March 28, 2023

An introduction to the field of pharmacogenomics, with examples of how genetic variation can affect response to medications.

Welcome to this introduction to pharmacogenomics video. my name is rachel huddart and i’m a scientific curator at the pharmacogenomics knowledgebase, or pharmgkb. this video will explain what pharmacogenomics is and go over a couple of examples of how let’s say we have a group of people with the same medical condition who are all being treated as you’d expect, some people

Will respond well to treatment and get better. however, other people might not see any effects of the medicine while others might have side effects. there are many reasons why people respond differently to the same drug, like age, other medicines that the person might be taking or their genetics. pharmacogenomics is the study of how genetics affects a person’s response to

A medication in pharmacogenomics research, we use the word ‘drug’ to refer to any medication and i’ll be the aim of pharmacogenomics is to use genetic information to select the right drug at the the word ‘pharmacogenomics’ is often used interchangeably and pharmacogenomics are also commonly shortened to ‘pgx’. on this slide, i’m going to go over some simple genetic terms

Before we move on to some examples your dna contains all the instructions to make you. each one of these instructions is called a gene. you can think of genes as being written in dna sequence, using the letters genes tell cells how to build proteins. proteins are large molecules that have many different if the dna sequence of a gene changes, shown by the purple area on the

Dna strand, this could change how the protein is built. it might be a small difference, so only the purple area of the protein is affected. however, dna changes can also cause larger changes in the protein so part of the protein could be missing or the protein might not be made normally, you have two copies of every gene at any single point in the dna sequence of a gene,

You actually have two letters; one in genetics, we use the term genotype to refer to this combination of letters. for example, you may have an a and a g at a particular point in your dna sequence and two cs at another point. your phenotype is a physical characteristic or trait which is influenced by your genotype. examples of phenotypes include eye color, hair color or

How quickly you metabolize or pharmacogenomics can affect the pharmacokinetics or pharmacodynamics of a drug. pharmacokinetics, shortened to pk, is usually described as what the body does to the drug. this can include drug metabolism, where the drug is broken down by enzymes in the body. pharmacodynamics, shortened to pd, is what the drug does to the body. an example

Of drug pharmacodynamics would be when a drug binds to a target in the body and has an effect. i’ll go over more detailed examples of how pharmacogenomics can affect drug pharmacokinetics for our pharmacokinetics example, we’re going to look at clopidogrel. clopidogrel is a blood thinner which is used to prevent cardiac problems like strokes or clopidogrel is an example

Of a prodrug. a prodrug is a drug that has to be broken down when a patient takes clopidogrel, it is broken down, or metabolized, in the liver to form an active metabolite. the active metabolite goes into the blood and stops platelets from sticking together. this prevents blood clots from forming. an enzyme called cyp2c19 converts clopidogrel to its active metabolite.

Cyp2c19 belongs to a group of enzymes known as cyp enzymes. these enzymes break down over the name of each enzyme in this group begins with cyp. this is followed by a series of letters and numbers which distinguish the different members of the group, like cyp3a4 changes in the genes which encode cyp enzymes can change how active the enzyme is and, as a result, how quickly

Or slowly a drug gets broken down. some changes may make the enzyme more active than normal while others may make it less active or even completely inactive. star alleles are used to define known genetic changes in cyp enzymes. some example star just like genotypes, people typically have two star alleles for each cyp gene. some genes which aren’t cyps also use this star

Allele system. future videos will discuss the combination of star alleles that a person has for a particular gene can be used to predict how much enzyme activity they have. this is called their metabolizer phenotype. these are the five metabolizer phenotype terms that are used in pharmacogenomics. enzyme function decreases as you go down the list, so ultrarapid metabolizer

Have the most activity, most cyp genes only use some of these groups rather than all of them. for example, an enzyme called cyp2c9 only has normal, intermediate, and poor metabolizer groups. now we’re going to come back to our clopidogrel example. we said earlier that the enzyme cyp2c19 converts clopidogrel to its active metabolite. if a patient taking clopidogrel is a

Cyp2c19 poor metabolizer, meaning they have very little to no cyp2c19 activity, they won’t make enough of clopidogrel’s active metabolite. this means that the platelets in these patients aren’t prevented from sticking together. as a result, these patients are at an increased risk of cardiac problems. the clinical pharmacogenetics implementation consortium, also known

As cpic, has a clinical guideline which has recommendations on prescribing clopidogrel to patients with different cyp2c19 links to an annotation of this guideline on pharmgkb and a video tutorial of the guideline now we’ll move on to an example of pharmacogenomics affecting a drug’s pharmacodynamics. if you remember from earlier in the video, pharmacodynamics describes

What the drug does to the body. for this example, we’re going to look at a group of antibiotics called aminoglycosides, aminoglycosides work by binding to molecules in bacteria called 16s-rrna. this binding stops the bacterium from being able to produce proteins. the inability to make proteins kills humans have a molecule called 12s rrna, which has a similar structure

To the bacterial 16s rrna. some people have certain variants in the gene mt-rnr1, which codes for 12s rrna. these variants make the 12s rrna molecule even more similar to the 16s rrna molecule in bacteria. this similarity is so high that aminoglycosides will bind to these 12s rrnas and kill the this binding and cell death is a particular problem in the inner ear, where

Aminoglycosides can kill sensory hair cells and cause hearing loss. cpic has published a guideline for aminoglycosides with recommendations for patients who have links to an annotation of the cpic guideline for aminoglycosides and a video tutorial are in summary, we know that people can respond to the same drug in different ways and that one of the factors that can cause

This is genetics. genetic changes can alter a drug’s pharmacokinetics or pharmacodynamics. thank you for watching this video. you can find links to further information or other

Transcribed from video
Introduction to Pharmacogenomics By PharmGKB