GENE POLYMORPHISM AND PHARMACOGENOMICS

Question 1

what are Adverse Drug Reactions (ADRs)?

Answer 1

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

Question 2

what is precision medicine?

Answer 2

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

Question 3

what is DNA?

Answer 3

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

Question 4

what are bases?

Answer 4

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

Question 5

what are base pairs?

Answer 5

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

Question 6

what is a gene?

Answer 6

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

Question 7

what are non-coding regions?

Answer 7

Regions of the chromosome in-between genes

Question 8

what is a chromosome?

Answer 8

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

Question 9

what is a genome?

Answer 9

An organism’s complete set of DNA

Question 10

what is transcription?

Answer 10

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

Question 11

what are exons?

Answer 11

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

Question 12

what are introns?

Answer 12

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

Question 13

what is translation?

Answer 13

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

Question 14

what is a mutation?

Answer 14

A change in DNA sequence

Question 15

what is a nonsynonymous mutation?

Answer 15

Mutation that ultimately results in a change in protein sequence

Question 16

what is an allele?

Answer 16

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

Question 17

what is a genotype?

Answer 17

Combination of alleles for a given gene within an individual

An individual’s genotype is defined by the 2 alleles present [chromosomes are paired]

Question 18

what is a SNP (single nucleotide polymorphism)?

Answer 18

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

Question 19

what is a haplotype?

Answer 19

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

Question 20

what are the benefits of precision medicine?

Answer 20

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

Question 21

what causes variation in the human genome?

Answer 21

polymorphism
deletion
insertion

Question 22

can variations cause no changes?

Answer 22

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

Question 23

what are silent mutations?

Answer 23

variations that cause no changes or effect

Question 24

can variations be harmful?

Answer 24

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

Question 25

what causes harmful variation?

Answer 25

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

Question 26

what is haemophilia?

Answer 26

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

Question 27

what are diabetes/heart diseases?

Answer 27

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

Question 28

what are variations causing latent changes?

Answer 28

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

Question 29

what are SNPs?

Answer 29

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

Question 30

How can SNPs be used to Inform Drug Treatment?

Answer 30

precision oncology | pharmacogenomics

Question 31

how does coagulation occur?

Answer 31

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

Question 32

what is the function of coagulation?

Answer 32

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

Question 33

what does the mechanism of coagulation involve?

Answer 33

Coagulation factors Phospholipids Calcium ions

Question 34

what are coagulation factors?

Answer 34

Plasma proteins made in an inactive form in the liver

Question 35

where are coagulation factors activated?

Answer 35

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

Question 36

where are phospholipids found for coagulation?

Answer 36

on the surface of activated platelets

Question 37

what is the function of calcium ions for coagulation?

Answer 37

required for several coagulation factors to be active

Question 38

what does coagulation lead to?

Answer 38

Leads to the generation of the protease thrombin

Question 39

what is the function of thrombin?

Answer 39

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

Question 40

what is the function of fibrin?

Answer 40

gives the blood clot mechanical strength

Question 41

what are the 3 coagulations pathways?

Answer 41

intrinsic extrinsic common

Question 42

what is the intrinsic coagulation pathway activated by?

Answer 42

Activated by exposed sub-endothelial collagen in vivo

Question 43

what is the extrinsic coagulation pathway activated by?

Answer 43

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

Question 44

what does the common coagulation pathway generate?

Answer 44

Generates thrombin | from prothrombin

Question 45

what is venous thrombosis?

Answer 45

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

Question 46

what does venous thrombosis lead to?

Answer 46

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

Question 47

give an examples of venous thrombosis

Answer 47

Deep vein thrombosis (DVT)

Question 48

what is the treatment for venous thrombosis?

Answer 48

Anti-coagulants

Question 49

what is Arterial thrombosis?

Answer 49

Platelets aggregate then encapsulated by clot formation

Question 50

what does Arterial thrombosis cause?

Answer 50

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

Question 51

give an examples of arterial thrombosis

Answer 51

Myocardial infarction (MI), Ischaemic stroke

Question 52

what is an immediate treatment of arterial thrombosis?

Answer 52

Fibrinolytics (“clot busters”)

Question 53

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

Answer 53

Anti-coagulants, anti-platelet drugs

Question 54

what is warfarin?

Answer 54

Most widely prescribed oral anti-coagulant

Question 55

what is warfarin prescribed for?

Answer 55

Administered to patients with ↑ thrombotic tendency

Question 56

give examples of conditions warfarin treats?

Answer 56

Atrial fibrillation Pulmonary embolisms DVT Heart valve recipients

Question 57

what is warfarin administered as?

Answer 57

as a prophylactic, slow onset of action (days)

Question 58

does warfarin have a narrow therapeutic range?

Answer 58

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

Question 59

what is the main adverse effect of warfarin?

Answer 59

bleeding/haemorrhage

Question 60

what is warfarin chemical known as?

Answer 60

VitK reductase (VKORC1) antagonist

Question 61

what is VitK?

Answer 61

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

Question 62

what is required in the warfarin mechanism?

Answer 62

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

Question 63

does warfarin have a narrow therapeutic window?

Answer 63

yes, requires constant monitoring

Question 64

what happens if the dose of warfarin is too low?

Answer 64

ineffective

Question 65

what happens if the dose of warfarin is too high?

Answer 65

risk of bleeding

Question 66

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

Answer 66

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

Question 67

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

Answer 67

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

Question 68

what is a future aim of precision medicine?

Answer 68

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

Question 69

what are the ethical and legal issues of precision medicine?

Answer 69

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

Question 70

what are the clinical issues of precision medicine?

Answer 70

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