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PHRM 847 > Quiz #1 > Flashcards

Quiz #1 Flashcards

1
Q

Pharmacogenomics

A

Using genomic approaches to identify genetic factors that are able to distinguish patients with different responses to a drug, and translate these findings into patient treatment

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2
Q

Major findings

A

Genetic mutations are responsible for ~50% of rare diseases identified
11,907 genetic loci strongly associated with common diseases
>2M mutations identified from cancers in 2017; >81M mutations identified from cancers now in 2024

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3
Q

Many actionable signatures have been revealed

A

Actionable signature: information used to make treatment decision
Genetic markers can distinguish patients:
* Who are most likely to respond to a drug
* Who are most likely to develop side effects
* Who should not take the drug
* The best dose to be taken
FDA has approved ~150 pharmacogenomic drug labels as of 2018

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4
Q

Genetic Factors Are Involved in Both PK and PD

A

Pharmacokinetics (PK): what the body does to the drug; ADME: absorption, distribution, metabolism, excretion
Pharmacodynamics (PD): what the drug does to the body; receptor, target, signaling, enzymes

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5
Q

Genomic revolution is here

A

Technology is here:
mRNA medicine, virus-based medicine, Antisense Oligonucleotide (ASO), CRISPR, Immunotherapy, …
Funding is here

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6
Q

Pharmacists’ Role

A
  • Recommending (or scheduling) pharmacogenomic testing to aid in the process of drug and dosage selection.
  • Designing a patient-specific drug and dosage regimen based on the patient’s pharmacogenomic profile that also considers the pharmacokinetic and pharmacodynamic properties of the drug.
  • Educating patients, pharmacists, and other health care professionals about pharmacogenomic principles and appropriate indications for clinical pharmacogenomic testing.
  • Communicating pharmacogenomic-specific drug therapy recommendations to the health care team, including documentation of interpretation of results in the patient’s health record.
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7
Q

The Competencies You Need to Establish: competency domain and pharmacist-specific knowledge

A
  1. to demonstrate an understanding if the basic genetic and genomic concepts and nomenclature
  2. to recognize and appreciate the role of behavioral, social, and environmental factors to modify or influence genetics in the manifestation of disease
  3. to identify drug- and disease-associated genetic variations that facilitate development of prevention, diagnosis, and treatment strategies; to appreciate differences in testing methodologies, and the need to explore these differences in drug lit evaluation
  4. to use family history in assessing predisposition to disease and selection of drug treatment
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8
Q

The Competencies You Need to Establish: genetics and disease

A
  1. to understand the role of genetic factors in maintaining health and preventing disease
  2. to assess the diff b/w clinical diagnosis of disease and identificaqtion of genetic predisposition to disease
  3. to appreciate that pharmacogenomic testing may also reveal certain genetic disease predispositions
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9
Q

The Competencies You Need to Establish: pharmacogenetics and pharmacogenomics

A
  1. to demonstrate an understanding of how genetic variation in a large # of proteins influence PK and PD related to pharmacologic effect and drug response
  2. to understand the influence of ethnicity in genetic polymorphisms and associations of polymorphisms with drug response
  3. recognize the availability of evidence-based guidelines that synthesize info relevant to genomic and pharmacogenomic tests and selection of drug therapy
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10
Q

The Competencies You Need to Establish: ethical, legal, and social implications

A
  1. to understand the potential physical and psychosocial benefits, limitations, and risk of pharmacogenetic and pharmacogenomic information for individuals, family members, and communities, especially with pharmacogenetic and pharmacogenomic tests that may relate to predisposition to disease
  2. to understand the increased liability that accompanies access to detailed genomic patient information and maintain their confidentiality and security.
  3. to adopt a culturally sensitive and ethical approach to patient counseling regarding genomic and pharmacogenomic test results.
  4. to appreciate the cost, cose-effectiveness, adn reimbursement by insurers relevant to genomic or pharmacogenomic tests, for patients ans communities
  5. to identify when to refer a patient to a genetic specialist or genetic counselor.
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11
Q

Inter-patient Difference in Drug Efficacy and Toxicity: PGx is Not Everything

A
  • Intrinsic factors
    – Genetic factors
    – Physiological factors
  • Extrinsic factors
    – Environmental factors
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12
Q

DNA (Deoxyribonucleic acid)

A
  • Thin (2nm diameter)
  • Linear polymer fiber
  • Double-stranded helix
  • 4 nucleobases:
  • Adenine (A) * Thymine (T) * Guanine (G) * Cytosine (C)
    Anti-parallel: A=T (2 H bonds); G=C (3 H bonds)
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13
Q

