Unveiling your genetic compass

NIKKI MACDONALD
Last updated 05:00 13/04/2013
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Sarah Lee, left, discovered she had an Alzheimer’s risk of 75 per cent, inherited from both her dad and mum, Eileen Smith.

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Imagine if a test tube of spittle and $205 could mine your past to foretell your future. Would you want to know if your genetic compass pointed toward cancer, or if you carried a silent coding quirk that put your children at risk of cystic fibrosis?

And what if the horoscope foretold a devastating and incurable disease such as Parkinson's or Alzheimer's?

"Are you ready to take that on?" asks 26-year-old Danielle Lambermon, who found out in 2007 that she was one of 43 Auckland Hospital patients with a tiny risk of contracting brain disease Creuzfeldt-Jacobs Disease through contaminated instruments.
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"I truly believe people don't see what the consequences could be. They think, 'It will be really good because then I'll know'. But will that make you live your life in a box? Would you do what you normally do? If you're not a strong personality it will mess up your life."

Direct-to-consumer (DTC) genomic testing, which uses genetic markers gleaned from a saliva sample to predict disease risk, has been widely available for five years. Once the sample is analysed - typically in a United States lab - test subjects access an online personalised risk profile for over 100 diseases, from brain aneurysm to restless legs syndrome, and find out if they are carriers for genetic conditions such as cystic fibrosis and breast cancer.

Initially costing about US$1000 (about NZ$1180) it was only ever going to be a niche service. But, for the first time last year, the controversial tests edged within reach of the average curious Kiwi, when major player 23andme, owned by Anne Wojcicki (partner of Google founder Sergey Brin) slashed its price to US$99 (US$173.95 for international customers).

About 180,000 people have already tested with 23andme, and an insurance industry study last March predicted US genetic testing demand would quintuple over the next decade.

It's not known how many Kiwis are spitting to map their genetic disease risks. But it's common enough that the courier collecting my test sample nodded at the paperwork: "Oh, it's one of those 23andme things."

The tests have been banned in Germany and some US states, and debate continues to rage about whether catch-all genomic tests provide empowering knowledge or meaningless - even dangerous - noise liable to obsess the worried well.

There's nothing new about genetic testing. For 50 years we've been testing newborns for genetic disorder phenylketonuria, which can cause intellectual disability. The test is accurate and the disease treatable.
But sickle-cell anaemia testing among African Americans in the early 1970s - when the disease could not be prevented or treated - illustrates genetic testing's potential pitfalls. As one commentator noted: "What they carried was stigma."

The public health system routinely provides testing for people with a family history of genetic disease - commonly breast and bowel cancer and neurological diseases. But testing is closely managed, involving genetic counsellors.

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And even then, not everyone wants to know. Take Huntington's - an incurable genetic brain-wasting disease. Worldwide, only one in four people with a family history get tested, and in New Zealand there's a one month stand-down between making the decision and testing.
Wellington Huntington's adviser Jeanette Wiggins says 18-year-olds who find out the minute the law allows almost always regret it.

"It's like a Pandora's box, once it's out you can't put it back, so you need to be really sure about why you are doing it and what you're going to do with the information. Do you tell your friends? If you're positive, every time you meet a new boyfriend or girlfriend do you tell them straight away?

"To think you could just post off a sample and they send it [the results] back to you, I think, would be really scary."
Emily*, 21, lost her father to Huntington's and planned to get tested at 18, which she did. But after consulting a genetic counsellor, she decided not to find out the results.

"You don't really think about the bigger picture, that even though it's a 50/50 chance it could be good, it could also be bad, and then you've got to live with that forever. I'm pleased I waited, because I definitely wasn't ready."
For Mendelian diseases controlled by a single gene, such as Huntington's and cystic fibrosis, genetic testing can be a powerful and accurate risk predictor. But for most diseases the role of genes is far less clear-cut.

Where hundreds or thousands of genes contribute to a disease, each increases risk in a tiny way, says Martin Kennedy, a Carney Centre for Pharmacogenomics professor.

