Genetics 7- The Future of Genomic Medicine Flashcards
What is Pharmacogenomics
Studying the genetic basis for the difference between individuals in response to drugs - allows ‘right drug, right dose, right patient’.
Drugs are metabolised in the liver by enzymes - Enzymes come from genes - Genes have variations among the population - you need to understand the genetic basis of people’s response to drugs to tailor their treatment to suit them.
Examples of pharmacogentics
EXAMPLE 1: Getting the DOSE right - 6-mercaptopurine (used to treat: leukaemia, Crohn’s disease, ulcerative colitis)
Some people metabolise 6-mercaptopurine quickly and others more slowly.
The ones who metabolise it slowly have more side effects so need a smaller dose.
People who respond to the drug fast have two copies of TPMT (Thiopurine Methyl Transferase)
People who metabolise it slowly are heterozygous for a mutation in that gene
A small population are homozygous for that mutation and hence barely metabolise the drug at all.
EXAMPLE 2: Getting the DRUG right - Type 1 Diabetes and MODY
MODY - Mature Onset Diabetes of the Young
Single Gene Disorder - can be caused by mutations in any of 36 genes.
MODY can be treated with an ORAL DRUG.
There are some children who have MODY (more rare) but are misdiagnosed and believed to have Type 1 Diabetes.
They could have oral treatment rather than insulin injections.
You need the right drug for the right patient and it is genetics that tells you that.
Direct-To-Consumer (DTC) Genetic Tests
Companies can sequence your genome and look for certain genetic markers e.g. BRCA1
Monogenic Diseases:
Can provide carrier status information (e.g. Tay Sachs)
Can predict risk of late-onset disease (e.g. BRCA1/2)
Essential to provide GENETIC COUNSELLING - some of the information may be very sensitive
Complex Diseases:
Limited clinical utility
May cause undue alarm
May offer false reassurance
Data privacy concerns
Predicting the risk of common disease: Type 2 Diabetes
T2D is caused by complex interaction between genetic and environmental factors.
Sibling relative risk is 3 times that of the general population
Over 60 confirmed T2D genes so far - explains just 10% of estimated genetic contribution.
Cost of DNA Sequencing - diploid genome sequence = $6000 - takes a few weeks
Applications of whole genome sequencing:
Identify new gene mutations in monogenic disease
Identify the differences between normal cells and cancer cells - allows the use of targeted treatments instead of using generalised poisons.
NOTE: There will be lots of differences between your genome and the reference genome - it is difficult to see what is normal variation and what’s causing disease.
DNA Sequencing was used to identify the mutations responsible for:
MILLER SYNDROME
DHODH gene
Multiple malformation syndrome
Characteristic facial features - includes ‘cupped’ ears
Absent toes
SCHINZEL-GIEDION SYNDROME
SETBP1 gene
Severe mental retardation
Multiple congenital abnormalities
Life-limiting
Ethical Issued of PGD
Involves discarding unused embryos
Disability rights arguments
Slippery slope - designer babies
Eugenics - improving a population by controlling breeding to increase the occurrence of desirable characteristics
What is allowed in PGD in the UK?
Severe early onset genetic disease e.g. Tay Sachs
Severe late onset genetic disease e.g. Huntingdon’s Disease
Disease with incomplete penetrance (symptoms are NOT always present in an individual with a disease-causing mutation) e.g. BRCA1/2 mutations
To choose tissue-matched baby than can provide umbilical cord blood to treat sick sibling
NOT ALLOWED to chose the sex of the baby for non-medical reasons
Limitations of PGD
IVF - physically and emotionally demanding - expensive
Only suitable for diseases where the genetic/chromosomal abnormality is known
Can only select for traits that are present/absent in the embryos obtained - can’t design the baby
