INTRODUCCIÓN A LA GENÓMICA BMJ

7/27/2019 INTRODUCCIN A LA GENMICA BMJ

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An introduction to genomicsLEARNING OUTCOMES

After completing this module, you should understand how genomic information canbe used to:

Make a more accurate or specific diagnosis of diseaseIndividualise treatmentPredict the effects of drugs.

Written by:

Peter Farndon, Peter Lunt, Jacqueline Batson

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Contributors:

Alain Li Wan Po

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Peer reviewed by:

Kathy Greenough, Imran Rafi, Damir Rafi

This module was funded by, and developed in association with, NHS NationalGenetics Education and Development Centre.

This is the first of a two module package on genomic medicine. It will define andexplore genomic medicine, looking at the role of an individuals genome and howinformation about this can inform:

Assessment of susceptibility to disease

Diagnosis

Treatment.

The second module extends the explanation of genomic medicine to the use ofinformation about an invader genome. An invader genome refers to DNA fromeither a cancer or pathogen. It will explore how this information can be used in thediagnosis and treatment of cancers and infectious diseases.

WHY THIS MODULE IS IMPORTANT

Genomics is already making a difference in clinical practice. This module is


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designed to explain what the genome is, how it can be examined, and howinformation from the genome is changing patient care. By extending their skills,over time clinicians should be able to:

Prescribe more safely by taking into account information about the patientsgenome

Interpret genomic data, including the results of direct to consumer tests,taking into account other determinants of health such as environmentalfactors

Explain genomic information in a way which allows patients to makeinformed decisions about their health.

Central to all of this will be the need to need to keep up to date with the predictedrapid pace of genomic developments.

KEY POINTS

Individual genomic variation plays a role in almost all diseases and theirresponse to treatment

The decreasing cost and increasing speed of genomic testing is makinggenomic information available for use in more areas of medicine

Increasingly, clinicians will want to take into account information about thepatients genome when deciding what to prescribe

Targeted treatments based on genomic information are alreadyavailable, mainly in the field of cancer medicine. Herceptin is a well known example

of thisCLINICAL TIPS

Our understanding of the genomic basis of disease and how this should

inform management is changing rapidly. Always ensure you have the latestinformation

When assessing whether a patient is at higher risk of developing a commondisease, you should continue to take a conventional history, including familyand lifestyle history. In future when the place of susceptibility informationfrom genomic studies has been evaluated, this can be added to traditionaldiagnostic and prognostic processes

You should continue to consult your regional genetics service for informationabout testing for single gene and chromosomal disorders

As genomic tests become available and clinically validated, be willingto consider where to incorporate them into your management protocols

INTRODUCTION

What is genomic medicine?


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Genomic medicine or healthcare involves the use of many pieces of geneticinformation in order to help to:

Assess a persons risk of developing a disease

Refine the diagnosis of disease, and predict prognosis

Individualise treatment

Predict the effects of drugs, and prevent adverse effects

Develop new treatments

Diagnose infections and track epidemics.

This process is also sometimes referred to as personalised or stratified medicine.

What are the key applications of genomic medicine?

An investigation of a genome can look either at:

A persons own genome: in other words, the DNA a person inherits fromhis or her parents

The genome of a tumour or pathogen. This allows:

Tumours to be studied and monitored

Individual treatments to be developed and optimised

Infections to be diagnosed and tracked. This may benefit either anindividual patient, or it may have wider public health implications.

This module concentrates on the implications of using a persons own genome toinform clinical care. Module two gives examples of how genomic information fromtumours and pathogens can be used in clinical practice.

Learning bite: key terms

Genomics is defined as the study of genes and their functions, and relatedtechniques. [1]

When applied clinically, the term human genome is commonly used to refer to allthe genetic information in a normal cell. This includes all of the chromosomes

within the cells nucleus, as well as the mitochondrial DNA.IS THERE A DIFFERENCE BETWEEN GENOMICS AND GENETICS?

