Tag Archives: Genetics

Three Hits Hypothesis

Quite a lot of diseases are brought about by the conflation of two factors. Mice infected with certain herpes viruses suffer no ill-effect unless a helminth infestation supervenes. Oral allergy syndrome arises when a certain pollen interacts with certain foods (usually raw fruits, vegetables and nuts). The hygiene hypothesis says that lack of exposure to certain gut bacteria sensitises the body to allergic reactions to a range of environmental allergens. The pathway for disease involves three hits:

Genetically predisposed person –> Exposure 1 –> Exposure 2 –> Disease.

An intriguing example of a three-hit condition is the severe disease of children – Burkitt’s lymphoma. This cancer arises in germinal centres of lymph nodes in the neck. It is known that Epstein-Barr (EB) virus infection is necessary for endemic Burkitt’s lymphoma to develop because it prevents apoptosis (cell death) when certain mutations occur in the cell. But endemic Burkitt’s lymphoma only occurs in the malaria belt, and why this is so has been a mystery until the last few years. Now we know that the malaria parasite Plasmodium falciparum ‘upregulates’ an enzyme that causes mutations in DNA in lymph cells. These mutations are a normal part of antibody production since rearrangements of chromosome segments is necessary for antibody specificity. But in people with falciparum malaria, the effect ‘spills over’ to cause mutations of cancer genes. The double hit of EB plus malaria sets the scene for carcinogenesis.[1] Why in the neck – perhaps because lymph cells in the necks of children work particularly hard eradicating throat and ear infections, in which case there is a ‘four hits’ hypothesis!

— Richard Lilford, CLAHRC WM Director

References:

  1. Thorley-Lawson D, Deitsch KW, Duca KA, Torgbor C. The Link between Plasmodium falciparum Malaria and Endemic Burkitt’s Lymphoma—New Insight into a 50-Year-Old Enigma. PLoS Pathog. 2016; 12(1): e1005331.
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Can Thinking Make It So?

When we think of risk factors for mortality we properly think behaviours (e.g. smoking / obesity) or genetics (e.g. family history). What about psychological factors – can unhappiness increase your risk of risk of cancer? Well, Batty and colleagues [1] have tackled this problem as follows:

  1. They assembled 16 prospective cohort studies where behaviours and psychological state had been measured and in which participants were followed up to see if cancer developed.
  2. They obtained the raw data and obtained an individual patient meta-analysis.
  3. They adjusted for the usual things known to increase risk of cancer (obesity, smoking, etc).
  4. They calculated relative risk of cancer according to antecedent psychological state.

They found a positive correlation between psychological distress and risk of cancer. But causality might have run the other way – (occult) cancers may have been the cause of psychological distress, not the other way round. So:

  1. They ‘left censored’ the data, thereby widening the gap between the point in time where the psychological state was measured and the point where cancer supervened.

The association between psychological state and cancer death persisted, even when they were separated by many years. What is the explanation?

  1. Failure to fully control for all behaviours (although behaviour could be the mechanism through which the cancer risk is increased in people with depression, in which case they ‘over-controlled’).
  2. Reduced natural killer cell function.
  3. Increased steroid levels, which can apparently affect DNA repair in some way.
  4. Some mechanism yet to be discovered.

In any event, the findings are intriguing, for all that practical implications may be limited.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Batty GD, Russ TC, Stamatakis E, Kivimäki M. Psychological distress in relation to site specific cancer mortality: pooling of unpublished data from 16 prospective cohort studies. BMJ. 2017; 356: j108.

Genetic Testing for Common Non-Communicable Diseases

News Blog readers will know that I am no fan of genetic testing for common conditions, such as asthma or diabetes (see previous post). My argument gains support from recent literature summarised in an editorial in the Annals of Internal Medicine.[1] An obese person with the lowest genetic risk is five times more likely to develop diabetes than a normal weight person with the highest genetic risk, for example. Moreover (and as pointed out in a previous blog), knowledge of genetic risk is ineffective in promoting behaviour change. Private screening not only externalises costs (such as counselling and treating) to the health service, but also results in less satisfied customers whose expectations have been raised to levels that are hard to meet. The libertarian CLAHRC WM Director would not ban direct-to-consumer testing, but would seek to regulate it in the same way as cigarette advertising is regulated. Of course, the threshold where providing information topples over into hype is a tricky one for a regulator to define.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Burke W & Trinidad SB. The Deceptive Appeal of Direct-to-Consumer Genetics. Ann Intern Med. 2016; 164: 564-5.

