“BY KNOWING your profile you can take control of your life and your health.”
So says the website of , a UK company offering genetic tests for a variety of diseases, including cancer, osteoporosis and blood clots – in exchange for an £825 fee.
Genetic Health may be one of the first UK companies offering such tests, but it is certainly not alone globally. In recent years there has been an explosion of companies offering consumers a genetic insight into their fate, based on a simple cheek swab or urine sample. In some cases, companies offer personal remedial advice and nutrients to counter the effects of any “bad” genes they identify.
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The companies offering the tests don’t have to have them checked or approved by regulatory agencies. They don’t even have to prove that the tests and advice they offer are scientifically valid or clinically meaningful.
That could be about to change. This week European regulators met in Paris to debate , while in the US – where the majority of genetic testing companies are based – last month to discuss the same issue. “There is now global consensus that gene tests need to be subject to independent pre-market evaluation,” says Stuart Hogarth of the University of Cambridge, who has been assessing the lack of regulation internationally. “In every country, there’s some kind of regulatory gap through which gene tests fall,” he says (see “Neither drug nor device”).
There’s no doubt that genetics influences disease risk to some degree. Several predictive medical tests for single-gene inherited diseases and certain cancers have been exhaustively researched and fully approved by regulatory authorities. These include tests for the BRCA1 and BRCA2 genes, whose presence increases the likelihood that a woman will get breast cancer by between 50 and 80 per cent.
Lifestyle genetics
The difference between these tests and so-called “lifestyle” gene tests for common diseases is that in the case of heart disease, for example, a large number of genes – each of which has only a small influence on disease risk – are likely to be involved, and there may be other confounding factors as well. “żěè¶ĚĘÓƵs are beginning to realise that shared lifestyle and environmental factors might be more important than genetic influences,” says Helen Wallace of GeneWatch, a UK-based genetics watchdog in Buxton, Derbyshire.
“żěè¶ĚĘÓƵs are beginning to realise that lifestyle and environmental factors might be more important than genetic influences”
By exaggerating the impact of genes on such diseases, critics fear that the entire field of genetics could be brought into disrepute. Worse, it may distract people from the simple lifestyle changes they can make to counter their risk of disease.
However, Genetic Health’s founder, Brian Whitley, defends the concept of genetic testing on both scientific and ethical grounds. “We stick to high-quality, large-scale epidemiological studies published in peer-reviewed journals [to decide which genes to test],” he says. “We accept some studies are later refuted, but that’s why we base ours on the strongest and most replicated studies.”
Genetic Health, whose portfolio includes tests for cardiovascular disease, lung cancer, obesity and prostate cancer, bases its profiles on 46 key genes. The role of some of these genes in disease is already relatively well established, such as the ApoE4 gene for cardiovascular risk, the FTO gene for obesity and the F2/V2 Leiden genes for deep-vein thrombosis (see “Killer genes remain elusive”). However, even for ApoE4, doubts exist about its clinical relevance, says Rory Collins, head of the UK’s Biobank project, which aims to clarify how genes, lifestyle and environment interact to cause disease. While the ApoE4 gene variant raises the amount of cholesterol in the blood, potentially leading to blockage of arteries, the jury is still out on the true extent of the gene’s effect on cardiovascular disease, Collins says.
“While the ApoE4 gene variant raises blood cholesterol, the jury is still out on the extent of its effect on cardiovascular disease”
Nor is it clear whether other, as yet unidentified genes compensate for “bad” genes. “They are seeing only a small number of variants and saying that’s the picture, when the real picture is probably much more complicated,” says Gail Javitt of the Genetics and Public Policy Center (GPPC) at Johns Hopkins University in Baltimore, Maryland.
Last month, she and Kathy Hudson, also at the GPPC, co-authored a statement in The American Journal of Human Genetics () calling for the federal government to “ensure the clinical validity of direct-to-consumer tests that make health-related or healthcare-affecting claims”.
The need for better regulation is something that everyone agrees on – Whitley included. He says he would like to see the UK Medicines and Healthcare Products Regulatory Agency (MHRA), which approves drugs and medical devices, regulating his product and others like it. “The MHRA have copies of all our clinical data,” says Whitley. “The science is there, it’s not quackery.”
Genewatch has sent the MHRA a dossier scrutinising the clinical relevance of all the genes listed by Genetic Health. It trawled the scientific literature for each gene and concluded that only three had large-scale randomised trials and meta-analyses to back them up. The MHRA is currently examining Genewatch’s dossier as well as additional evidence submitted by Genetic Health.