Professor Peter Farndon sets the scene for what genomic technologies andinformation can offer to patient care

The difference between genetics and genomics


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Genomics is the study of the whole genome, and the complex interplay betweengenes and the environment. This kind of interaction underpins most commondiseases. Examples include:

Ischaemic heart disease

Asthma

Neuropsychiatric illness.

The term genetics is now often used when changes to just one pair of genes orchromosomes result in a condition. Often these conditions are strongly inherited.Genetic disorders are often serious and rare. There are over 6000 knownexamples, including:

Familial hypercholesterolaemia. This is caused by a mutation in a singlegene [2]

Down syndrome (Trisomy 21). This is caused by an extra copy ofchromosome 21.

KEY FEATURES OF THE GENOME

Scientifically, the term human genome refers to the genetic informationcontained in one of each pair of the 22 autosomes, and the X, Y, and themitochondrial chromosome

The term human genome sequence refers to the complete sequence of

the three thousand million base pairs making up a single copy of thesechromosomes

Clinically, the term human genome is normally used to refer to all thegenetic material in a cell. This is made up of 22 pairs of autosomes, one pairof sex chromosomes, and the mitochondrial chromosome

The length of DNA making up the 46 nuclear chromosomes is abouttwo metres

RECENT DISCOVERIES ABOUT THE GENOME

The completion of the human genome project has provided a number of surprises.

For example [3] :

There are actually fewer genes that code for proteins than we originally thought;only about 23,000. But there are many more than 23,000 proteins, meaning that asingle gene may code for more than one protein. Only about 2% of the totalsequence of human DNA codes for proteins. The parts of genes that code forproteins are known as exons. All the protein coding sequences in the genomecollectively make up the exome.


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As well as the genes which code for proteins, other genes produce RNA moleculeswith special functions. Some of these classes of RNA play an important role inregulating the function of genes. About 50% of human nuclear DNA is made ofrepeated sequences. This may be DNA sequences which have been copied andinserted, or DNA copies of viral sequences which have been integrated within the

human genome.

The organisation of the genome can appear chaotic. Genes are not spreadregularly throughout the genome, but instead are clustered in groups. Somesmaller genes are even read from the opposite DNA strand in the introns of othergenes:

GENOMIC VARIATION BETWEEN INDIVIDUALS

How do genomes vary between people?

Genomic variation varies in magnitude, and can involve differences in any of thefollowing:

Single nucleotides

Short stretches of nucleotides

Large blocks of DNA

Sections of a chromosome

Whole chromosomes.

We will now highlight two important types of genomic variation. They are useful to

know about, because they are often used in research as well as in clinicaldiagnosis. They are single nucleotide polymorphisms, and copy numbervariants.

Single nucleotide polymorphisms (SNPs)

A SNP (pronounced "snip) is a single base change at one point in the DNA, whencompared with a standard or reference genome. The single base is replaced byone of the other three bases. For example, a SNP may replace a cytosine withthymine in a particular sequence.

SNPs are found throughout the genome in both coding and non-coding DNA. On

average, a SNP is found once in 300 base pairs. SNPs are particularly useful inresearch studies to identify a particular location in the genome, because they canbe used as flags or markers. A technique which uses SNPs as markers in this

way is a genome wide association study (GWAS). This is described later in themodule.

SNPs may have no effect, or they may play a role in normal variation, drugmetabolism, and susceptibility to complex conditions. By definition, for a base


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change to be called a SNP it must be present in at least 1% of the population.

Copy number variations (CNVs)

Copy number variations are a major source of structural variation within thegenome. They vary in size from 1000 to several million base pairs.

Copy number variations are either:

Deletions, where a section of DNA is missing

Insertions, where a section of DNA is duplicated .This may be once, orseveral times.

Like SNPs, they are present in all people, and are responsible for normal humanvariation as well as for predisposition towards a variety of diseases.

