Say Aa:Why pharmacogenetics is something worth talking about

The role of genetic variation in medicine is a surprisingly simple concept, and something you consider every time you see a patient, say John-Joe Reilly and John D Blakey

Certain phrases are guaranteed to grab the attention of medical students—such as “beer,” “free stuff,” and “genetics.” Unfortunately, the last of these is usually avoided with the same fervour with which the others are pursued. An extensive survey (n=4 in the coffee room), found genetics was perceived to be complicated, confusing, and of limited relevance to patients. We highlight how millions of dollars and work hours have resulted in an explosion of available genetic data and introduce how this will profoundly influence prescribing practice in the future. And we promise not to draw a single pedigree.

A common scenario

Mrs B is referred to the respiratory outpatients department by her general practitioner as she has noticed increasing breathlessness on exertion and has a productive cough. As she has smoked a packet of cigarettes a day for the past 25 years, you feel confident she has chronic obstructive pulmonary disease (COPD). Examination and spirometry support your preliminary diagnosis, but your minor triumph is shortlived: Mrs B tells you about her next door neighbour, a chain smoking octogenarian who never gets out of breath. You are tempted to rubbish her suggestion, then an unexpected synapse recalls that less than a third of chronic heavy smokers get COPD.¹

Mrs B says it can't just be the cigarettes and wants to know why she has been affected when her neighbour continues to dig his allotment unimpeded. You explain that an individual's genetic makeup can influence everything from the initial decision to try cigarettes, through the metabolism of inhaled toxins, to the likelihood of malignancy (fig 1).

Fig 1 Potential sites of influence of genetics in the development of COPD factors, with examples of genes studied.

The evidence base

Most doctors are aware that genetics has an influence, but they are usually hazy on where this information comes from. So before we discuss their consequences, you might want to review how we identify the influence of genetic variants (fig 2).

Fig 2 An idealised approach to the identification of polymorphisms influencing an outcome of interest, whether that is disease susceptibility, manifestation, progression, or drug response. Questions are in red boxes, and strategies to address them are in blue boxes. Note that “genes of interest” for association studies are commonly not selected as described above, but based on biological plausibility: these are termed “candidate gene” studies

Usually, the most difficult aspect of such investigations is pinning down which of the specific variants are responsible for the influence we see. If you haven't come across a study that tries to do this already, you soon will, as there has been an exponential growth in the number of genetic association studies published. Anyone tempted to search PubMed for this type of study should be wary because contradictory results have been commonplace in the past. However, findings are becoming ever more reliable as study populations become larger (such as the genealogical database of Icelanders,²the 1958 birth cohort, and in the near future, the UK Biobank), are subjected to new ­methods of analyses and to meta-analyses, and adhere to standards of best practice.³

Influence on prescribing practice

The first principle of medical practice is to do no harm (genetics and ethics: get a coffee). However, thousands of adverse drug reactions are reported each year for drugs we continue to use because they are beneficial in most patients. This is like locking up all people who are arrested on the basis that most of them are guilty. Genetic testing offers a means of identifying individuals at risk of adverse reactions in advance.

As an example, over half a million prescriptions are dispensed each year in the UK for azathioprine, an antimetabolite drug that requires frequent monitoring for serious adverse effects, such as bone marrow suppression. Single nucleotide polymorphisms (SNPs: see terminology box) exist in a gene coding for an enzyme that metabolises azathioprine. Certain of these lead to a 50-fold variation in enzyme activity, and so predispose to serious drug toxicity or lack of efficacy.^{7 8} Genetic testing to guide azathioprine treatment is increasingly common in the United States, and will be soon in the UK.

After avoiding doing any harm, we should try to do some good. The National Institute for Health and Clinical Excellence (NICE) recommends that treatment of patients with COPD, like Mrs B, should be started with a b adrenoceptor agonist, such as salbutamol. It has long been noted that the variation in response to salbutamol is wide. Recently, regular use of this drug in asthma has been shown to be ineffective in patients with a b adrenoceptor single nucleotide polymorphism.⁹ Identification of such patients groups would allow alternative treatments to be provided.