Service Implications of Personalised Medicine

Personalised medicine is a slightly slippery term, since medicine can be bespoke with respect to a patient’s biological features (affecting probabilities of outcomes) or a patient’s psychology (affecting preferences / values / utilities). Ideally, medicine should, as much as possible, be tailored to both. But in this short blog we will concentrate on medicine that is personalised on the basis of biology (precision medicine, if you like). We select this focus because it is becoming increasingly possible to focus treatment according to different, often genetic, test results. Previously treatment was determined by the clinical diagnosis formed on the basis of clinical and standard tests, such as the ECG, image or biochemistry. However, a much finer level of granularity is increasingly available as a result of genetic testing. This type of precision medicine is increasingly important for cancer where interest has focussed on somatic (acquired), as well as germ-line (inherited), genetic variation. Treatment is no longer based purely on tissue of origin and histological appearance, but on the genetic mutations that are part and parcel of the carcinogenic process and that strongly influence responses to treatment. Treatment is also influenced by genetic factors affecting non-cancer diseases, but in this case it will be inherited, rather than acquired, genetic variations that are salient. Lastly, inherited genetic variations may provide advance warning that certain patients can, or cannot, tolerate certain treatments – pharmacogenetics.

Since CLAHRCs are concerned with how the service must adapt to improve access to safe and effective care, precision medicine is a topic of relevance to CLAHRCs, and a point of contact between service delivery and biomedical researchers.

But what are the service change requirements of precision medicine? Well, many new targetted therapies have no real service implications since they simply involve substitution of one medicine for another. The service implications are nugatory in a health service that already has well developed and smoothly functioning supply chains that can ensure availability of the relevant drugs. However, precision medicine is not always so straightforward, so here are some scenario types where the service may need to be adapted to a degree.

First, genetic diagnosis has an important collateral effect that arises when the laboratory findings have implication for the individual that lie outside the presenting feature. For instance, a genetic test in a patient with breast cancer may show that she has a high risk of cancer of the ovary. Preparing for such a scenario has human resource and educational implications. These might be somewhat modest, but more radical implications arise when a finding in one person may impact other family members who are often scattered across the world. This raises logistical issues in arranging for people to be contacted, counselled and tested. The workload and hence human resource implications are considerable. Currently, a project called the “100,000 genomes project,” is unfolding in England. Genetic samples are being taken from patients with numerous diseases. This is the basis for a tractable research project to model the service implications of enhanced genetic testing. CLAHRC WM collaborators at the Health Services Management Centre, University of Birmingham are investigating this issue with support from the regional West Midlands Academic Health Science Network (WM AHSN). Clearly, the ‘new genetics’ is going to have quite large service implications and we should prepare for it in advance.

Second, patients may obtain testing privately and then present to publically funded services with the results. The service needs to ensure that it has the capacity to respond, at the very least, by ensuring that accurate counselling is available. Continued professional development will be needed to ensure that staff are up to date. The resource implications may be mitigated by making information available online or even establishing online question and answer facilities. Informal testing also has implications for regulatory oversight of providers of genetic testing to ensure high-quality and prevent testing for attributes that society deems it inappropriate to test for.

Third, there are implications for health economic evaluation and the cost-effectiveness of targeted therapies. However, the principle behind precision medicine is that the effect of therapy will be greater when therapy is targeted. That means that companies should be able to charge more for their medicines per patient to recoup costs. However, the general improvement in effectiveness will have disequilibrium effects, meaning that, ceterus parabus, the willingness-to-pay threshold for a QALY will have to deflate. Precision medicine does, of course, have implications for the private insurance industry since they will be on guard to ensure that they are not exposed to moral hazard when people have covert testing and only declare this if their risk is low.

Taken in the round, however, precision medicine would seem to have real, but fairly, modest service delivery implications. But we do need to plan carefully by evaluating the human resource and educational implications of dealing with collateral effects and making sure that necessary testing capacity is scaled to predicted demand.