When a copy number variation involves a repeated sequence, this may includegenes and/or non-coding DNA.

What are the clinical effects of genomic variation?

Variation within the DNA sequence or the number of copies of a sequence can:

Have no effect

Be part of normal variation

Result in increased or decreased susceptibility towards a condition

Directly cause a condition.

Some common changes are part of normal variation and have no known clinicalconsequences. Other variants, which are also common, can be associated withaltered disease susceptibility or severity. Often these act in combination with

multiple other variants of small effect. This is believed to play a role in thedevelopment of many common diseases such as ischaemic heart disease,diabetes and asthma. Some variants have a positive impact, for example variantsin the CCR5 gene which protect against the development of HIV. [4]

Variants which cause a major clinical effect are usually rare. Typically these are theMendelian disorders, such as familial hypercholesterolaemia, sickle cell disease,and haemophilia A.

GENOMIC TECHNIQUES

How can the genome be examined?

A number of different techniques are available to examine the genome. They look


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at its organisation at a number of different levels.

The order of bases can be identified by sequencing. In sequencing, bases areread one after the other to determine their order. This information is then comparedwith a reference or normal sequence of DNA. Advances in technology areconsistently decreasing both the cost and the time taken to do this.

A technique called microarray can examine a DNA sample to determine whether aknown sequence of DNA is either missing, present or duplicated.

Conventional light microscopy to examine chromosomes has been supplemented

by fluorescence in situ hybridisation (FISH). This allows smaller changes inchromosomes to be visualised, some of which are too small to detect using astandard microscope alone.

Learning bite - What genomic techniques are commonly used in

clinical and research practice?

Genome wide association studies

A genome wide association study involves comparing genetic variants, usuallySNPs, in thousands of people with a particular disease with those who do not havethe condition.

If a particular SNP allele is found more commonly in the case group, then thatSNP is said to be associated with the condition. The SNP itself may conferincreased susceptibility, but more often the SNP is acting as a marker for asusceptibility gene in the same region of the genome. Further studies are thenundertaken in the area of the genome containing the variant to find genes that may

increase susceptibility to, or give protection from, the condition.

Genome wide association studies are especially useful for finding geneticvariations which contribute to the development of common and complex diseases.Examples include bipolar disorder, coronary artery disease, rheumatoid arthritis,and types I and II diabetes. They also identify genetic variations which affect eitherdrug response, or susceptibility to adverse drug reactions. [5]

Genome wide association studies form the basis of many types of direct to

consumer genomic testing, in particular those which give an estimate of a personsrisk of developing common and complex diseases.

Microarray comparative genomic hybridisation

This technique is used to detect copy number variations above a certain size.Usually the threshold is set at variations greater than 50,000 base pairs. [6] Acomparison is then made between samples from cases and samples taken fromreference patients or controls.


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Microarray comparative genomic hybridisation has become an essential diagnostictool, particularly for geneticists and paediatricians, and is predicted to replacetraditional karyotyping.

It can be used [7] :

To detect microdeletion and microduplications, or larger chromosomaldisorders. An example of this is as a diagnostic tool in children with globaldevelopmental delay and dysmorphic features

In cancer research, in the diagnosis and classification of different cancers.

Here it can be used to identify the particular subsets of genes which areover or under-expressed in a patient's cancer.

Whole exome sequencing

The exome is the part of the genome which codes for proteins, and representsaround 2% of the total DNA. Sequencing the exons has given a high yield of

clinically important mutations so far. The technique of whole exome sequencing isbeing adopted into diagnostic laboratories.

Clinically, some of the most promising applications of this technique are in diseasediagnosis. It is particularly useful where family history suggests an inheritedMendelian disorder, but testing for genes previously known to be associated withthe condition has proved negative.[ [8]

Whole genome sequencing

Whole genome sequencing (WGS) determines the sequence of nucleotide basesthroughout the entire genome, rather than only the protein coding regions. This is

an expensive technique, but costs are falling rapidly; a thousand dollar genometest may well now be in sight.