Genome

A

A genome is an organism’s complete set of DNA, including all of its genes. Each genome contains all of the information needed to build and maintain that organism.
* In humans, a copy of the entire genome—more than 3 billion DNA base pairs—is contained in all cells that have a nucleus. (the exact number sometimes changes due to new research finding)
– Kilobase (kb)=1,000bp
– Megabase (Mb)=1 million bp

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14
Q

Genes

A
  • Gene: an evolving concept
    -A gene is a sequence of DNA or RNA which codes for a molecule that has a function. A gene is the basic physical and functional unit of heredity. Genes, which are made up of DNA, act as instructions to make molecules. In humans, genes vary in size from a few hundred DNA bases to more than 2 million bases.
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15
Q

Genes Classification

A
  • Classification
    – Protein coding genes: Genes that are expressed to be proteins
  • Only1-3% of the human genome are protein-coding sequences
  • ~20,000 genes found in the human genome
    – Noncoding genes
  • Final product is an RNA, not a protein
  • Transfer RNAs (tRNA): transfer amino acids to the RNA template to make proteins
  • Ribosomal RNAs (rRNAs): the RNA component of ribosome
  • microRNAs (miRNA): play very important role in regulating protein-coding gene expression
  • Others: long noncoding RNA (LncRNA), antisense RNA, Pseudogenes
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16
Q

Gene Nomenclature

A

In general, symbols for genes are italicized, whereas symbols for proteins are not italicized.
* Abbreviation
– EGFR: Epidermal Growth Factor Receptor gene
* Family based assignment
– CYP3A4: Cytochrome P450 gene family 3 subfamily A gene #4
* Arbitrary assignment
– C9ORF106: Chromosome 9 Opening Reading Frame #106

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17
Q

Sequence Position

A
  • After the Human Genome Project, we have a reference genome
  • Each nucleotide has its unique position in the reference genome
  • This position is often called a “locus” (pl. loci)
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18
Q

Chromatin and Chromosome

A
  • Chromatin
    – Unwounded DNA with protein
    – Observed through interphase
    – DNA is accessible for transcription, etc.
  • Chromosome
    – Tightly packed DNA
    – Observed only during cell division (metaphase)
    – DNA is not used
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19
Q

Human Genome

A
  • 46 chromosomes (23 pairs)
    – 22 pairs of autosomes
    – 1 pair of sex chromosomes
  • Male: XY
  • Female: XX
  • Karyotype: The complete picture of the genome in a cell; used to determine limited diseases of a baby when mom is pregnant
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20
Q

Why Pairs?

A

increase genetic diversity for the population
one chromosome from dad and one from mom

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21
Q

Expression of Genetic Information

A

central DOGMA
used to think it was just a one way proces, now know that’s not true

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22
Q

Transcription

A

mRNA maturation process
matured mRNA have no introns

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23
Q

Translation

A

RNA to Protein
Starts with AUG (making amino acid “Methionine”)
Stops at one of the three stop codons (UAG,UAA, UGA)
Open reading frame (ORF)
– Coding DNA Sequence (CDS)
– AUG to the codon before stop codon
– Protein starts with Methionine

24
Q

Genetic Coding System

A
  • 64 codons
    – 3 stop codons UAA, UAG, UGA
    – 1 initiation codon (ATG)
  • 20 amino acids
25
Q

Regulation of the Expression of Genetic Information

A

Expression of genetic information is precisely regulated by many factors in multiple steps
DNA to RNA: transcriptional regulation
RNA to protein: post-transcriptional regulation
protein: post-translational regulation

26
Q

Sequence Variations

A
  • Present in any given human genome (roughly how many?)
  • Present between individuals
  • Present in a population
  • Sequence variation (polymorphism) largely influences diversity and adaptability of humans to a changing environment
  • Whether a variation has a functional consequence depends on its location and nature
27
Q

Nature of a Polymorphism

A
  • A polymorphism is a sequence variation at the same position of homologous chromosomes (diploid genome)
  • There are NO polymorphisms in the genome of a single germ cell (haploid genome)
28
Q

Allele and Genotype

A
  • Allele: The DNA sequence(s) at a locus of one of the two homologous chromosome
  • Genotype: The combination of alleles at the same locus of the homologous chromosomes in a genome/cell.
29
Q

Homozygote and Heterozygote

A
  • Homozygote: when an individual has a pair of identical alleles at the locus, the genotype is homozygous Heterozygote: two different alleles at the same locus, the genotype is heterozygous.
    – Hemizygous/hemizygote: one allele presents, while another allele is missing.
    – A hemizygous genotype is also heterozygous
30
Q

