1 - Intro Flashcards

(43 cards)

1
Q

Define pharmacogenomics

A

General study of all of the different genes that determine drug response

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2
Q

How can genetic variations affect PK?

A
  • Drug uptake channels
  • Transporters
  • Drug metabolizing enzymes (CYP), etc.
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3
Q

How can genetic variations affect PD?

A
  • Drug receptors
  • Receptor gated channels
  • Enzyme targets
  • Second messengers
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4
Q

Define allele

A

2 copies of a gene, one from each parent

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5
Q

Define locus

A

Region on a chromosome

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6
Q

Define genotype

A
  • Entire genetic makeup of the cell/ organism

- 2 alleles for a specific gene or group of genes

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7
Q

Define haplotype

A
  • Group of alleles (or polymorphisms) on the same chromosome that are inherited together
  • Can refer to a combination of alleles or to a set of SNPs found on the same chromosome
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8
Q

Define wild type

A
  • Normal sequence of the gene in the population

- Gene that is most often expressed in the population

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9
Q

Define polymorphism

A

Variation in DNA sequence present in 1% or more of the population

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10
Q

What are the types of polymorphisms?

A
  • Single nucleotide polymorphism (SNP)
  • Variable number tandem repeats (VNTR) – more than 1 nucleotide change (in tandem repeats)
  • Gene insertion or deletion
  • Multiple copies of a gene
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11
Q

Types of single nucleotide polymorphisms (SNP)

A
  • Nonsense mutation -> premature stop codon SNP
  • Silent mutation -> synonymous SNP (nucleotide change that still results in the same AA)
  • Missense mutation -> non-synonymous SNP
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12
Q

What is the difference between SNP deletions and insertions?

A
  • Deletion SNP will cause frame shift; almost certainly results in premature stop codon
  • Insertion SNP will cause frame shift; typically results in premature stop codon
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13
Q

What can VNTR’s cause?

A
  • No effect on activity
  • Result in frame shift (causing no activity)
  • No frame shift but no activity
  • Loss of some activity
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14
Q

What is a gene deletion and what does it cause?

A
  • Deletion of thousands of base pairs

- Results in loss of gene (no activity)

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15
Q

What is a gene duplication and what does it cause?

A
  • Duplication of the sequence of a gene

- Results in more activity, but the increase in activity isn’t always linear w/ increasing copies of said gene

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16
Q

Define intron

A

Removed from gene and doesn’t appear in final mRNA

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17
Q

Define exon

A

Sequence that makes up the final mRNA

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18
Q

What can polymorphisms w/in introns cause?

A
  • May not change gene activity but could change gene expression
  • In the intron-exon boundary, may result in splice variant
19
Q

What can polymorphisms w/in exons cause?

A

Likely affect gene activity (unless a synonymous SNP)

20
Q

What can be caused by improper splicing?

A
  • Mutation could result in the forced formation of a splice variant (splice variant may still have activity)
  • Mutation could also truncate the protein (almost certainly will result in an inactive protein)
21
Q

Define promoter

A

DNA sequence where transcription factors bind to initiate transcription (+1 is the position of first base of the primary RNA transcript)

22
Q

Define enhancer

A
  • DNA sequence that binds proteins that increase the rate of transcription
  • Usually located far upstream or downstream of the gene
  • Can be more than 1 for a given gene
  • Can also be found w/in introns
23
Q

What can polymorphisms in the promoter cause?

A
  • Can alter transcription of the gene
  • Could reduce transcription but also possible that the gene won’t express at all (may occur by reducing binding of transcription factors)
  • However, depending on the polymorphism, transcription may also increase
24
Q

What can polymorphisms in the enhancer regions cause?

A
  • Can affect transcription of the gene
  • Enhancers are sometimes found w/in introns (another reason why polymorphisms w/in introns can affect transcription of genes)
  • The polymorphism can disrupt the enhancer
25
What is caused from a nonsynonymous SNP in exons?
Usually results in a malfunctioning protein – may have no activity or lower activity
26
What can SNPs in introns cause?
- Have no affect - Decrease transcription - Influence splicing producing a truncated protein or a splice variant - Disrupt enhancer sequences decreasing transcription
27
What is caused from a synonymous SNP w/in exons?
No impact on protein sequence but can change expression of the gene
28
Changes to a reading frame will eventually result in ____
A stop codon
29
What is caused from tandem repeats of multiples of 3 bases?
- Won't cause a shift in reading frame | - Will introduce additional AA's into the protein, it it occurs in an exon
30
What is caused from deletions of multiples of 3 bases?
- Won't cause a frame shift | - Will delete AA's from the protein sequence, if occurs in an exon
31
What is caused from tandem repeats/deletions in multiples of other than 3 bases?
Will result in frame shift and eventually a stop codon
32
What do mutations outside of the reading frame (ie: before the start or after the stop codons) NOT cause?
Frame shifts
33
What is the mutation of CYP 2C19 *2 and what does it cause?
- 681 G > A | - Results in splicing defect and no activity
34
What is the mutation of CYP 2C19 *3 and what does it cause?
- 636 G > A | - Results in insertion of a stop codon and no activity
35
What are CYP 2C19 *2 through *8 referred to as?
Defective
36
What is the mutation of CYP 2C19 *17 and what does it cause?
- 806 C > T | - Increased activity
37
What metabolizes omeprazole?
CYP 2C19
38
What are the 3 types of CYP 2C19 w/ respect to omeprazole metabolism?
- *1 / *1 = homozygous = EM - def / *1 = heterozygous = IM - def / def = homozygous = PM
39
What does a PM of CYP 2C19 for omeprazole cause?
- Omeprazole metabolized into inactive metabolite - PM causes much higher intragastric pH for a longer period of time b/c higher omeprazole concentration and lower inactive metabolite concentration * Example of when it's good to have defective alleles
40
Define linkage disequilibrium
When 2 or more alleles appear together in greater or lower frequency than would be expected by random chance
41
Briefly describe CYP 2D6 *5
Polymorphism where thousands of base pairs are missing, resulting in the effective deletion of the CYP 2D6 gene => PM
42
Give an example of gene duplication
- CYP 2D6 *2XN - Extra copies of CYP 2D6 gene are present (N = 2, 3, 4, 5, 13) => more enzyme is produced - Results in UM
43
Define phenotype
The net effect of the activities of the 2 copies of the genes an individual has