorphisms
—- gene: major metabolizing enzyme for S warfarin and vitamin K oxidoreductase (VKOR).
CYP2C9
Warfarin inhibits —, thus
preventing the formation of
reduced vitamin K1,
which is a necessary cofactor for
— and activation of
clotting factors II, VII, IX, X, (F2, F7, F9 and F11) and
proteins C and S.
-VKOR
γ-carboxylation
A common SNP in the VKORC1 regulatory region, —–,
significantly contributes to the interpatient variability in warfarin
response, as it modulates VKORC1 gene expression
c.1639G>A
genotypes:
-AA high sens 3mg/d
-AG int sens 5mg/d
-GG low sens 6-7mg/d
Warfarin dose requirements vary by ancestry, with higher dose
requirements among individuals of — ancestry and
lower
requirements among patients of — ancestry compared with
patients of European (AG) ancestry.
-this variability is explained by
-African GG
-asian AA
-VKORC1
genotype frequency
There are two common nonsynonymous SNPs in the — at codons 49
(p.Ser49Gly) and 389 (p.Arg389Gly).
ADRB1
- these SNPs also appear to modulate blood pressure and clinical responses to ß1receptor blockade
The —– and —– SNPs are in strong linkage disequilibrium
Ser49Gly and Arg389Gly
The Ser49Arg389 haplotype is associated with an increased risk for death among patients with —-
-this risk can be abolished with — ttt
coronary heart disease
-atenolol
— patients who were— for the Ser49Arg389
haplotype were found to have greater blood pressure reductions with
metoprolol, compared with carriers of the Gly49 and/or Gly389
alleles
-Hypertensive
-homozygous
Among patients with heart failure, the Arg/Arg389 genotype was
associated with greater improvements in left ventricular ejection
fraction with carvedilol and metoprolol treatment
—Arg/Arg389 ADRB1
Although a common polymorphism, —, results in lower protein expression, its contribution to individual differences in
opioid response is unclear (OPRM1)
A118G
The evidence associated with the OPRM1 gene is ranked as CPIC
level –, meaning that no prescribing action is recommended
based on genotype results.
level C
HLA genes are highly polymorphic with — alone having over 1500
identified alleles
HLA-B
diplotype definition: presence of 1 or 2 —- alleles mean positive HLA phenotype and absence of the — allele mean negative HLA phenotype
HLA-B*57:01
-HLA-B57:01 test has a positive predictive value of –% for
immunologically confirmed hypersensitivity: Some HLA-B57:01 positive patients can be safely treated with —-
-HLA-B*57:01 genotype test has a high negative predictive value (>
–%)
-~50% - abacavir
->99%
Some clinical laboratories in Asia are offering more comprehensive
HLA testing for certain drug-induced — diseases:
-skin
- Carbamazepine: HLA-B15:08, HLA-B15:11, HLA-B*15:21
which HLA is the most common serotype in Southeast Asia
HLA-B*15:02
The RYR1 gene contains instructions for the body’s cells to produce a
protein called the ryanodine receptor (RyR1) which is important for
— function
muscle
The — gene provides instructions for making the main piece
(subunit) of a structure called a calcium channel in the skeletal
muscles.
CACNA1S
Variations in the RYR1 and CACNA1S genes are associated with the
development of —– in patients exposed to which drugs
-malignant hyperthermia
-Succinylcholine: Depolarizing muscle relaxants and
-Fluorinated inhaled anesthetics: halothane, isoflurane, desflurane,
enflurane, sevoflurane
Mutations of the RYR1 AND CACNA1S
genes are —; patients are susceptible to developing malignant hyperthermia when one variant allele is
inherited
autosomal dominant
implications for family members of patients who develop
malignant hyperthermia
- Pharmacogenomic testing for RYR1 and CACNA1S can help
determine susceptibility
-Education of a high-risk result implications on family members
could be done in conjunction with genetic counselors
-mt-RNR1 is a gene in the mitochondrial DNA that codes for the —-
-12S
ribosomal RNA (rRNA)
Certain genetic variations in the mt-RNR1 gene lead to changes in the
shape of the ribosome, which can make the human ribosome look more
like bacterial ribosomes, ———- interferes with bacterial protein synthesis by binding to
30S ribosomal subunit, resulting in a defective bacterial cell membrane
Aminoglycosides
- Certain variations in the mt-RNR1 gene cause the human ribosome to look
more like bacterial ribosomes
* Aminoglycosides lose their specificity for bacterial ribosomes, bind to
human ribosomes
presence of high risk variant (m.1555A>G) leads to
aminoglycoside-induced hearing loss (Mt-RNR1 variations)