There is another kind of precision medicine with more radical service implications, and this is the genotypic approach to characterising microbes. This has large implications for two reasons. First, existing microbial typing laboratory procedures will become obsolete (or demand for them will be greatly reduced), with implications for retraining and possible redundancy. Second, testing may well move from the lab back into the ward with large implications for education of the clinical workforce.

Although precision medicine may have rather modest implications for service delivery, there are other lab discoveries with much greater implications. For example, cell therapy has large implications for service delivery, quality control, and methods for up-scaling, and new treatments come along, some of which change pathways completely, such as intracranial thrombectomy for stroke, as discussed in a previous blog.[1]

— Richard Lilford, CLAHRC WM Director

References:

  1. Lilford R. Provocative Idea for Thrombectomy Services in Acute Stroke. NIHR CLAHRC West Midlands News Blog. 14 August 2015.

Why Do You Want to Know About Genetic Risks of Disease When the Relative Risk Difference is Moderate?

If you smoke, you increase the risks of certain multi-factorial diseases five- to ten-fold. But various genetic variations carry much smaller risks for these diseases thanks to evolutionary pressures. So why would a person want to know their genetic risk? Smokers should quit even if their genetic risk is low. And non-smokers should continue to abstain, even if their genetic risk is low. Consistent with this observation, a recent BMJ article shows that knowledge of one’s genetic risk does not influence a person’s behaviour.[1] The point in continuing research into genetic associations is to unravel pathophysiological mechanisms on the assumption that this knowledge will translate into better treatments for established diseases. Precision medicine, it seems, does not entail precision preventive medicine.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Hollands GJ, French DP, Griffin SJ, et al. The impact of communicating genetic risks of disease on risk-reducing health behaviour: systematic review with meta-analysis. BMJ. 2016; 352: i1102.

Psychiatry Comes of Age

In a recent post the CLAHRC WM Director opined that psychiatry was taking its first reductive steps – we are starting to understand the neurochemical mechanisms behind diseases that appear in the mind. Well our toddler has started to run and the new era has been ushered in with a brilliant recent publication in Nature.[1] The story starts, as it increasingly does in modern science, with a large collaborative effort – in this case the international Psychiatric Genomics Consortium, which carries out genetic association studies. Their Biobank harbours 39,000 cases of schizophrenia and 45,000 controls. There are many genetic polymorphisms across the genome that are associated with schizophrenia – about 100 in fact, as mentioned in a previous post. But one constellation of polymorphisms stands out in terms of the strength of its association with schizophrenia. This constellation resides in the HLA gene cluster. Genes in this cluster encode proteins that help the immune system identify foreign antigens, such as those found on the cell surface of microbes or transplanted tissue. Polymorphisms in the HLA cluster are associated with autoimmune disease, meaning that the immune system has mistakenly identified an antigen on a normal host cell for attack. Does this mean that schizophrenia might be an autoimmune disease? Well, sometimes perhaps (see below), but there is another mechanism by which HLA variants may predispose to this devastating disease. It turns out that the part of the HLA complex most closely associated with schizophrenia is the gene responsible for one of the complement proteins known as complement component 4. And this molecule is not just active in eliminating pathogens and cellular debris – it also affects nerve cells by directly accelerating the pruning of synapses. Synaptic pruning is a normal part of adolescent brain remoulding, but excessive pruning, associated with over-active complement 4, features as part of the pathogenesis in many cases of schizophrenia.[1] Enter NIHR CLAHRC East of England Director Peter Jones. Jones hypothesises that around 10% of cases of acute onset schizophrenia result from an acute autoimmune brain syndrome. He is testing this hypothesis by means of a RCT involving immunosuppression. Presumably it is no co-incidence that some cases of schizophrenia result from a form of autoimmune disease, and that genes in the HLA constellation are so frequently associated with schizophrenia. If so, much of the damage may have been done when the acute brain syndrome appears – we may need to look for an earlier, more tightly targeted therapy, and we suspect that preventing complement-mediated damage will play a role. Incidentally, this is a further example of massive scientific achievement emanating from an international collaborative effort, rather than the genius of just one individual. The future prominent scientist will increasingly be the one with the social skills to engineer a prominent place for herself on the committees that shape protocols and scientific papers, such as the Global Burden of Disease project discussed in a recent post.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Sekar A, Bialas AR, de Rivera H, et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016; 530: 177-83.