"The actual predictive value at the moment for anything other than Mendelian disease is pretty limited, in my view ... There's not that much that is grippingly useful right now ... Genes aren't the whole story - there's your interaction with the environment. Medical advice is still eat well, don't smoke, exercise."
While genomic tests are potentially useful for the much-heralded future of personalised medicine, in which treatment will be tailored to genetic profiles, there's still a major gap between what genetics predict and what actually happens.

One of the most common genetic mutations is linked to iron-overload disease haemochromatosis, but many who carry the defective gene never develop the condition. And while about one in five people with blood-clotting problems carry the genetic mutation associated with venous thrombosis, about 7 per cent of the population carry the mutation but never develop clots. 23andme assesses both haemochromatosis and venous thromboembollism risk.

In the case of pharmacogenomics, or the way genes influence how a patient reacts to a drug, what you had for breakfast can have more impact than your genetic profile, Kennedy says.
Nonetheless, he has submitted a saliva sample to the New Jersey Coriell Institute's personalised medicine research project and believes DTC testing companies have done much to raise the public profile of genetics.

Professor Mac Gardner, Capital & Coast District Health Board medical geneticist, undertook a 23andme test out of professional curiosity. While generally impressed with the quality of information and interpretation provided, there were still constraints on its usefulness.

Tests such as those offered by 23andme look for DNA markers rather than analysing the entire genome sequence. Genome-wide association studies identify markers that appear more often in people with a given disease. The critical question, says Gardner, is how many markers you test for, and which ones.

A 2006 US Government Accountability Office study sent identical samples to four companies, with some wildly varying results. One donor was told he was at below-average, average, and above-average risk for prostate cancer and hypertension. "That was inadequate science, because they hadn't looked at enough markers," Gardner says.

The complexity of the risk information also presents problems, he says. Whereas in the health system the geneticist or genetic counsellor acts as interpreter, guiding patients through the process, consumers left to draw their own conclusions risk under or over-interpreting the data.

"The power of taking a pencil and paper and drawing up an old-fashioned family tree may convey considerably more useful information than sending your DNA to San Francisco."

But is this just a paternalistic medical profession fighting to retain control of medical information? Perhaps doctors underestimate human resilience.

Sarah Lee might be expected to oppose DTC genetic testing, having received what most would consider crippling news when she sent a saliva sample to Navigenics in 2009. Having watched Alzheimer's erode away her father Ray Smith, the 45-year-old Aucklander wanted to know if she might suffer the same fate.
When the results came back, her risk was estimated at 75 per cent, meaning she had inherited a predisposition from both her mother's and father's side, despite no family history in her maternal line.

But rather than giving up on life, Lee tried to change the things she could, quitting her stressful corporate risk-manager job to work part-time in business administration.

"Anybody who is a glass-half-empty person, I'd say don't do it, because they are going to see it as the man with the hood knocking at the door. Whereas the glass-half-full person is going to take it as 'Ok, what in my life can I change?'

"It's not a death sentence or a life sentence, it's just 'this is what is possible'."

Tim* has an aunt and mother with Huntington's, and his grandmother died of it. When he and his wife decided to have children last year he wanted to find out if he had the defective gene, so he could prevent passing on the disease. The news he was positive stunned him speechless and he has chosen not to tell his employers.
"You thought you could prepare for that sort of news, but I don't know if you could ... It hit us harder than we thought it would initially, but longer term we seem to be doing better than we thought we would.

''Wellington tech blogging pioneer Richard MacManus undertook genomic testing with 23andme last year and was so pleased with the experience he offered to buy the tests for his family.Any concerns about the implications of bad news were outweighed by curiosity, even in the case of incurable diseases such as Alzheimer's and Parkinson's, which you have the option not to view.

''If I hadn't unlocked them, I would always wonder about it. So for me, knowing was more comforting than not.''

While MacManus' test did not turn up anything startling, it did pick up an elevated risk of type one diabetes: 4.1 per cent - four times the average risk of 1 per cent.  That came as no surprise, as he developed late-onset diabetes five years ago. MacManus surmises that if he had known of his risk he would have avoided sugary foods and tried to exercise more.

