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How rapid advances in genetics are personalising medicine

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Our genes can increase our risk of illness, but advances in understanding how they physically interact with each other already offer some better-tailored treatments. Donna Chisholm reports.

At just 24, Tyla Ridsdale calls himself a ticking time bomb. Because of his genes, he’s at substantially higher risk than most of us of developing heart disease, despite working out regularly and eating a healthy diet.

Tests a year ago confirmed Ridsdale has a genetic double whammy. He’s inherited a condition called familial hypercholesterolemia (FH), which causes high cholesterol levels from birth; he also carries a series of other genetic variations that together substantially elevate his risk of a heart attack or coronary disease. FH probably contributed to his grandfather’s death at 37, and also affects his mother and uncle.

The genetic tests put Ridsdale, a software instalment specialist, in the top 1% or less of the population for cardiac risk. The knowledge is potentially life-saving, in that it shows he’s three times more likely to respond to statin treatment than those at low risk, but it’s also, at times, depressing. The drugs he’s on have side effects including a slightly increased risk of diabetes, for example, and he knows that because of his FH and what doctors call his polygenic risk score for heart disease, lifestyle changes alone won’t be enough to alter his prognosis.

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Polygenic risk scores are worked out from the total number of genetic variations in the genome that are either associated with, or protect from, disease. These genetic variations can be detected through genome sequencing, or gene chip technology that fragments DNA and can read up to one million variations.

Scientists’ rapidly expanding knowledge of the effect of not only single genetic mutations, but also more subtle variations, known as SNPs, in non-coding DNA – what used to be dubbed “junk” DNA – is about to revolutionise treatment for large numbers of us, and is already leading to faster diagnoses of rarer disorders that might otherwise take months to identify.

Experts say the potential is immense for genetic information to personalise screening programmes and identify people at high and low risk of disease before symptoms are even apparent. The implications for health-care spending, improved efficiency and reduced cost to taxpayers are extraordinary.

New research out of the Liggins Institute at the University of Auckland is at the forefront of international efforts to reveal the genetic links in apparently widely disparate diseases, an approach that could see existing drug treatments “repurposed” for use in new conditions.

Tyla Risdale. Photo/Tony Nyberg/Listener

The missing links

Mood disorder, osteoarthritis and ADHD. Type 1 diabetes, rheumatoid arthritis and asthma. Insulin sensitivity, throat cancer and bowel cancer. On the face of it, these groups of conditions would seem to have nothing in common, but Liggins scientists have revealed the genes that predispose us to these and many other illnesses and traits are more closely related than we knew. Their research, by PhD student Tayaza Fadason under the supervision of Liggins associate director of research Justin O’Sullivan, with help from genetic epidemiologist William Schierding and biostatistician Thomas Lumley, mined data from more than a million people in genome-wide association studies and was published in December in Nature Communications, one of the world’s leading science journals.

In the largest cluster, Crohn’s disease, inflammatory bowel disease, body height, muscle strength, insulin sensitivity, colorectal cancer, throat cancer and cholesterol levels were all linked with changes in the activity of genes involved in the metabolism of omega-3 fatty acids. These same genes are also controlled by SNPs associated with where people sit on the continuum of short to tall – and a predisposition to being stronger or weaker, or having higher or lower levels of fatty acids, which help the body make hormones that increase or decrease inflammation.

Another cluster involves the expression of genes that contribute to how the body recognises cells, for example to determine whether a cell is foreign or not. Those variants are involved in asthma, diabetes, allergic rhinitis, rheumatoid arthritis and cervical cancer, among other things. “It is easy to see how changing the expression of genes that contribute to how we recognise cells might be important for immune-related disorders,” says O’Sullivan.

Other clusters, associated with DNA repair, are more obviously intuitive – for example, those linking predispositions to smoking behaviour, emphysema and chronic bronchitis, and others that associate basal cell skin cancers with melanoma, certain hair colours and freckles.

Although we think of DNA as looking something like a spiral staircase, Liggins scientists have taken a novel approach, examining the traditional helix as it sits in the nucleus of cells. Here the helix is tightly packed and folded in on itself, putting some genes in closer proximity to – and affecting the expression of – other genes nearby.

