Complex Diseases and Pharmacogenetics Flashcards
What are the two different types of genetic diseases?
mendelian or complex
What is a mendelian disease/ trait?
A condition with clear mendelian inheritance patterns, caused by a single gene with limited environmental influence
What is an example of mendelian trait?
blood groups (ABO) (co-dominant but a single gene)
What is a complex disease/ trait?
A disease controlled by multiple genes, and where the phenotype is controlled by the interaction of many genes and the environment
quantitative traits e.g., height and weight
What is an example of a complex disease?
Cardiovascular disease
What are the causes of phenotypic differences?
Genetic differences
Shared environment
Unique environment
What is an SNP?
A single nucleotide polymorphism - DNA sequence variations that occur when a single nucleotide is changed
Can be in coding or non-coding region
Even in non-coding region it can have an effect
How do you examine association between SNP and disease risk?
Association studies- gene specific
hard to prove the SNP is linked to the disease- hard to find cases vs controls?
Hypothesis driven
What is the most common type of variation in a genome?
SNPs
What is meant by heritability?
It is an estimation of the genetic contribution to increased risk of disease
What are the two ways to measure heritability?
Twin Studies and Genome Wide Association studies
What are Genome Wide Association Studies?
Where you study the genomes of different people and look for an association between specific genetic variations and the different diseases that the people in the study have
Examine association SNPs and disease across entire genome
Hypothesis free
What are the benefits of GWAS?
Can identify SNP-variant associations I.e., risk loci for complex disease
Identify at risk individuals
Discovery of novel biological mechanisms
Inform drug discovery or repurposing
Identify ethnic differences
What are the limitations of GWAS?
Doesn’t identify casual variants- further testing required
Can’t identify all heritability (more rare variants won’t be noticed)
Threshold- won’t identify rare variants
Environmental influence- epigenetics
When are SNP’s said to be associated with certain conditions?
When SNPs are found to be more frequent in people with a disease compared to people without the disease
What specifically is GWAS lookin for?
Shared SNPs
What is meant by missing heritability?
The gap between the association found by the GWAS and what is known about the heritability of the disease
What are the 5 factors contributing to missing heritability?
- Rare SNPs
- Interactions are not taken into consideration
- Miscalculated estimation of heritability
- Diagnosis
- Low frequency variants with immediate effects
What are dizygotic twins?
50% shared genetic component
How do Twin studies work?
Since monozygotic twins share 100% of their genetic material, they can be analysed as any variation will be due to the environment, not genetics
What is pharmacogenetics?
The study of differences in response to drugs due to genetic differences amongst people
What can pharmacogenetics specifically help with?
The development of personalised medicine
Improve drug therapy and prescribing in the future
What is the ideal scenario for a drug to work under?
Increased efficancy with decreased side effects
What are the four classes of drug responses?
No effect
Recovery
Side effects
Death
What is pharmacokinetics?
What the body does to the drug
What is the order of pharmacokinetics?
absorption-> activation-> target -> inactivation-> excretion
After target it also goes to effect
activation can also be skipped
What are the stages in pharmacokinetics that are concerning metabolism?
activation and inactivation
during activation it can be metabolised to be activated (aka prodrugs)
Why is absorption important?
The majority of drugs are given orally
Majority of drugs are absorbed in small intestine
Use specific trnasporter proteins
What is the definition of personalised medicine?
Tailoring treatment to patients depending on specific characteristics of their disease
What are the most prevalent drug-metabolising enzymes?
Cytochrome P450 enzymes including CYP2D6 and CYP2C19
How many phenotypes of CYP2D6?
4
ranging between 2 fully functional alleles and 2 non-functional alleles leading to ultra rapid metabolizer and poor metabolizer
What is the best way to study Mendelian disease?
Family studies through pedigree charts
Why might there be false positives when looking at over 10,000,000 SNPs?
Larger sample, more of a likelihood that diseases occur purely by chance
Give some examples of the modifiable factors affecting CVD
Drinking habits
Eating habits
Smoking
High blood pressure
Sedentary lifestyle
Give some examples of the non-modifiable factors affecting CVD
Age
Sex
genetics
How do you examine association between SNP and disease risk?
Association studies- gene specific
hard to prove the SNP is linked to the disease- hard to find cases vs controls?
Hypothesis driven
What are drug targets?
receptors
enzymes
ion channels
transport protein
I.e., beta-1 receptor (heart)= SG lower level of receptor activation
Hypertension- beta-blockade (slows heart rate/ force of contraction)