So far, whole genome sequencing is mainly used in research studies. It appears tobe useful for identifying variation in regulatory sequences, as well as in codinggenes.

What are the challenges around interpretation of genomic tests?

The amount of information generated from genomic technologies can be huge, and

interpreting the information from genomic technologies can be challenging. It isimportant to establish whether a change is the cause of a genetic condition, orwhether it is a neutral variant. Computer algorithms are being developed toautomate the process, but the variants need to be checked against the referencesequence.

It is important to make a clinical assessment to establish whether the clinicalphenotype is compatible with the findings from the genomic test. Clinicians needing


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to interpret these findings will require a detailed understanding of the genesinvolved, as well as the likely effect of structural variants.

CLINICAL APPLICATIONS OF GENOMIC INFORMATION: DISEASEDIAGNOSIS

Genomics can help in the diagnosis of disease in two main ways:

It can provide more efficient techniques for diagnosing Mendelian disorders

It can help in making an accurate sub classification of disease. For example,genomic techniques can establish which gene is involved in diseasedevelopment when there are several genes known to be potentiallycausative, such as in retinitis pigmentosa. [9]

HOW CAN GENOMIC TECHNIQUES HELP TO DIAGNOSE CONDITIONS DUETO RARE GENETIC VARIANTS?

Genomics and the diagnosis of single gene disordersGenomic techniques can identify the genes responsible when clinical features orfamily history suggest that a person may have a Mendelian disorder. [10]

Exome sequencing allows the protein coding sequences of many different genes tobe read simultaneously. Whole genome sequencing involves an assessment of all

regions of the genome, including regulatory sequences as well as coding genes.The availability of these techniques means that there is no longer the need tospecify a particular gene to analyse before requesting a genetic test.

For example, a neurologist might have a small group of patients, all in the same

family, who have the same well characterised movement disorder, which is as yetundiagnosed. With newer genomic techniques such as whole exome sequencingor the targeting of a known group of genes, the neurologist will now have a goodchance of identifying the genetic mutation underlying the disease. [10]

Clinically, knowing this mutation is important for a number of reasons:

It can increase knowledge about the diseases pathophysiology

Understanding the underlying biochemical dysfunction opens the wayfor targeted treatments to be developed

An accurate diagnosis can be valuable even in the absence of a treatmentIt can avoid the need for unnecessary investigations and ineffectivetreatments

It can also provide psychological benefit to patients and their families

It can allow other family members to be tested specifically for the samealtered gene


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Family members may be at risk of developing the conditionthemselves, or of being a carrier.

For some patients, identification of the genetic abnormality has led to the adoptionof targeted treatments [11] [12] :

One example is a 15 month child who presented with symptoms of aninflammatory bowel disorder. [12] Whole genome sequencing identified anovel mutation in an X-linked gene

He was diagnosed with a newly identified X-linked disorder,

and successfully treated with a transplant of hematopoietic progenitorcells.

Genomics and the diagnosis of disorders involving copy number

variants

Variation in the number of genes, also known as copy number variation, is knownto be associated with some developmental disorders and malformation syndromes.Genomic technologies can help in the diagnosis of children with dysmorphic ormalformation syndromes, as well as those with learning disabilities.

It is estimated that about half of children with a severe learning disability have acausative genetic variation. [13] A laboratory technique using DNA microarrays candetermine whether children have the correct number of copies of a particularsequence.

Microarray comparative genomic hybridization substantially increases the number

of children diagnosed with a causative genome variation. It also appears to work

well as a first line test in children with learning disabilities, as an alternative toconventional karyotyping. Again, it is not necessary to first specify the gene, orgenes, that need to be tested. [13]

CLINICAL ASPECTS OF GENOMIC INFORMATION: PREDICTION OF DISEASESUSCEPTIBILITY

Can genomic techniques accurately predict whether anasymptomatic person will develop a common disease?

