GENE POLYMORPHISM AND PHARMACOGENOMICS Flashcards Preview

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Flashcards in GENE POLYMORPHISM AND PHARMACOGENOMICS Deck (70):
1

what are Adverse Drug Reactions (ADRs)?

Unintended events that occurs at drug doses used in humans for prophylaxis, diagnosis, therapy or modification of physiological functions

2

what is precision medicine?

Influence of genetic variation on drug response in patients by correlating gene expression or presence of single-nucleotide polymorphisms (SNPs) with a drug's efficacy or toxicity

3

what is DNA?

Paired double-stranded helical molecule capable of replicating and responsible for directing an organism’s inherited activities by directing the expression and composition/structure of cellular proteins

4

what are bases?

The basic chemical building blocks of DNA that determine its sequence
Adenine (A) Guanine (G) Thymine (T) Cytosine (C)

5

what are base pairs?

A single pair of complementary bases from opposite strands of the DNA double helix
A is always paired with T G is always paired with C

6

what is a gene?

A discrete unit of hereditary info consisting of a specific DNA sequence that carries the instructions to make specific proteins

7

what are non-coding regions?

Regions of the chromosome in-between genes

8

what is a chromosome?

Thread-like structure in the nucleus consisting mainly of a long DNA molecule comprising 50-300,000 base pairs which code for thousands of genes.
Humans each have 23 pairs of chromosomes

9

what is a genome?

An organism’s complete set of DNA

10

what is transcription?

generation of RNA from a DNA template. This is initially in the form of a primary transcript

11

what are exons?

blocks of a gene whose DNA sequence will ultimately determine AA sequence

12

what are introns?

blocks of a gene which do not code for protein and which are removed during the processing of primary transcript to generate mRNA

13

what is translation?

process in which protein is made using mRNA sequence as a template

14

what is a mutation?

A change in DNA sequence

15

what is a nonsynonymous mutation?

Mutation that ultimately results in a change in protein sequence

16

what is an allele?

One member of a number of different forms/variations of a gene

17

what is a genotype?

Combination of alleles for a given gene within an individual
An individual’s genotype is defined by the 2 alleles present [chromosomes are paired]

18

what is a SNP (single nucleotide polymorphism)?

DNA sequence variation when a single base differs at the same genetic location between different chromosomes

19

what is a haplotype?

Combination of SNPs present at different genetic locations that are transmitted together on the same chromatid (=replicating chromosome)

20

what are the benefits of precision medicine?

Advanced screening
Better drugs
Design/administration of “customised drugs"
Improved dosing regimens
Improved drug discovery and approval process

21

what causes variation in the human genome?

polymorphism
deletion
insertion

22

can variations cause no changes?

yes Most variations in the genome occur in noncoding regions and have no known effect
Some changes that occur in coding and regulatory regions also have no known effect

23

what are silent mutations?

variations that cause no changes or effect

24

can variations be harmful?

yes some variations in coding and regulatory regions have harmless effects
Influence benign individual characteristics Examples: Eye colour, Stature, Shape

25

what causes harmful variation?

Specific variations in coding and regulatory regions result in harmful effects
These changes alter function or expression of important proteins needed for health

26

what is haemophilia?

“simple” disease in which variation in ONE gene (Factor VIII)
causes disease

27

what are diabetes/heart diseases?

“complex” diseases. Symptoms seen only after many variations have occurred in different genes in the same cell

28

what are variations causing latent changes?

These coding region and regulatory variations are not harmful on their own
Changes only becomes apparent if they eventually cause some people to be at higher risk for disease only after exposure to environmental factors

29

what are SNPs?

DNA sequence variations that occur when a single nucleotide (A,T,C,or G) in the genome sequence is altered at the same genetic location between different chromosomes

30

How can SNPs be used to Inform Drug Treatment?

precision oncology
pharmacogenomics

31

how does coagulation occur?

Catalyses conversion of fluid blood to a solid fibrin gel/clot
Responsible for making a fibrous network “wall” at the site of a lesion

32

what is the function of coagulation?