''Whether that would have made any difference, I don't know.''The head of Auckland University's medical genetics group, associate professor Andrew Shelling, sees the risk of a patronising medical profession telling patients they're too fragile or dumb to handle the knowledge.And he has seen first hand the power of information, having carried out some of New Zealand's first testing for breast cancer mutation BRCA, which had been ''incredibly empowering'' for families who had seen generations of their women die young.

But there are still niggling concerns: all screening carries a risk of false positives, and false negatives, causing people to either worry unnecessarily or to believe themselves low risk when they're not; risk assessments are only as good as the research, and the science remains immaturecompanies such as Pathway Genomics. However, a survey last year found only 5 per cent of New Zealand family doctors thought GPs were best placed to give genetic counselling following a DTC test.fudcMacManus also has a professional interest in genomic testing - he figures if your body is a computer, your genome is the software that powers it.

So he's writing a book about how we might use technology to reprogram the body.That feeds into the much-vaunted brave new world of personalised medicine, in which everyone's genome is sequenced, and healthcare tailored to your genetic profile. Carrier status for diseases such as cystic fibrosis might even be used to find a mate, says ntsGAndrewnte Shelling: ''You can imagine a world where there might be an iPhone app that you shine around at the bar and work out genetic compatibility.''But how realistic is that vision?Price will not be the limiting factor. Next stop is exome sequencing, which is more manageable than a full genome sequence but would provide more comprehensive genetic risk information than 23andme.

New player DNA DTC is already offering exome sequencing straight to the consumer for about $1000 - less than many targeted tests for a single disease.So it's an economic no-brainer to test everything in one hit. The question is how do you do that responsibly, without sending patients into unnecessary panic and over-burdening the health system?ntsGMartin nteKennedy's ''mad plan'' is for everyone to have either an exome or complete genome analysis at birth. That information, including sensitivity to particular drugs, would become part of your electronic medical record.

However, Paul Ockelford, Auckland haematologist and Medical Association chairman, argues just because we can, doesn't mean we should.Take super sensitive CAT scans - highly effective at ruling out various causes of abdominal pain. They often pick up unrelated minor abnormalities which then have to be investigated further.''Where do you want to stop and how much do you want to worry about this?''

Vocal critic of DTC testing Dee Mangin, Otago University's associate professor of public health and general practice, rails at the hijacking of the term ''personalised medicine'' to mean genomic medicine.

''My idea of personalised medicine is that you take what medical research has to offer, then you look at the patient and the other illnesses they have and you look at their life and their priorities and you come to a shared decision about whether to use particular treatments or not. It's not running someone's genome through a computer.''

But Auckland cardiologist Patrick Gladding is ''absolutely convinced'' that genomic testing will underpin the healthcare of the future. Gladding acknowledges that consumer-controlled testing risks fuelling the self-absorption of the worried well, and he believes the public should not know everything. Like Kennedy, he sees the most likely scenario as a genomic test at birth highlighting the top five areas of interest, which the patient can then monitor through their lifetime.

While most of the DTC testing debate centres on accuracy, value and ethics there are also practical and privacy implications. In the United States, special legislation was passed in 2008 to prevent discrimination in insurance or employment based on genetic test results. But New Zealand has no such legal protection. The health insurance industry presently has a moratorium on tailoring premiums to risk based on genetic test results, but there is still a legal obligation to declare the fact you have been tested.

And if you take out life insurance after a genetic test, that could form part of your premium assessment, says Financial Services Council chief executive Peter Neilson. Otherwise those with a significant risk of dying younger would all take out insurance, pushing up prices for everyone.There are undoubtedly benefits in knowing your genetic risks if you can act on that information. But Shelling gives sage advice: ''Go in with your eyes wide open. You are likely to receive a whole lot of slightly dull information. Occasionally, you might find out something very interesting and there's always the risk you might find out something quite sinister. Think about how you would react if you did find out something that was going to affect the rest of your life.''

*Not their real names.

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