At present, the answer is usually no. Family history and lifestyle information arecurrently more useful predictors of risk when it comes to the development of

common diseases such as heart disease and diabetes. [14]However, genomic technologies have been successful in uncovering many of thegenetic components involved in the development of common and complexdiseases. An example of this is the discovery of a number of genes associated withsusceptibility to disease.

What are susceptibility genes?


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A susceptibility gene is a gene which increases a persons risk of developing aparticular disease. Alterations in some genes which are known to confersusceptibility have a major effect, and are sufficient on their own to substantiallyincrease a persons risk of developing a particular disease. BRCA1 and BRCA2 arewell known examples. In their mutated form, these genes strongly predispose

towards the development of breast and ovarian cancers.

Most genes found to confer susceptibility contribute a much smaller effect,particularly those known to play a role in the development of common complexconditions such as heart disease and diabetes. Here, the relationship betweensusceptibility gene and disease development is more complicated:

A single gene usually plays a minimal role on its own, but when found incombination with other genes it can have a measurable effect on the risk ofdisease development

Although this is measurable across a large group of people, currently this

type of information seems to have little predictive value for any oneindividual.

Genome wide association studies have identified hundreds of areas of the genomewhich are involved in the development of common diseases, for example type 1and type 2 diabetes, psoriasis and inflammatory bowel disease. [15] The nextchallenge is to determine whether this information can be used to accuratelypredict the risk of disease development in an asymptomatic individual. [14]

New information about the genes involved in pathophysiology provided by genomewide association studies also holds potential for the development of new and novel

therapies, targeted towards the particular genetic variations that have beendiscovered.

DIRECT TO CONSUMER GENOMIC TESTING

Several commercial companies offer direct to consumer genomic testing for a fee.Often these are requested online, and the results may be communicated over thephone, by post or electronically.

In this video, Professor Ian Day explains how a patient could obtain a direct toconsumer test, and the kinds that are available.

How would a patient get a DTC test, and what kinds are there?Patients and individuals may wish to find out genomic information for a variety of

reasons. Usually, if it is to answer a specific clinical need about an inheritedcondition in their family, they will ask to consult the regional genetic services. Otherpeople feel they want to know more about their genetic makeup and ask for testsout of curiosity.


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In this video, Professor Ian Day considers why someone would purchase a direct toconsumer test.

Why would someone want a DTC test?

Many direct to consumer tests look for SNPs, which are associated with physicalcharacteristics as well as susceptibility to common conditions.In this video, Professor Day considers what types of information can be providedby commercially available direct to consumer tests, as well as the predictive valuesof these different types of information.

What do DTC tests test for?Many of the results in direct to consumer tests are based on the results of genomewide association studies. These tests have varying degrees of clinical utility.

Results can include information about:

The relative risk (or odds ratio) of developing a number of common andcomplex conditions compared with the general population. Often they alsogive a lifetime risk of developing the condition

Variants in enzymes involved in the metabolism of medicines, which canpredict a persons response to a particular medicine or group of medicines.

These are also known as pharmacogenomic predictions. Pharmacogenomicpredictions relate to both the effectiveness and tolerability of medicines.

Some companies also offer services which have much higher diagnostic andpredictive values such as:

Carrier status testing for autosomal recessive conditions such as cysticfibrosis

Presymptomatic testing for autosomal dominant single gene disorders

Presymptomatic testing for susceptibility genes with a high predictive value,such as BRCA1 and BRCA2.

Our expert Professor Day ordered a direct to consumer test for himself. In thisvideo, he describes his experience, and wonders what information from the testingshould he pass on to his GP?

What should he tell his GP?

