pharmacogenetics

Question 1

what factors influence our drug response?

Answer 1

environmental factors (age, diet, organ function) and genetic factors (as coded by DNA)

Question 2

How are genes associated with Mercaptopurine and the drug azathioprine?

Answer 2

This drug inhibits DNA replication and is commonly used to treat RA, leukemias, IBS etc. It generally causes myelosuppression. However, the metabolism of this drug requires a number of enzymes including TPMT - so if we genetically test for deficiencies in this gene, we can avoid toxic effects by insufficient metabolism of the drug

Question 3

What has evolved P450 historically?

Answer 3

P450 has been altered over history by the foods we eat (natural toxins in food) - this is relevant b/c the P450 is not necessarily fit for every drug that we encounter pharmaceutically

Question 4

How many different isotopes of P450 are there?

Answer 4

approx. 57 human variants of P450 isoenzymes identified - they are important in a number of different metabolism processes in the liver

Question 5

What is the challenge with Warfarin dosing?

Answer 5

Warfarin is difficult in the clinical setting because the relatively small therapeutic window - warfarin. We have to measure it with their INR to measure their clotting tendency to determine how much Warfarin they need. You keep adjusting the dose until you’re at a therapeutic range.

Question 6

What two genes are particularly important in determining Warfarin dose?

Answer 6

CYP2C9 gene and the VKORC1 gene

Question 7

What is the most commonly mutated region in your genes?

Answer 7

The HLA region - It is the most diverse region in the human genome - rapidly evolving and balancing selection -

Question 8

What drug induced Stevens Johnson syndrome?

Answer 8

Carbamazepine -
in 2004 scientists found an extremely strong link between HLA B gene and stevens johnson syndrome (almost 100% specificity) - because of this, the FDA advised everyone of asian descent to be typed for this allele - It is highly region specific

in 2011 we found another gene associated HLA A which is also a predictor for Stevens johnson syndrome when taking Carbamazepine - but now this is more widespread globally

Question 9

Which HLA alleles are population specific?

Answer 9

HLA B = population specific

HLA A is not population specific

Question 10

What gene is associated with cystic fibrosis?

Answer 10

CFTR gene
- not ether are a number of different defect variations that effect different regions of the gene - some effect synthesis and some reduce the protein transcription -

Question 11

Why is it that some cystic fibrosis drugs don’t work for every CF patient ?

Answer 11

because some drugs effect a different cystic fibrosis mutation effect- if you’re not synthesising the CFTR gene at all, then you’re not going to need a promotional transcript

Question 12

What class of CF does the kalydeco/ivacaftor drug work with?

Answer 12

It works with class 3 and 4 mutations - b/c in these classes the channels are present, but they aren’t opening properly - therefore the drug works well in this scenario -

Question 13

What are some barriers to clinical usage of genetic tests for pharmaceuticals?

Answer 13

• not that many genes are studied
• it’s not an immediate test - sometimes we need immediate drugs
• cost of testing can be nearly 400 euro per person
• lack of knowledge about test results