More on Whole Genome / Whole Exon Germline Sequencing – This Time in Children Who Get Cancer

News Blog readers may remember a previous post on germline mutations in children with autism spectrum disorder (with and without congenital anomalies). Now germline mutations have been compared in children with cancer and controls.[1] Among 1,120 affected children, 8.5% had predisposing germline gene mutations. This was an underestimate because it included only genes that were identified in advance, on the grounds of established relevance to carcinogenesis. The real value may be 50% higher. Only 40% of patients with likely pathogenic mutations had any family history. The CLAHRC WM Director suspects that children with germline mutations are at risk of second primary cancers, and that some second primary cancers previously attributed to treatment of the primary cancer are in fact caused by germline mutations. The CLAHRC WM Director proposes a study to examine the incidence of such mutations in children with secondary cancers.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. CZhang J, Walsh MF, Wu G, et al. Germline Mutations in Predisposition Genes in Pediatric Cancer. N Engl J Med. 2015; 373:2336-46.

Health care in a parallel world: the Birmingham screwdriver

Imagining health care in a parallel world can reveal a lot about the health care system we enjoy in this one.

Counterfactual narratives have long been popular. Livy speculated about a confrontation between Rome and Alexander the Great, had the latter chosen to expand his empire westwards instead of eastwards.[1] Kingsley Amis wrote about a world where the reformation failed and Roman Catholicism continued to dominate Europe for centuries.[2] An alternate health service seems a minor alteration in comparison. What would it look like?

I recently took part in a workshop on type 2 diabetes in adolescents and young adults. Most of the speakers were medical researchers, and the audience clinicians. I was the public health afterthought. The talks focused on pathophysiology of type 2 diabetes, speculating on whether South Asians might exhibit a distinct illness trajectory to Europids. This effortlessly morphed into a speculative discussion of genetics. The medical academics were fascinated, leaning forward on their seats, vying with each other to interject. A single question about whether South Asians and White British might possibly have different lifestyles was brushed aside. The essential genetic homogeneity of the human species compared to its great ape cousins was ignored,[3] (see also our previous blog).

Although irrelevant to patients, pathophysiology and genetics fascinate doctors because they are the core of our undergraduate professional training. Pharmacological treatments predominate our therapeutic thinking because they are the logical response to pathophysiology. Doctors enjoy a near monopoly on prescribing and it is the defining and distinguishing feature of the profession. As the profession is a key influencer of the health services and research agendas, the ability to deliver the right drugs to the right patients is a central preoccupation of the health care system and the understanding of pathophysiology in order to develop and test drugs dominates the research agenda. From my background reading on the public health aspects of diabetes I learned that only 16.7% of newly diagnosed type 2 diabetics are offered structured diabetes education and only 3.6% attend.[4] How could an important and effective intervention be afforded such a low priority?

In another world a profession of health educators is in the ascendant. The profession dominates the provision of health care. Clearly the most important intervention for anyone developing a chronic disease is structured education. This conveys factual information about prognosis, life skills, confidence, and self-efficacy. The first intervention follows diagnosis. It serves an anthropological, as well as an educational, purpose, marking a life transition into a new state. Ongoing education reinforces skills, builds knowledge, and addresses the disease progression. Alongside service delivery, a vigorous research agenda constantly refines the educational interventions. New educational materials are developed. Innovative modes of delivery test new communication technologies, gamification (the use of game thinking and mechanics in non-game contexts to engage users), and virtual learning communities. Patients become co-producers of educational interventions. Stratified education is emerging where psychometric testing and preference elicitation allows patients to be matched to the most appropriate educational intervention. The primary outcomes of health care are the same: quality of life and length of life. The process measures by which we mark our progress are very different: self-efficacy, knowledge, and measurable skills replace physiological parameters. Even the typology of disease might change, with categories defined by the type of educational intervention as much as by pathophysiology.

What does this tell us? Sometimes they are so ingrained, we can’t see our own assumptions. The French call this déformation professionnelle. To a man with a hammer, everything looks like a nail. Which is why a hammer was referred to as the Birmingham screwdriver.