Learning bite: direct to consumer genomic testing advice for

clinicians

In 2009, the BMJ published a review article offering practical advice to clinicians onpersonal genomic screening. [16] Suggestions include:

Doctors should use caution when a patient presents with screening results,


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because the accuracy and usefulness of different services are unknown

Many, if not most tests for single gene (Mendelian) disorders do have a highclinical validity. However:

Doctors should be prepared to discuss the risk of a false

negative for a disease in families with a high risk for a Mendeliancondition which was not discovered on testing

Doctors should be prepared to discuss the risk of a falsenegative when Mendelian or monogenic disease testing is carried out

and only one or a few mutations have been tested (unlesssequencing has been performed)

If a patient presents with results of personal genomic screening that includeabnormal results of validated tests for Mendelian disease - such as cysticfibrosis or haemochromatosis - the patient should be given genetic

counselling and personalised medical management

At present very few tests for common traits are clinically useful

Doctors should be prepared to discuss the current status ofevidence regarding clinical validity and usefulness, which is generallylimited

Doctors assessment of risk for common diseases should be basedon validated clinical methods, such as family history and clinical and biochemicalmeasures.

PHARMACOGENOMICS - TARGETED THERAPEUTICS

What is pharmacogenomics?

Pharmacogenomics deals with the influence of genetic variation on drug response.

Why is this important?

The effects of some medicines vary between patients, both in terms of theireffectiveness and safety. These variations are not always possible to predictclinically.

An example is warfarin, which when first prescribed can take many days ofcareful titration before a stable and therapeutic internationalised normal ratio

(INR) is reached

An effective daily dose of warfarin for anticoagulation varies from around0.5mg to 30mg [17]

Many factors influence dose requirements and effect, including diet, age,and genetic background related to population ancestry

However, there are clear associations between the dose requirement and


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effects of warfarin and variants of the metabolic enzyme (CYP 2C19) and ofthe pharmacodynamics enzyme vitamin K epoxide reductase complexsubunit 1 (VKORC1) [18]

After research has identified important genomic variants, for example thoseassociated with warfarin dosing, studies to prove their clinical utility must first beconducted before they can be adopted into routine use in the NHS.

What is the aim of pharmacogenomics?

The aim of pharmacogenomics is to improve the match between the patient (andtheir disease) and their treatment. This can result in either increased efficacy, or

reduced toxicity of drugs. To improve the match, some drugs are prescribed onlyafter a positive companion diagnostic test.

Clinical tip

The terms pharmacogenomics and pharmacogenetics can be usedinterchangeably from a clinical perspective.

PHARMACOGENOMICS AND COMPANION DIAGNOSTICS

In this video, Professor Munir Pirmohammed explains what pharmacogenomics isand gives examples of companion diagnostic tests which improve the efficacy ofHerceptin and the safety of abacavir.

Pharmacogenomics, with Professor Munir Pirmohamed

Pharmacogenomics key terms

Stratified medicine is when treatments are aimed at sub-groups of patientswith specific biomarkers

Personalised medicine is when other factors that are specific to the patientare taken into account, for example:

Diagnostic markers such as biochemistry results

Patient preference

Companion diagnostics are gatekeeper tests which are needed before aparticular drug or other treatment is given:

An example is the HER-2/neu assay, which is carried out onbreast cancer tissue to find out whether a patient will respond toHerceptin [19]

The growth of pharmacogenomics in recent years has dramatically increased thenumber of genetic variants which have been discovered which appear to play arole in variability in drug response. [17] These discoveries bring the hope of greaterpersonalisation of medicine.


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Predicting whether a patient will develop adverse effects with a

drug

As explained in the video, a genetically guided companion diagnostic test is nowpart of the standard of care for patients with HIV who are treated with the anti-

retroviral drug abacavir:

Case study 1: abacavir [20]

Mary is a 23 year old woman who has recently been diagnosed with HIV. Herconsultant wants to start treatment with an anti-retroviral combination containingabacavir, as Mary has been intolerant of the first line anti-retroviral treatment.