Influential polymorphisms are not simply confined to gene products with which a drug interacts directly, such as a receptor in the case of salbutamol or a metabolising enzyme (for azathioprine). They may have indirect effects by altering the microenvironment in which the drug acts: for example, if Mrs B was given clarithromycin for a chest infection, she would be at high risk of cardiac arrhythmia if she had a particular variant of a potassium channel subunit (KCNE2).¹⁰ Polymorphisms in other parts of the pathway on which the drug acts can also be influential—for example, possessing a SNP in the region of the type 2 dopamine receptor may predispose Mrs B to quitting smoking successfully with nicotine replacement therapy.¹¹

Regional prescribing practice

Next on the ethics checklist is a consideration of justice. Although we consider this to infer that everyone should have equal quality of care, we treat people unequally to achieve this. It is a small step from providing wheelchair ramps alongside stairs to giving patients different drugs or doses based on their genotype to ensure equal benefit. You might have seen a junior doctor order a thrombo­philia screen to guide a patient's anticoagulation ­therapy, but did you know this involves SNP genotyping (box 3)?

A complex and challenging issue in medicine is achieving equality, as access to most new healthcare technologies is largely determined by geographical proximity to tertiary centres and willingness to meet high costs. Altering management decisions based on genotyping differs from this presumption in three main respects: Firstly, SNP genotyping costs have tumbled from several pounds to a few pence per SNP tested. Hence initial outlay is relatively small in comparison to potentially costly complications.

Secondly, a patient's location in a remote or developing area is not limiting. Mouthwash or bloodspot samples can be transported in bulk over thousands of miles, whereas using a courier for access to other new technologies (such as sending patients for magnetic resonance imaging) is generally inadvisable.

Finally, pharmacogenetics has an ace up its sleeve: genotyping is highly unusual among biological tests in that the answer is always the same because an individual's genetic complement doesn't change. It is much easier to administer a test that is performed once at a mutually convenient time and location.

Implications for individuals

In the short term, tests for individual SNPs with large effects on efficacy or adverse reactions will become increasingly common. They will be beneficial to patients, cost effective, and will have minimal negative implications. But consider how many people are affected by single gene diseases such as cystic fibrosis in comparison to those affected by complex disorders such as asthma; this is indicative of the limitation of single SNP testing in pharmacogenetics. Most drug efficacy and side effect profiles will prove to be a product of multiple interacting factors, and each combination of some of these factors will come with an estimated “risk.”

A terrific challenge for us as (soon to be) doctors lies in synthesising this into a meaningful summary for patients, so they are able to make informed choices. You could argue that this is the same for any risk factor—for example, contraceptive pills and deep venous thrombosis (see clinical box 3)—but genetic risk factors are less straightforward. Firstly, testing positive for SNPs that raise the chance of disease is misleading if you also have polymorphisms that confer a protective effect, but are as yet unknown or untested.

Secondly, the effect of multiple polymorphisms in the same individual is often not additive. Possessing several SNPs that each have little or no effect in isolation can lead to a marked increase in risk for a given outcome: a phenomenon known as epistasis (J-JR wishes to emphasise this has nothing to do with nosebleeds; JDB thinks you are above that). Thirdly, as Mrs B will testify, polymorphisms may only exert their effect (COPD) under specific environmental conditions (smoking).

Although we are some years away, large panels of markers that explain most of the variation in treatment response will be assembled. These results will be combined with demographic and lifestyle data to produce a measure of likely drug efficacy or the chance of an adverse drug reaction. Formal risk calculations without genetic information are already applied to statin prescribing, blood pressure targets, and prediction of postoperative survival, among others, and this is a logical extension of the idea. However, unlike the scoring systems that we are used to, where we can tell our patients to lose weight or stop smoking, a genetic risk factor cannot be removed. Perhaps some of the art of drug selection and prescription will be lost from medical practice, but new challenges will also arise in the post-genome era.

The more you deal with patients, the more it will become apparent that there is a great variability in disease susceptibility, manifestation, and drug responses. Our growing knowledge of the impact of genetic polymorphisms is bringing us closer to understanding the reasons for this variation, and has the potential to make therapy safer and more effective in the near future.

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