— Tom Marshall, Co-Director CLAHRC WM, Prevention and Detection of Diseases

References:

  1. LiviuS T. The History of Rome (book IX, sections 17–19). English Translation by Rev. Canon Roberts. New York, NY: E.P. Dutton and Co. 1912.
  2. Amis K. The Alteration. London: Jonathan Cape. 1976.
  3. Prado-Martinez J, Sudmant PH, Kidd JM, et al. Great Ape Genetic Diversity and Population History. Nature. 2013; 499: 471-5.
  4. The Healthcare Quality Improvement Partnership (HQIP). National Diabetes Audit 2012 – 2013. Report 1: Care Processes and Treatment Targets. Leeds: Health & Social Care Information Centre. 2014

Use of Language: Race is to Ethnicity as Sex is to Gender

The CLAHRC WM Director has often puzzled over the use of “gender” vs. “sex”, and “ethnic group” vs. “race” in scientific writing. They are not synonyms; gender and ethnicity are social constructs, while and sex and race are biological. The former are not “polite” terms for the latter. Philip Steer, Emeritus Editor of an exceptionally lively speciality journal BJOG: An International Journal of Obstetrics and Gynaecology, has written a sure-footed article on this topic.[1] Agreeing that race is the appropriate term to describe groups with a similar place of origin, irrespective of culture, he recommends the National Library of Medicine MeSH groupings. Five continental groupings (African, American, Asian, European, and Oceanic) are broken down by sub-region – for example, European into ‘White European’ and ‘Mediterranean’. Gone is the term Caucasian, which was used to describe broader origins than just the Caucasus area and which, the CLAHRC WM Director learned, has eugenic overtones.

The article makes some other interesting points. Africa has the greatest human genetic diversity among the continents, accounting for as much as 80% of all human genetic variation. This is because of the bottleneck created by the exodus from Africa of a relatively small group of Homo sapiens about 70,000 years ago. These migrants mated with Neanderthals and spread out to colonise the rest of the globe. All of this is of interest to CLAHRC Africa, which has an interest in preventing hypertension and stroke. Salt is the prime causal suspect and there is evidence that some African people may be especially prone to salt-induced hypertension as a result of a widespread allele. Since intake of salt has increased rapidly over the past century we are developing protocols to identify the main source of salt in the diet. In due course we will design an intervention to tackle this. We are working closely with colleagues in the African Population Health Research Center (APHRC) and Malawi on this project.

However, the whole question of race will become progressively less important in science and medicine in the future for two reasons. First, gene sequencing will increasingly enable scientists and doctors to hypothecate genetic variation at the individual level, rather than the level of the group/race.[2] [3] The arrival of personalised medicine will reduce the importance of race and it has always been the case that there is far more variation within, than between races. Second, mating across racial boundaries will increasingly dilute correlation between race and genetic configuration and vitiate the effects of Homo sapiens great migration out of Africa.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Steer P. Race and Ethnicity in Biomedical Publications. BJOG. 2015: 122(4): 464-7.
  2. Burchard EG, Ziv E, Coyle N, et al. The Importance of Race and Ethnic Background in Biomedical Research and Clinical Practice. New Engl J Med. 2003; 348: 1170-5.
  3. Jeffers C. The Cultural Theory of Race: Yet Another Look at Du Bois’s “The Conservation of Races”. Ethics. 2013; 123(3): 403-26.

From the Labs

The CLAHRC WM Director has never been able to resolve the following paradox – when treating infections, microbial chemosensitivity is tested in the laboratory to select the antibiotic for use in the patient, but when treating cancer, in vitro chemosensitivity testing is not carried out. Part of the answer may come from a recent paper in Nature,[1] which shows that most cancers are polyclonal – they are constituted of a mix of different cell types which assist each other’s growth in a symbiotic way. So a biopsy may yield cells from only one clone and give a misleading result when tested in the lab. Of course, the bug that is cultured in the lab may also not be the one that is actually causing the disease, so the dissonance is not completely resolved.

However, cell culture is giving way to molecular genotyping for both infections and cancer. In time, the genetic signature will do more than just classify cancers and germs, but will also enable virulence and chemosensitivity to be determined. The massive organisational implications of these scientific advances at home and abroad are core CLAHRC business, as discussed earlier in this News Blog.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Murusyk A, Tabassum DP, Altrock PM, Almendro V, Michor F, Polyak K. Non-cell-autonomous driving of tumour growth supports sub-clonal heterogeneity. Nature. 2014; 514: 54-9.