Before starting abacavir, the consultant requests a blood test to check for thepresence of the HLA-B*5701 allele. This is a variant of HLA-B, a gene involved inthe function of the immune system. This variant has a prevalence of around 6-7%of European populations.

Mary tests positive for HLA-B*5701, and the consultant prescribes a different anti-retroviral combination. He explains that patients who test positive for this version ofthe gene are more likely to experience severe and sometimes fatal hypersensitivityreactions to abacavir, and for these people this drug should be avoided.

A companion diagnostic test is also recommended before patients are prescribedazathioprine. Patients who are deficient in the enzyme thiopurine methyltransferase(TMPT) are unable to metabolize azathiprine effectively.

Case study 2: azathioprine

Stephen is a 13 year old boy being treated for an exacerbation of Crohns diseasewhich has been unresponsive to steroid treatment. His consultant wants to add on

azathioprine to try and control his symptoms, and hopefully bring about remissionof the flare up.

She requests a blood test to assess the levels of his TMPT enzyme:

Approximately 11% of the population have reduced TMPT activity [21]

These patients have an increased risk of developing leukopaenia withazathioprine

In this group, azathioprine should be used only with cautionApproximately 0.3% of the population have an absolute TMPT deficiency[21]

In these patients, azathioprine can cause life threatening bonemarrow toxicity and myelosupression

This group should not be given azathioprine


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The test comes back showing that his TMPT activity is low, but he is not entirelydeficient. She decides to give Stephen azathioprine at a lower dose, and carefullymonitor his full blood count. Within a few days his bowel symptoms start toimprove. His white cell count remains stable, and within normal limits.

HOW CAN GENOMIC MEDICINE HELP TO PREDICT HOW EFFECTIVE A

DRUG WILL BE IN A PARTICULAR PATIENT?Often a drug which is effective for many patients can fail to work in others:

Codeine is a common example of this phenomenon

Codeine exerts its analgesic effects largely through

metabolism by cytochrome P450 2D6, which converts it to morphine[22]

Patients with P450 2D6 genotypes resulting in poormetabolism receive little or no analgesic effect from codeine.

The cytochrome P450 2D6 enzyme: a clinically important exampleof pharmacogenomics

Cytochrome P450 2D6 (CYP2D6) is a member of the cytochrome P450 family ofenzymes which is most commonly involved in drug metabolism. CYP2D6 plays arole in the metabolism of around 20-25% of drugs on the market, including [23] :

Beta blockers

Antidepressants

Antiarrhythmics

Antipsychotics

Tamoxifen.

Variants of this enzyme have been well-studied. For example [17] :

CYP2D6 *3, -*4, -*5 and -*6 alleles result in inactive versions of the enzymefrom that copy of the gene

These variants increase the probability that a patient will havea high plasma level of some drugs

In clinical terms, this means an increased risk ofadverse effects

Patients with the variants benefit from a reduced dose ofthese drugs

This variant occurs in 5-10% of the white population, and 1-2%of Japanese and Chinese people [17]


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Patients may have a variant where they have extra copies of CYP26D,meaning they will have increased activity of the enzyme

This variant reduces the efficacy of some drugs

Patients with this variant benefit from an increased dose of

these drugs

This variant occurs in 30% of Ethiopian people [17] , and 12% of thewhite population

Methods for the rapid and effective testing of these variants are available inresearch settings. Testing could allow prescribers to prescribe a dose which is both

safe and effective, depending on their patients variant of this enzyme. Informationabout CYP2D6 variants are often included in results from direct to consumergenomic testing.

One example of where CYP2D6 testing may come into routine clinical use is withpatients with breast cancer who are prescribed tamoxifen. [24]HOW CAN GENOMIC INFORMATION GUIDE DEVELOPMENT OF NEW DRUGS

WHICH TARGET SPECIFIC GENETIC ERRORS?