Wallace sees Genetic Health as a test case that could herald proper regulation of such companies, as and when they spring up. “The MHRA should be given powers to do pre-market assessments of clinical validity,” she says. Hogarth agrees. “We must keep pressing for reform,” he says. Otherwise, there’s a danger that nothing will happen until there’s a scandal and someone gets hurt through following misguided advice, he adds.
As for the amount and type of evidence regulators would need to make a reliable assessment, this also needs to be thrashed out.
Wallace questions whether any study could definitively link a specific gene to a defined risk of a common disease. “A split is developing between geneticists who think that bigger studies are needed to quantify risk and those who think that the idea of quantifying risk in the general population should largely be abandoned because we already know that most of the effects are too small to be useful for this purpose,” she says.
As an absolute minimum, she believes any study used to justify genetic testing should include more than 5000 people, or be a meta-analysis of similar size. Even then, companies should have to prove – through clinical trials – that any advice or medication they offer actually benefits patients. “Otherwise, how can you know whether it does harm or good,” says Wallace.
Genetics – Keep up with the pace in our continually updated special report.
Neither drug nor device
Predictive gene tests sold directly to the public slip through the regulatory net because they’re neither standard pharmaceuticals nor medical devices – both of which are regulated in most developed countries.
“So how do you ensure companies tell the truth about their products?” asks Stuart Hogarth of the University of Cambridge. What is needed, he says, is for a regulatory agency such as the US Food and Drug Administration (FDA) to step in and pull a product from the market if the test is found wanting, or stop it from coming to market in the first place.
The FDA is currently considering how such tests should be regulated, and is expected to make a decision in the coming months. Meanwhile, in the European Union, a directive on in-vitro testing is being revised and could include provisions for the regulation of consumer gene tests.
The need for regulation is becoming more urgent. Last year, the Genetics and Public Policy Center (GPPC) at Johns Hopkins University in Baltimore, Maryland, compiled a list of 17 . Some focus on skincare, some on athletic potential, some on weight loss and others on more generalised predictions of disease risk. Some offer dietary supplements and others products to remedy “faulty” genes. Suracell, for example, claims to detect gene variants that impair DNA repair and offers customers customised nutrient formulas to compensate.
Suracell was one of four companies criticised last year in an undercover by the US Government Accountability Office (GAO). The other companies investigated – Sciona, Genelex and Market America – were also criticised for misleading consumers by making medically unproven and ambiguous predictions.
In the wake of the GAO report, the US Federal Trade Commission, which monitors suspect trading practices, issued an advising them to be sceptical of companies offering genetic tests. “The advice [they offer] rarely goes beyond standard, sensible dietary recommendations,” it said. The FDA’s Steve Gutman agreed, telling a Senate committee analysing the GAO report: “The tests largely appear medically unproven and useless.”
Killer genes remain elusive
Finding the genes responsible for disease has not been easy – even in the case of inherited disorders involving a single gene mutation, such as cystic fibrosis. Identifying gene variants linked with more common diseases is infinitely more complicated – not least because so many people get them, and they must therefore share very common genetic factors.
Here, we list some of the few genes most strongly implicated in common diseases so far.
• Heart disease: People with a variant of the Apolipoprotein E4 (ApoE4) gene overproduce cholesterol, but the clinical effect is thought to be tiny compared with environmental factors such as smoking, unhealthy eating or lack of exercise.
• Obesity: More than 600 genes have been provisionally linked to obesity, but so far only one has any strong evidence behind it. The FTO gene was recently shown to raise the risk of obesity by 70 per cent in people with two copies of the gene, and added 3 kilograms to their weight compared with non-carriers.
• Deep-vein thrombosis: Two gene variants have been strongly linked to a higher risk of life-threatening blood clots in veins. One is Factor V Leiden – a variant of the gene that makes a blood-clotting protein called Factor V. The other is a mutation of the gene that makes another clotting protein, Factor II.
• Detoxification: Variants of the genes that make liver detoxification enzymes called cytochrome p450s have been linked to a variable ability to break down poisons and drugs. So too have variants of glutathione transferases – enzymes that help clear toxins from the body.
• Breast cancer: The BRCA 1 and BRCA 2 variants raise the risk of breast cancer in women by 50 to 80 per cent. However, of the 32 other gene variants that have been linked to cancer, an analysis last year showed none was valid (Journal of the National Cancer Institute, ).