-Confirmatory mt-RNR1 genotyping of each family member is not required
Genetic material is extracted from the nucleus when the cell at
— (during sell division)
prometaphase
because at this stage, the genetic material is condensed and appears as road shape structure called chromosomes
2q34 refers to:
Chromosome 2, long arm, region3 and band 4
banding technique uses — stain where each chromosome shows distinct alternate light and dark bans, and Each arm is divided into numbered regions (e.g. 1. 2, 3. …) from centromere outward
* In each region the bands are numerically ordered
Gimsa
what type of chromosomal abnormality leads to 3n(69) triploidy
Euploidy numerical cytogenic or chromosomal abnormality
what type of chromosomal abnormality leads to trisomy 21
Aneuploidy numerical cytogenic or chromosomal abnormality
what type of chromosomal abnormality leads to monosomy
Aneuploidy numerical cytogenic or chromosomal abnormality
—– is a rare condition where ovum is fertilized with 2 sperms, it is a type of — chromosomal abnormality
-triploid
-Euploidy numerical cytogenic or chromosomal abnormality
what are types of structural chromosomal abnormalities
-A-reciprocal translocation
-B-robertsonian translocation
in B-robertsonian translocation, breaks occur close to the centromeres of —- chromosomes (numbers—)
-acrocentric chromosomes
(13, 14, 15, 21, 22)
-what are the cytogenic disorders involving autosomes
–what are the cytogenic disorders involving sex chromosomes
-down synd (trisomy 21)
-edwad synd (trisomy 18)
-patau synd (trisomy 13)
-sex chrom: kilnefelter synd (47, XXY)
Marfan syndrome is what type of chromosomal abnormality
-monogenic (single-gene) disease
-autosomal dominant
-FBN1 mutation on gene encoding for fibrillin (connective tissue) leading to skelatal, eyes and CVS system abnormality.
clinical features: floppy mitral valve, tall stature and long fingers, aortic aneurysm & aortic dissection.
sickle cell anemia is what type of chromosomal abnormality
-monogenic (single-gene) disease
-autosomal recessive
-HBB gene mutation encoding for hemoglobin
-LETHAL AS HOMOZYGOUS and
heterozygous generally unaffected
Rett syndrome is what type of chromosomal abnormality
-monogenic (single-gene) disease
-X-linked dominant
-MECP2 gene mutation leading to brain damage
-normal girl up tp 18 months where mental retardation appears such as regressive language and movement, microcephaly and seizures
Hemophilia A
-monogenic (single-gene) disease
-X-linked recessive
-F8 gene mutation leading to coagulation defect (factor Vlll) - leading to bleeding
DM, CHG, and HTN are what type of genetic abnormalities
Polygenic (Multiple-gene )Diseases
Multifactorial (Complex)Diseases are influenceed by both — and —
envoronment (AIDS, influenza, and measles) AND genetics (sickle cell and hemophilia A)
Mutagenicity is related to — changes in DNA composition or chromosome structure
heritable
—- is a general term for any type of DNA damage, chromosomal
alteration which may not always lead to a heritable mutation..
Genotoxicity
Not all exposures cause a mutagenic event as there are — repair DNA systems present
biological
—- are also referred to as
expression profiles
Transcriptomics
—-—the study of how an
individual’s genetic makeup affects gene
expression, protein expression and activity,
and metabolism in response to exposures to
potentially toxic compounds.
* —–—the study of how the
genome as a whole responds to exposures to
potentially toxic compounds.
* —–—the evaluation of mRNA
expression levels in cells or tissues.
—– are also referred to as
expression profiles. —- may be
used in toxicological studies to evaluate the
effects of an exposure on mRNA expression
TOXICOGENETICS
TOXICOGENOMICS
TRANSCRIPTOMICS
—- may be used in
toxicological studies to evaluate the effects of an exposure on gene
and mRNA expression.
MRNA AND GENE
Proteomics: the study of the relative levels of protein expression and activity in animals, cells, or tissues.
— may be used in toxicological studies to evaluate the effects of an exposure on protein
expression and activity
Metabolomics
the study of the relative production of metabolites
in animals, cells, or tissues
—- is cellular division which
occurs in non-reproductive
(somatic cells)
Mitosis
—- is
cell division which occurs in the reproductive (germ) cells
meiosis
Toxicogenomic data from —— studies may be complemented by proteomics and metabolomics studies to evaluate the effects of an exposure
DNA microarray
——– methods may replace microarrays genotyping methods for high-throughput genotyping.