In this video, Professor Munir Pirmohamed highlights other areas of medicinewhere pharmacogenomics is likely to be used. He explains how new medicines willbe developed based on information about genetic variations or mutations.

Developing new types of therapiesAn important future application of pharmacogenomics will be its role in thesystematic development of new drugs that are targeted at the pathophysiological

consequences of specific genetic errors. For a new drug to be developed in asystematic way, a specific molecular target must first be discovered and validated.This target may be within the genome of the person affected by the disease, orwithin the genome of a cancer or microbial cell.

A major strength of genomic techniques in the development of new drugs is likelyto be in identifying these new targets within cells. A number of new medicines havealready been developed based on genomic knowledge of these cellular targets,mainly within the field of cancer medicine. [25] [26]

For some, this has been possible by understanding what the genetic changes do.For example, a genetic change may result in the formation of a completely newprotein, as in chronic myeloid leukaemia. [27] Or, it may change the shape of anenzyme, as in malignant melanoma.

The first truly effective targeted agent to be developed was imatinib (Glivec) whichis used in the treatment of Philadelphia-chromosome positive chronic myeloidleukaemia. Imatinib targets the new protein formed in chronic myeloid leukaemiadirectly. Another example was the development of vemurafenib, a treatment formelanoma, based on an understanding of the effects of a mutation in the BRAF


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gene.

In this video, Professor Peter Farndon highlights an application of genomicinformation in the development of a targeted drug for malignant melanoma:

Targeted drug development

Imatinib and vemurafenib are examples of drugs containing molecules which aredesigned to target specific genetic alterations, or their effects. An approach in thedevelopment of treatments for other diseases is to develop monoclonal antibodieswhich target a particular molecule. A drug based on this principle has beendeveloped for neurofibromatosis type 2. A clinical trial is underway to determine theeffectiveness of this.

The pace of development of these kinds of targeted medicines is increasinglyrapidly; seven were licensed by the food and drug administration (FDA) in theUnited States in 2011 alone. Genomic information is also being used to developbetter vaccines, including therapeutic vaccines. Therapeutic vaccines are vaccines

which treat a disease rather than prevent it.Learning bite: pharmacogenomics and implications for futureprescribing

Pharmacogenomic testing is only starting to enter clinical practice. Its impact iscurrently being felt in specific clinical situations. Large scale trials are underway toshow where testing will improve clinical outcomes.

Companion diagnostic tests are already available for some drugs and are likely tobecome a more common part of the prescribing process [28]

Currently companion diagnostics are mainly limited to specialist fields such

as HIV and cancer medicine

These may be extended to drugs such as warfarin, as more is understoodabout their clinical utility

As more information becomes available, testing for known variants ofimportant drug metabolising enzymes such as CYP2D6 is likely to inform

prescribing. [28] Patients who have purchased direct to consumer genetictesting may already have this information.

Extensive research is being carried out to develop new companion diagnostic tests

and novel treatments. Before being adopted into the NHS, developers will need toshow that they improve clinical outcomes.

Clinicians will need to become familiar with the basic principles ofpharmacogenomics in order to prescribe safely and keep up with currentdevelopments.


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Learning bite: what do doctors need to know about genomic

medicine?

Learning bite: how can I keep up to date on advances ingenomics?

Much of the information about advances in genomics and their clinical applicationsare currently in research journals or reported at professional conferences. TheNHS National Genetics Education and Development Centre provide an overviewon this website: http://www.geneticseducation.nhs.uk/genomics-in-health

To find original publications and articles on genomics, here are some frequentlyused terms which may be helpful when combined with terms relevant to yourparticular field of interest:

Genomics (or genomic medicine)

Translational genomics

Personalised medicine

Companion diagnostics

Pharmacogenomics (or pharmacogenetics)

Exome sequencing

Whole genome sequencing

Next generation sequencing

GWAS (genome wide association studies)

Tumour profiling (or cancer genome)

Microbial genome or microbiome.

REFERENCES

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