Nature of a Genotype: Mendel’s Law

A

Each of the parents passes a randomly selected allele (one of the two homologous chromosomes) to the offspring (Law of Segregation)

31
Q

Types of Polymorphisms: SNP

A
  • Single nucleotide polymorphism (SNP)
    – A single nucleotide is changed to another
    – The most common DNA sequence variation account for >90% of all genetic variations
    – Occurs 1 SNP/~300-750bp in the genome
    – A total of 55M SNPs deposited in the SNP database (dbSNP)
    – Most PGx polymorphisms are SNPs
32
Q

Type of SNPs

A
  • SNP in the coding region (cSNP)
    – Non-synonymous SNP: changing amino acid in the protein
  • Missense SNP: amino acid substitution (could lead to either gain- or loss-of-function for the protein depending on what amino acid it changes to)
  • Nonsense SNP: amino acid changes to a stop codon (normally lead to loss-of-function)
    – Synonymous SNP: does not change amino acids, usually does not change gene/protein
    function
  • Silent SNP: no amino acid change
  • Noncoding region SNPs
    – Intronic SNP
    – SNPs in the gene flanking regions and intergenic regions
    – SNPs in the UTR region
33
Q

SNP in the coding region (cSNP)

A

Nonsense SNP: amino acid changes to a stop codon; truncated protein (loss of function)

34
Q

Types of Polymorphisms: CNV

A
  • Copy number variation (CNV)
    – A DNA region (many contain a part or even one or more entire genes) has 0-n
    copies in a population
    – Structural variation
    – 1kb-several Mb
    – Making each chromosome longer or shorter!
35
Q

Types of Polymorphisms: insertion/deletion

A
  • Insertion/deletion (Indel)
    – Nucleotide(s) present or absent from a locus: 0
    or 1 copy
    – Can be 1 to N nucleotides
    – Single nucleotide indel is a specific form of SNP
    – Large ones are actually CNVs
    – Example: CYP3A5*7
    Insertion and deletion, other than 3 nucleotides, often causes frameshift of the open reading frame leading to truncated protein for degradation.
36
Q

Types of Polymorphisms: repetitive DNA variation

A
  • Repetitive DNA variation
    – Short tandem repeat (STR): a short sequence (1- 1000bp) repeats N times: (X)n
  • n=0, 1: Indel; number of nucleotides involved >1kb: CNV – Variable number of tandem repeat
    – Micro-satellite/Mini-satellite: 1-4 bp
  • Multi-allelic
    Often in the UTR region, or certain cases of neurodegenerative disorders like Huntington’s disease
37
Q

UGT1A1 -53 (TA)n Polymorphism

A
  • (TA)n, n=5,6,7,8
  • Occurs in the TATA box of the promoter Common alleles: 6 and 7
    – 6 copies : UGT1A11
    – 7 copies : UGT1A1    28
  • Reduced UGT1A1 gene expression
38
Q

Nomenclature

A
  • Not yet completely uniformed
    – But most important alleles have been “starred”
  • Cytochrome P450 genes
    – Human Cytochrome P450 Allele Nomenclature Committee
  • Cytochrome P450 enzymes account for 70 percent to 80 percent of enzymes involved in drug metabolism.
  • approximately 60 cytochrome P450 genes in human
39
Q

Nomenclature “rs” number

A
  • “ID” for SNPs
  • Commonly used
  • Single SNP/polymorphism
    – No particular meaning, difficult to remember
    – Unique, no need to uniform once new ones identified
    rs = reference SNP
40
Q

Nomenclature in clinical setting

A

This type of nomenclature is widely used in clinical setting by doctors and pharmacists
Gene/allele name: italic
Protein name: regular
Be careful: asterisk vs dot

41
Q

From PGx Genotype to Phenotype

A

Variations in CYP2C19
§ Ultrarapid metabolizer (UM)
§ Extensive metabolizer (EM)
§ Intermediate metabolizer (IM)
§ Poor metabolizer (PM)

42
Q

How a Genotype Determines a PGx Phenotype?