next-generation DNA sequencing
statement
In the pharmaceutical industry, toxicogenomics is already able to predict
the toxicities of many compounds, especially those that are hepatotoxins
or nephrotoxins
Genes that influence drug toxicity have been generally grouped into
one of three categories:
- those that code for drug-metabolizing enzymes
- those that code for transporters
- those that code for human leukocyte antigens (HLAs)
lower activity variants of the metabolizing enzymes CYP2C9 of warfarin
CYP2C9-, and CYP2C9–, are at higher risk for over-anticoagulation
or bleeding
CYP2C92, and CYP2C93
VKORC1 has several polymorphic alleles, and the —— variant
has been found to be significantly associated with dose variability and
to contribute to the risk of patients experiencing over-anticoagulation
or bleeding events
c.1639G>A
During Korean War, the G6PD deficiency was found to be responsible for
the severe hemolytic anemia suffered by some soldiers with the use of
——
Primaquine
medications that can cause hemolytic anemia in the presence of
G6PD deficiency include
-Primaquine
-antimicrobial Dapsone used to treat leprosy
and
-Rasburicase used to treat hyperuricemia in cancer patients
6-MP is metabolized to cytotoxic metabolites that cause significant adverse
effects.
* 6-MP is inactivated in part by thiol methylation catalyzed by the polymorphic
thiopurine —— enzyme.
* Low-activity variants of the — enzyme have been identified.
thiopurine S-methyltransferase (TPMT)
Patients who are genetic ——– for the low-activity variant of TPMT have
intermediate levels of TPMT activity,
while those who are ———- for the
low-activity allele have low or no TPMT activity.
-heterozygotes
-homozygotes
- Decreased TPMT activity puts patients at risk for developing significant
——– with azathioprine and 6-MP administration, because high
levels of 6-MP are then available for metabolism to the cytotoxic
metabolites that accumulate.
myelotoxicity
- A low-activity variant of UGT1A1, UGT1A1*28, has been identified and is
associated with an increased risk of cancer patients developing severe
——- during ——- treatment due to increasing levels of SN-38.
-neutropenia
-irinotecan
- Very serious dermatological reactions that include Stevens-Johnson Syndrome
(SJS) and toxic epidermal necrolysis (TEN) can occur in some patients taking ———-
carbamazepine
An association has been found between the risk of developing SJS and TEN and
the presence of a genetic variant of HLA-B, HLA-B*15:02
* This association appears to be most prevalent in patients of ——- ancestry.
Asian
HLA-B*57:01, has been found to be
associated with a severe hypersensitivity reaction to ——–.
abacavir
-not SJS or TEN like carbamazepine, but a clinical syndrome involving
multiple organs.
statement
- CPIC guidelines are designed to help clinicians understand HOW
available genetic test results should be used to optimize drug therapy - – Not WHETHER tests should be ordered
Key assumption:
* – Clinical high-throughput and ——- will become
more widespread
* – Clinicians will be faced with having patients’ genotypes available
even if they did not order test with drug in mind
preemptive genotyping
which resources create gene/drug pairs guidelines that provide guidance on how to use eisting pharmacogenomic test results to optimize medication therapy
CPIC and DPWG
centralized database of genetic testing labs worldwide and their offering created via voluntary submissions
genetic testing registry (GTR)
searchable database of curated phg literature and information including clinical guidelines and drug labeling from around the world
also includes imp pharmacogene summary and phg pathway diagrams
PharmGKB
online repository for pharmacogene nomeclature key info about imp phgenes
phrmacoene variation consortium (pharmVAR)
pharmGKB Strength of evidence
-level 1A: cpic pgx guidelines
-level 1B: preponderance evid shows association
-level 2A: qualifies for 2b where the variant is within a Very Important
Pharmacogenes
-level 2B: moderate evidence of an association
– Level 3: single significant not yet replicated study or multiple studies but lacking
clear evidence of an association
* – Level 4: case report, non-significant study or in vitro, molecular or functional assay
evidence only
Within the context of pharmacogenomics, testing involves
searching for genetic variations linked to medication — or —
rather than to disease susceptibility.
efficacy or toxicity
Currently there is no international standard for ———–.
genetic testing
In many instances, ———– testing will carry little risk for ethical, legal,
and social concerns.
pharmacogenomics
An individual may experience ——— from family, friends, and
coworkers on knowledge that a specific disease will not respond to
therapy or if one is identified as a “poor metabolizer” of a specific medication.
Stigmatization is defined as “a social process that begins with
distinguishing and labelling some feature of a person such as
occupation, disease, or skin color.”
Recent examples of potential “blockbuster” drugs that have been recalled
from the market for adverse drug events or toxicity include –
cerivastatin,
cisapride, alosetron, and troglitazone
- The ability to recover R&D expenses from these market failures by reintroducing
these agents for a targeted patient group would provide SHORT-term revenues for the
industry
