Pharmacogenetics and personalised medicines Flashcards
What is pharmacogenetics and pharmacogenomics
Pharmacogenetics is the study of genetic factors influencing a response to a drug. 1930s saw that the inability to detect bitter taste from phenylthiocarbamide was inheritable. 1975 saw individual variation in the response to the hypertensive debrisoquine
Pharmacogenomics is the application of individualised drug therapy in practice in conjunction with a genomic diagnostic test.
Would be able to select a drug that is ideal based on an individuals genetic likelihood to respond to the treatment, or if they would see toxicity from the medicine. would avoid adverse drug reactions.
E.g., identifying gremlin mutations such as CYP poor metabolisers - affects opioids, warfarin, tamoxifen, B-blockers. Or somatic mutations that cause cancer, such as BRCA1/2 gene in breast cancer. would guide the best treatment, and prevent unnecessary attempts at treating it.
Epigenetics is patterns of DNA methylation variation in mitochondrial DNA
Single nucleotide polymorphisms
SNPs are very common, with each individual predicted to have 11-12000 synonymous SNPs and 10-11000 non-synonymous SNPs - this would significantly affect 250-300 genes with loss of function.
Synonymous would not see any change to the phenotype, e.g., GCT changed to GCC - both of which would still encode alanine
Non-synonymous would result in a point mutation in a protein - change in 1 AA.
Loss of function occurs from premature STOP codons, frameshift mutations (single bp insertion/deletion), or from mutation of the mRNA splicing site.
Single SNPs in non-coding regions can increase or decrease protein expression in different tissue.
Individuals can be homo- or heterozygous for genes affected by SNPs due to paired chromosomes. Closely spaced SNPs (within same gene) are often genetically linked and inherited together as a haplotype.
Copy number variation
These are large duplications or deletions in the genome (1-1000 kbps). 0.4% of the genome differs by these types of changes in unrelated individuals
What ways can genetics affect drug function
Can alter selectivity of binding site, activity or function, regulation (e.g., after chronic exposure to drug), changed expression or localisation. Off-target side effects of a drug may also be changed
Can also alter liver metabolism and transport across membranes (affecting absorption, distribution and elimination). may not be able to access intracellular targets. can reduce elimination of active drug, or reduce formation of active metabolite.
SNPs and SNP combinations (haplotypes) can reduce CYP activity. CNVs can also duplicate (ultra-rapid metabolisers) or delete CYP isoform genes. e.g., CYP2D6 for tamoxifen conversion into active 4-OH tamoxifen.
CYP2C19 * 2 (reduced activity) and CYP2C19 * 17 (gain of function) are haplotypes that alter the production of the active metabolite of clopidogrel (P2Y12 antagonist anti-platelet drug for post-MI). 1 or 2 copies of CYP2C19 * 2 leads to increased risk of thrombosis after post-MI stent and increased risk of major coronary event. * 17 has been weakly associated with increased bleeding risk and greater therapeutic effect. some hospitals test for haplotype
Genetics of cancer
somatic and gremlin mutations.
It is heterogenous with 200 diseases
requires multiple gene mutations, such as proproliferative (e.g., EGFR, Ras), tumour suppressor (e.g., BRCA1/2), and genes that promote invasion/metastasis.
Examples of basic personalised therapy in cancer
Done due to the variability in causes and the risks of conventional chemo.
Tamoxifen for the inhibition of oestrogen-positive breast cancer.
Trastuzumab for HER2-positive breast cancer.
15-20% of breast cancer is triple negative however (for ER, HER2, and progesterone receptors), and is associated with BRCA1/2
Personalised medicine in cancer that has single mutation
B-Raf can have V600E mutation - present in 50-70% of melanomas and other cancers. the Ras-Raf-MAPK pathway drives cell proliferation, and the V600E mutations leads to a stabilised active conformation - constitutive activity.
Vemurafenib (type 1 - ATP binding site). was developed and had higher affinity for the active B-Raf conformation - therefore has higher affinity for V600E than normal. effective for advanced melanomas - 50% - cancer can become resistant. Dabrafenib was also produced and is more selective and effective against brain metastasis.
Adagrasib was produced to treat NSCLC that have the k-RasG12C mutation (11-16% have it).
Limitation of this method is the multifactorial nature of cancer. not just one pathway that causes it. combination therapy benefits as such. This method of treatment also requires immunohistochemistry or tumour genotyping to identify the mutations
Examples of idiosyncratic drug events from genetic differences
Abacavir was seen to cause hypersensitivity reactions through its interaction with MHC (with over 1000 genetic variants), binding to the antigenic peptide leading to heightened T-cell activation. It inititates this reaction by binding to the MHC encoded by HLAB * 5701 variant. routine diagnostic screening now advised in the UK and USA.
Clozapine sees idiosyncratic reactions with HLA-DQB1 * 0201
Considerations for genetic association studies for personalised medicines
most diseases are not monogenic. they have a complex interplay of several genes. inter individual variations to drug responses are complex interplay of genetic, environmental and developmental factors.
Genome wide association study looks for association between genes and disease traits. it is unbiased as it does rely on our knowledge of biology - can associate novel genes in diseases.
150,000 individuals were used for a T2DM genome study to identify genes implicated. the magnitude of the effects from an individual associated allele is small with most T2DM loci (63 identified total) only having odds ratio of 1.05-1.15
Impact of genetics on warfarin
8/100 patients have a bleeding event per year.
Can occur due to CYP2C9 variants or vitamin K epoxide reductase (VKOR) haplotypes.
VKOR affects efficacy and CYP2C9 effects plasma concentrations - safety
there are several variants of CYP2C9 1* -3 * that can be in any combination (e.g., 1* /1* , 2* /3* , etc…) VKORC1 can be GG, AG, or AA. Doses can be predicted depending on the combination of the individuals VKOR and CYP2C9 genes.
Still not recommended to do genotype-guided dosing by FDA/NICE due to uncertainty whether CYP2C9 and VKOR are the only predictive gene variants for it.
Personalised cystic fibrosis medicine and genes
1/25 people are carriers of mutant CFTR genes. it is a recessive disorder. there are over 2000 mutations in CFTR that are associated with the disorder, leading to different levels of severity in CFTR channel function
90% of patients carry CFTR deltaF508 (deletion of Phe508) and 40% are homozygous with this mutation. this affects cell surface expression. It prevent proper folding of the channel which means the channels ill not be sent to the Golgi apparatus and subsequently to the cell membrane. instead will be degraded.
Lumacaftor is a pharmacological chaperone that increases the trafficking of the channel to the cell membrane. due to high costs it is not readily available for prescription on the NHS
Practicality of implementation of personalised medicines
better clinical efficacy and safety compared to current appoaches and would save using ineffective medicines.
Need to develop future cheap pharmacogenomic tests that are clinically robust and predicative. Sequencing costs are continually reducing and in a few decades it is likely possible to sequence everyones genome.
May enable drugs that were withdrawn for idiosyncratic adverse events to be able to be used again by minimising risk through genetic studies prior to administration
Ethical and philosphical issues may arise such as confidentiality of individuals genome, as well as whether they should be denied treatment on the basis of genetic evidence. should also consider that there may be limitations to health predictions based on genome sequencing alone.