Trap exudate, microorganisms and foreign bodies
Stop bleeding by consolidating structure of the platelet plug
Provide a framework for initiation of repair

33

what does the mechanism of coagulation involve?

Coagulation factors
Phospholipids
Calcium ions

34

what are coagulation factors?

Plasma proteins made in an inactive form in the liver

35

where are coagulation factors activated?

at sites of vessel injury by proteolytic cleavage to become active proteases

36

where are phospholipids found for coagulation?

on the surface of activated platelets

37

what is the function of calcium ions for coagulation?

required for several coagulation factors to be active

38

what does coagulation lead to?

Leads to the generation of the protease thrombin

39

what is the function of thrombin?

converts fibrinogen (soluble) to fibrin (insoluble, gel-like)

40

what is the function of fibrin?

gives the blood clot mechanical strength

41

what are the 3 coagulations pathways?

intrinsic
extrinsic
common

42

what is the intrinsic coagulation pathway activated by?

Activated by exposed sub-endothelial collagen in vivo

43

what is the extrinsic coagulation pathway activated by?

Activated by tissue factor after trauma to vascular wall
and adjacent tissue

44

what does the common coagulation pathway generate?

Generates thrombin
from prothrombin

45

what is venous thrombosis?

Intravascular clot forms in deep veins, particularly in the legs, when flow sluggish

46

what does venous thrombosis lead to?

Fragment may bud off (venous thromboembolism) and block blood vessel (pulmonary artery = fatal)

47

give an examples of venous thrombosis

Deep vein thrombosis (DVT)

48

what is the treatment for venous thrombosis?

Anti-coagulants

49

what is Arterial thrombosis?

Platelets aggregate then encapsulated by clot formation

50

what does Arterial thrombosis cause?

Blocks BF to target tissues:
Coronary artery/MI Cerebral artery/ischaemic stroke

51

give an examples of arterial thrombosis

Myocardial infarction (MI), Ischaemic stroke

52

what is an immediate treatment of arterial thrombosis?

Fibrinolytics (“clot busters”)

53

what is an long term/ prophylaxis treatment of arterial thrombosis?

Anti-coagulants, anti-platelet drugs

54

what is warfarin?

Most widely prescribed oral anti-coagulant

55

what is warfarin prescribed for?

Administered to patients with ↑ thrombotic tendency

56

give examples of conditions warfarin treats?

Atrial fibrillation Pulmonary embolisms
DVT
Heart valve recipients

57

what is warfarin administered as?

as a prophylactic, slow onset of action (days)

58

does warfarin have a narrow therapeutic range?

yes, difficult to maintain patients within a defined anti-coagulation range

59

what is the main adverse effect of warfarin?

bleeding/haemorrhage

60

what is warfarin chemical known as?

VitK reductase (VKORC1) antagonist

61

what is VitK?

VitK=co-factor for -glutamyl carboxylase (GGCX) in liver

62

what is required in the warfarin mechanism?

Post-translational carboxylation required for activity of FII VII IX X
Required for Ca2+ binding

63

does warfarin have a narrow therapeutic window?

yes, requires constant monitoring

64

what happens if the dose of warfarin is too low?

ineffective

65

what happens if the dose of warfarin is too high?

risk of bleeding

66

what factors need to be considered when taking warfarin that may complicate things?

Weight/Diet/Disease state/Other medications/Genetic factors

67

what genetic variability cause warfarin to have variable pharmacokinetics/efficacy?

Liver enzyme responsible for inactivation CYP2C9
VitK reductase VKORC1 (site of warfarin action)

68

what is a future aim of precision medicine?

“Genomics-first approach” in which drug administration decisions predicted by genomic analysis of individuals

69

what are the ethical and legal issues of precision medicine?

Privacy and confidentiality of genetic info
Fairness in the use of genetic info
Psychological impact and discrimination
Reproductive issues

70

what are the clinical issues of precision medicine?

Education of doctors, other HCPs, people identified with genetic conditions, and the general public