“There is the possibility that all these complex diseases might have things in common that we totally miss because of the ways of looking at finding the mechanism responsible,” says Fadason. For the Nature Communications study, he examined variations in the genome for more than 1300 phenotypes (the physical expression of a disease or trait).

Making links: PhD student Tayaza Fadason (right) with Liggins Institute’s Justin O’Sullivan. Photo/Tony Nyberg/Listener

New uses for current treatments

But if we can’t do much about our genetic makeup, why is this work so important? The answer lies in the future – when treatments will be increasingly personalised – but also the present in that it will lead to a fresh look at drugs that haven’t been previously considered as potential treatments. A database of drugs known to work on diseases involving a large number of genetic variants already exists, and O’Sullivan says it’s an obvious next step to comb that information for ways existing treatments could be used to treat different conditions.

“We see relationships between diseases that we weren’t quite sure about before, that hint at what the underlying mechanisms are and what pathways are involved. If we can understand those, we can target and maybe moderate them and increase the expression of certain genes or the efficiency of their proteins,” says O’Sullivan.

“This is about individualising medicine and stratifying populations to understand health and well-being, and all the aspects of why some of us respond to diets and why some of us don’t; why some of us respond to drugs and some of us don’t.”

The scientists believe it will also help doctors take a more holistic approach as they try to understand and treat the causes of individual diseases. “If you look at diseases in silos, you miss the whole picture … you miss out on the inter-relationships that may be the key to successful treatment,” O’Sullivan says.

The study revealed the genetic commonalities in nicotine receptor pathways, linking a predisposition to smoking behaviour with a predisposition to diseases that are known to be smoking-related, such as chronic obstructive pulmonary disease, lung cancer, emphysema and bronchitis. But the research shows the causes of those diseases mightn’t be so chicken-and-egg straightforward. “We think the mutations that predispose someone to being a smoker also predispose to the other diseases. If you were to take up smoking, and you didn’t have the mutations that affect the genes that predispose to those multi-morbid conditions, we think you may be less likely to develop these other disorders as a result of your smoking.”

O’Sullivan says the mutations can change the expression levels of two nicotine receptors in the brain; the assumption is this causes a greater need for nicotine, “but we don’t know for sure if that is the case”.

The research could, of course, have smokers throwing up their hands and claiming their genes, and not them, are to blame for their habit. The work certainly suggests why some people may have a harder job than others to stop smoking, but further research is needed.

Former caregiver Russell Edge, 61, of Onerahi in Northland, developed chronic obstructive pulmonary disease about 10 years ago after starting to smoke heavily in his 20s and 30s. “There are traces of truth in this stuff, but you can determine your own destiny,” says Edge. Giving up, however, is an ideal that’s so far eluded him. He’s tried four or five times in the past 15 years, but still has his first of 30 cigarettes of the day when he wakes at 5am. “Even the doctor, fairly recently, said it’s in your genes if you are more likely to start smoking, and it’s also in your genes whether you’ll develop things like lung cancer.” Edge says he’ll keep trying to quit.

Liggins researchers have also investigated whether SNPs contribute to Type 1 diabetes by affecting the functioning of genes on segments of DNA that appear to be distant from them, but with which they actually come into contact because of the way the DNA is coiled into the cell nucleus. In a study published in Frontiers in Genetics, they identified nearly 250 genes that come into physical contact with diabetes-linked SNPs and belong to networks involved in the immune system.

“We have always thought the pancreas is the final destination [in the development of diabetes],” says lead author, PhD student Denis Nyaga, “but now we are seeing that other organs are affected, including the liver, and the T cells, before it reaches the pancreas.” Says O’Sullivan: “If you can catch these changes in the early stages, maybe you can moderate the course of the disease.”

Predicting risk: from left, Stephen Robertson, Patrick Gladding and Martin Kennedy. Photo/Supplied

It’s time to implement

Cardiologist Patrick Gladding, Tyla Ridsdale’s specialist and founder of the Theranostics Lab (which offers DNA testing for coronary artery and atrial fibrillation risk), says genetic risk prediction has taken a quantum leap in recent years and it’s time it should be more widely implemented here – but New Zealand is “getting further and further behind the ball”. Although support for clinical genomics was lacking in the past, he says “the evidence is now here”, thanks to big data projects like the UK Biobank (which provides genetic information from 500,000 volunteers to approved researchers around the world) as well as supercomputers and artificial intelligence to process and visualise the data.