A
  • A genetic variant can change PK (ADME)
    – Alters the enzymatic activity during drug ADME (e.g., the
    case of CYP2C19)
    – Directly leads to inter-patient difference in drug
    concentration, duration, dose, etc.
    – As a consequence, leading to inter-patient difference in
    toxicity profiling and efficacy.
  • A genetic variant can change PD:
    – Alters the drug target activity/property
    – Create new drug target
    – Alters the structure of protein (e.g., drug receptor)
    – Change drug-receptor binding
    – Directly leads to inter-patient difference in drug toxicity and efficacy
43
Q

Allele and Genotype Frequency

A
  • In a PGx testing, the direct readout is the individual’s
    GENOTYPE (the combination of alleles)
  • The two homologous chromosomes are usually read simultaneously
  • You can only calculate the allele frequency from the population based on the number of genotypes observed
44
Q

Allele Frequency

A

*For a given population of N individuals
*The number of homologous chromosomes or alleles is 2N

45
Q

Allele Frequency Based on Observed Genotype Data

A
  • For a population of N individuals with
    – Q number of persons with T/T
    – R number of persons with T/C
    – S number of persons with C/C
  • We have
    – Number of T allele = 2Q+R Then T allele%=(2Q+R)/2N
    – Number of C allele = 2S+R Then C allele% = (2S+R)/2N
    N=Q+R+S
46
Q

Calculate allele frequency

A
  • Genotype data of MDR1 2677G>T polymorphism in a population of 210 patients
47
Q

If genotype frequencies are known, How to figure out MAF?

A

Allele%=homozygote%+1/2heterozygote%
* Genotype data of MDR1 2677G>T polymorphism in a population of 210 patients

48
Q

Common and Rare Allele

A
  • allele frequencies usually stay stable in a population
    – Common/major/reference allele: the one with higher frequency >50%
    – Rare/minor/mutant allele: the one with lower frequency <50%
  • Terms commonly used:
    – Minor allele frequency (MAF)
    – Rare allele frequency (RAF)
    – A rare allele in one population can be a common allele in another population
49
Q

Crossover and Recombination

A
  • A phenomenon occurs between homologous chromosomes during meiosis
  • Recombination: the result of crossover, which leads to recombinant chromosomes
  • An important way to exchange genetic information
  • Occurs during meiosis to produce gametes
50
Q

Haplotype

A

*A haplotype is a group of genes within an organism that were inherited together from a single parent
*Also refer to the inheritance of a cluster of single nucleotide polymorphisms (SNPs), which are variations at single positions in the DNA sequence among individuals

51
Q

The Application of Haplotype in PGx

A
  • Haplotype can provide more information in PGx research
  • The function of a gene is a combined result of all functional alleles
    – SNP1: T>C increases gene expression
    – SNP3: A>G leads to an amino acid change Val to Met which decreases the enzyme activity
    – SNP4: G>T alters microRNA binding leading to an increased mRNA level
    Then
    – HaplotypeC-A-T will have the highest enzyme activity
    – HaplotypeT-G-G will have the lowest enzyme activity
    – HaplotypeC-G-T may have an intermediate level of enzyme activity
52
Q

Linkage Disequilibrium (LD)

A
  • LD: Non-random association of alleles at different loci on the same chromosome
    – When there are infinite recombination: no LD – When there is no recombination:
    complete/perfect LD
    – When recombination occurs in a portion of chromosomes: incomplete LD
53
Q

Two Extreme Situations

A

If the distance between two loci is short enough, there will be no recombination in a population
– This leads to a co-segregation of both loci into next generation
– This called a complete linkage (prob=100% or 1)
– DNA is inherited segment by segment!
– Each segment is called a haplotype block
* If the distance between two loci is long enough, there will be a large number of recombination between the two loci in a population
– This leads to almost an independent segregation of the two loci into next generation, a situation same as that two loci are located on two different chromosomes
– There is no linkage between the two loci (prob= 0% or 0)
– Not all loci on the same chromosome are in linkage!

54
Q

Measures of LD

A

– R2: how strong is the correlation between two variables
* R2 measures the extent of correlation between a pair of variables or the extent of concordance in genotypic association between loci
* Varies between 0 and 1
* Measures the strength of LD
* R2=0: noLD
* R2 = 1: complete LD/Perfect LD
* R2 ≥ 0.8: strong LD

55
Q

The Application of LD in PGx

A
  • LD is useful in PGx research and testing
  • tagSNP: a SNP that can be a representative for other SNPs due to strong LD
  • If R2 between locus 1, 2, and 3 are all ≥0.8
  • And between locus 4, 5 and 6 are also ≥0.8
  • Then we can choose any SNP from 1, 2, 3 as a tagSNP and any SNP from 4-6 as another tagSNP
  • This will simplify the research and reduce the cost
  • Can be used in clinical practice to select a tagSNP for PGx testing

PHRM 847 (13 decks)

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