GENE POLYMORPHISM AND PHARMACOGENOMICS Flashcards
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
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
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
what are bases?
The basic chemical building blocks of DNA that determine its sequence
Adenine (A) Guanine (G) Thymine (T) Cytosine (C)
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
what is a gene?
A discrete unit of hereditary info consisting of a specific DNA sequence that carries the instructions to make specific proteins
what are non-coding regions?
Regions of the chromosome in-between genes
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
what is a genome?
An organism’s complete set of DNA
what is transcription?
generation of RNA from a DNA template. This is initially in the form of a primary transcript
what are exons?
blocks of a gene whose DNA sequence will ultimately determine AA sequence
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
what is translation?
process in which protein is made using mRNA sequence as a template
what is a mutation?
A change in DNA sequence
what is a nonsynonymous mutation?
Mutation that ultimately results in a change in protein sequence
what is an allele?
One member of a number of different forms/variations of a gene
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]
what is a SNP (single nucleotide polymorphism)?
DNA sequence variation when a single base differs at the same genetic location between different chromosomes
what is a haplotype?
Combination of SNPs present at different genetic locations that are transmitted together on the same chromatid (=replicating chromosome)
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
what causes variation in the human genome?
polymorphism
deletion
insertion
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
what are silent mutations?
variations that cause no changes or effect
can variations be harmful?
yes some variations in coding and regulatory regions have harmless effects
Influence benign individual characteristics Examples: Eye colour, Stature, Shape
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
what is haemophilia?
“simple” disease in which variation in ONE gene (Factor VIII)
causes disease
what are diabetes/heart diseases?
“complex” diseases. Symptoms seen only after many variations have occurred in different genes in the same cell
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
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
How can SNPs be used to Inform Drug Treatment?
precision oncology
pharmacogenomics
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
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
what does the mechanism of coagulation involve?
Coagulation factors
Phospholipids
Calcium ions
what are coagulation factors?
Plasma proteins made in an inactive form in the liver
where are coagulation factors activated?
at sites of vessel injury by proteolytic cleavage to become active proteases
where are phospholipids found for coagulation?
on the surface of activated platelets
what is the function of calcium ions for coagulation?
required for several coagulation factors to be active
what does coagulation lead to?
Leads to the generation of the protease thrombin
what is the function of thrombin?
converts fibrinogen (soluble) to fibrin (insoluble, gel-like)
what is the function of fibrin?
gives the blood clot mechanical strength
what are the 3 coagulations pathways?
intrinsic
extrinsic
common
what is the intrinsic coagulation pathway activated by?
Activated by exposed sub-endothelial collagen in vivo
what is the extrinsic coagulation pathway activated by?
Activated by tissue factor after trauma to vascular wall
and adjacent tissue
what does the common coagulation pathway generate?
Generates thrombin
from prothrombin
what is venous thrombosis?
Intravascular clot forms in deep veins, particularly in the legs, when flow sluggish
what does venous thrombosis lead to?
Fragment may bud off (venous thromboembolism) and block blood vessel (pulmonary artery = fatal)
give an examples of venous thrombosis
Deep vein thrombosis (DVT)
what is the treatment for venous thrombosis?
Anti-coagulants
what is Arterial thrombosis?
Platelets aggregate then encapsulated by clot formation
what does Arterial thrombosis cause?
Blocks BF to target tissues:
Coronary artery/MI Cerebral artery/ischaemic stroke
give an examples of arterial thrombosis
Myocardial infarction (MI), Ischaemic stroke
what is an immediate treatment of arterial thrombosis?
Fibrinolytics (“clot busters”)
what is an long term/ prophylaxis treatment of arterial thrombosis?
Anti-coagulants, anti-platelet drugs
what is warfarin?
Most widely prescribed oral anti-coagulant
what is warfarin prescribed for?
Administered to patients with ↑ thrombotic tendency
give examples of conditions warfarin treats?
Atrial fibrillation Pulmonary embolisms
DVT
Heart valve recipients
what is warfarin administered as?
as a prophylactic, slow onset of action (days)
does warfarin have a narrow therapeutic range?
yes, difficult to maintain patients within a defined anti-coagulation range
what is the main adverse effect of warfarin?
bleeding/haemorrhage
what is warfarin chemical known as?
VitK reductase (VKORC1) antagonist
what is VitK?
VitK=co-factor for -glutamyl carboxylase (GGCX) in liver
what is required in the warfarin mechanism?
Post-translational carboxylation required for activity of FII VII IX X
Required for Ca2+ binding
does warfarin have a narrow therapeutic window?
yes, requires constant monitoring
what happens if the dose of warfarin is too low?
ineffective
what happens if the dose of warfarin is too high?
risk of bleeding
what factors need to be considered when taking warfarin that may complicate things?
Weight/Diet/Disease state/Other medications/Genetic factors
what genetic variability cause warfarin to have variable pharmacokinetics/efficacy?
Liver enzyme responsible for inactivation CYP2C9
VitK reductase VKORC1 (site of warfarin action)
what is a future aim of precision medicine?
“Genomics-first approach” in which drug administration decisions predicted by genomic analysis of individuals
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
what are the clinical issues of precision medicine?
Education of doctors, other HCPs, people identified with genetic conditions, and the general public