“Genomics is ready for primetime – ready to be used clinically in the public health service – but there is no guidance coming from the Ministry of Health or Pharmac. The genomics revolution is allowing other countries to better assess risk and treat patients appropriately and properly allocate resources such as some frighteningly expensive drugs.” In Ridsdale’s case, two drugs are available, but neither is Pharmac-funded. One is an injectable agent called a PCSK9 inhibitor that costs about $10,000 a year if patients pay for it themselves. Ridsdale’s uncle in Australia already receives the drug, which is funded there. Gladding says New Zealand taxpayers won’t be able to afford the treatment for everyone, so it will have to be targeted to those most in need – and that’s best done with genomics.

He says the ministry is missing the bigger picture of the role of genetics in healthcare delivery. “People are working their behinds off in the hospitals, waiting lists are extraordinary and the frustration is you could do something about it, but you can’t because you’re hamstrung by lack of interest. A lot of it is putting fingers in the dike and not looking ahead to what is around the corner when that is the solution to your fingers in the dike.”

The costs of genomic testing are coming down. It costs about $70 for a cardiac polygenic risk assessment such as Ridsdale had, but few laboratories do them; Ridsdale’s samples had to be sent to a lab in Christchurch and his polygenic risk score was done at the Liggins Institute. “We are severely limited by access to the tools we need – and the lack of endorsement, validation and support, or a pathway for funding, from the Government.”

But Gladding cautions that the introduction of more widespread genetic testing needs to be widely debated, to give doctors a “social licence” or mandate to proceed. Privacy rules also need to be updated, so people are protected from discrimination – for example by insurance companies – on the basis of their genetic risk. At present, genetic tests are mainly done on people who have a family history of a disorder.

The UK’s National Health Service started a Government-funded genomics programme on October 1, with the principal aim of testing to diagnose rare diseases, but encompassing many other areas including drug targeting and cancer diagnosis and treatment. In December, Genomics England’s 100,000 Genomes Project reached its goal of sequencing 100,000 patient genomes. Researchers say the project has already resulted in one in four participants with rare diseases being given a diagnosis for the first time, and helped half of all participating cancer patients to be directed into a clinical trial or receive a targeted drug.

In November, another New Zealand scientist, the University of Otago’s Professor Martin Kennedy, an expert in psychiatric genetics, was one of more than 160 authors in the world’s largest study of genetic links to alcohol dependence, published in the journal Nature Neuroscience. The genetic profiles of about 660 participants in the Christchurch Health and Development Study were among the nearly 53,000 analysed in the research: 15,000 people had alcohol dependence, the others were controls.

It found that genes associated with the risk of developing dependence may be different from those linked to alcohol consumption. It also shows that there is a genetic distinction between people who are pathological and non-pathological drinkers. Some of the genes overlapped with those linked to schizophrenia, ADHD, depression and cigarette and cannabis use.

Kennedy says although the research is basic and in its early stages, “if you’re a psychiatrist or a doctor trying to figure out what is wrong with the person in front of you, these kinds of genetic tools could be very useful. They should help with diagnosis, and perhaps better management of patients.” But, he says, as a scientist, two of the most interesting revelations are the genetic correlations of alcohol dependence with other psychiatric conditions and the lack of correlation with consumption.

“Knowing that different biological factors contribute to different parts of this illness could prove really important. As the biology becomes clearer, you may see pathways for which other drugs exist. And if you are trying to design prevention programmes or interventions to reduce alcohol dependence, it helps to understand the biology.”

Revelation: there is a lack of correlation between alcohol consumption and the risk of alcohol dependence. Photo/Getty Images

Cataloguing a Kiwi genome



The genomes sequenced in genome-wide association studies, which provide the data for international research, are from mostly European populations, but how different are they from those of New Zealanders with Māori and Pacific ancestry?

In an opinion column in the New Zealand Medical Journal last August, a group of researchers argued that as genomic medicine gathers pace, Māori and Pasifika people risk being left behind by the advances, causing even greater inequity in healthcare outcomes, unless we do more to create and catalogue a uniquely New Zealand genome.

“The DNA and genomic data that connects to whakapapa is considered a taonga, and its storage, utilisation and interpretation is a culturally significant activity,” said the column authored by more than 20 researchers, led by Professor Stephen Robertson, the Cure Kids professor of paediatric genetics at the University of Otago.

Robertson, who has done groundbreaking genetic research on Māori, is co-lead researcher of the Aotearoa New Zealand genomic variome, a fledgling project involving the universities of Otago, Massey and Auckland. Robertson told the Listener it was too soon to talk about the research effort, but that the success of any bid to construct such a catalogue would hinge on it being led by iwi and Māori and Pacific representatives. This would ensure the use of such a resource would be focused on matters that were priorities to Māori communities.

The researchers said, “Such resources are not proposed to primarily enable comparisons between those with Māori and broader Pacific ancestries and other Aotearoa peoples, but to place an understanding of the genetic contributors to their health outcomes in a valid context.”

Holding out hope

Despite the genetic cards stacked against him, Tyla Ridsdale is doing his best to fight back with lifestyle changes. After getting “addicted to running”, he’s lost 15kg in the past year and completed 40km and 80km running and walking events.

But he knows there’s no way to solve his problem without medication: his total cholesterol has been as high as 11 (more than twice as high as it should be), and was around 7 or 8 by the time he was 16. It’s now about 5.9 and he’s on the maximum dose of statins.

He’s holding out hope for access to the PCSK9 inhibitors – he belongs to Facebook support groups, and has set one up locally, in which participants overseas discuss how much the drugs have lowered their levels. But for Ridsdale, and other Kiwi patients, that sort of help could be a long time coming.

Disease connections

The Liggins Institute researchers identified groups of diseases associated with clusters of genetic variations. These included:

  • Fat metabolism: Crohn’s disease, inflammatory bowel disease, body height, muscle strength, insulin sensitivity, colorectal cancer, throat cancer, cholesterol levels.
  • Nicotine metabolism pathway: Pulmonary function, chronic obstructive pulmonary disorder, chronic bronchitis, lung cancer, smoking behaviour, emphysema, pulmonary artery enlargement, sudden cardiac arrest.
  • DNA repair: Hair colour, melanoma, facial pigmentation, sun-sensitive skin, sunburn, freckles, basal cell carcinoma, skin pigmentation.
  • Homeostasis (maintaining a stable physiology): Osteoarthritis, ADHD, mood disorder, BMI, schizophrenia, bipolar disorder, urate levels (gout), glucose regulation hormone.
  • Lipids for cell recognition (determining types of cell, and whether a cell is foreign or not): Asthma, Type 1 diabetes, seasonal allergic rhinitis, cervical cancer, leucocyte count, neutrophil count, allergy, rheumatoid arthritis, biliary liver cirrhosis.

Frank Bloomfield. Photo/Supplied

From the first breath

Genomics and AI are being used to tackle rare disorders in babies.

One area where genome sequencing is already being used clinically is in the diagnosis of rare disorders in newborns, such as spinal muscular atrophy, which can be treated with a new drug – but at the enormous cost of about US$100,000 a month for the first year, and ultimately $400,000 a year for life.

Consultant neonatologist Professor Frank Bloomfield, the director of the Liggins Institute and a clinician at Starship Hospital, says inherited metabolic conditions can be difficult to diagnose using current techniques; “micro arrays”, in which segments of the genome are sequenced, are being used to give diagnostic pointers. Internationally, some sick babies are having their entire genome sequenced and the results are interpreted with the aid of artificial intelligence (AI) to trawl computerised health records.

Whole genome sequencing is only rarely done here, but its use will increase, says Bloomfield. He says in one hospital in California, which is a world leader in the field, the technique is diagnosing up to 30% of newborns with an unexplained illness, which he calls a phenomenally high return rate for genetic testing.

The government here has committed to centrally linked electronic health records for mothers and babies – this will eventually roll out to all patients – which can be used for AI-assisted interpretation of genetic results.

This article was first published in the February 23, 2019 issue of the New Zealand Listener.