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Published online: 10 April 2007; | doi:10.1038/news070409-4
Tests for heart-disease risk could be misleadingGenetic variants may not really be linked to heart troubles after all.Heidi Ledford 
| Tangled web: it's hard to tease out genetic contributions to complex conditions like heart disease. Punchstock |
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A
study looking at 85 genetic variations thought to be linked to heart
disease — some of which are already used in clinical tests — has been
unable to confirm that any of these links are real.
The findings, published this week in the Journal of the American Medical Association1,
highlight a recurring problem as geneticists struggle to extend their
reach to complex diseases such as diabetes, obesity and heart disease.
These diseases cannot be attributed to mutations in a single gene or
genetic pathway, and teasing each genetic contribution from the tangled
knot of environmental and genetic factors is so challenging that it can
sometimes go wrong.
Often,
researchers have found, preliminary results from relatively small
studies turn out to be false positives, and are overturned when
followed up in larger populations. This survey of heart disease genes
may be such a case.
At
the same time, the push for personalized medicine — the long-promised
ability to tailor medical care to an individual's genetic make-up — has
created an incentive for companies to rush from preliminary results to
clinical tests, researchers say. The result can be misleading tests,
they warn.
The weakest link
Thomas
Morgan of the Washington University School of Medicine in St Louis,
Missouri, and his colleagues culled through the literature to find
published accounts of genetic risk factors for acute heart disease.
They then tested 1,461 Caucasian patients from Kansas City, Missouri,
hospitals for these genetic quirks, and compared those results to the
incidence of heart disease.
They
found no significant association between any of the specific gene
variants and development of acute coronary syndrome. "We were unable to
unequivocally validate even a single one," says Morgan. "This raises
serious questions." At least 7 of the 85 gene variants looked at by
Morgan are used in commercial genetic tests, which may be ordered and
used by physicians on their patients as they see fit. These specific
tests are not typically available for direct purchase by individuals.
Morgan
thinks his survey is more complete than previous assessments, thanks to
the larger sample size. It is possible that other researchers have also
found no link between these genetic factors and disease, he adds, but
they may have found it hard to publish negative results.
Pressure
to produce a positive association can encourage some researchers to
skew their data, he notes, analysing just the right subgroups that will
give them the association they are looking for. "Even though the plan
may be to analyse all cases and all controls, if nothing comes up with
that analysis, someone will say, 'let's look at what happens in all
women or all men'," agrees John Ioannidis, an epidemiologist at the
University of Ioannina, Greece. That decreases the effective size of
small studies even further, leaving them more vulnerable to random
chance.
Testing times
Robert
Zee, a geneticist at Harvard Medical School in Boston, Massachusetts,
who published the initial work on three of the gene variants that
Morgan studied, argues that Morgan's results are just as open to fault.
"One needs to interpret all of these genetic findings — including this
particular paper — with caution," he says. "We still cannot yet claim
that none of these would be a suitable risk factor."
Morgan's
study, argues Zee, is itself quite small by today's standards, and it
evaluated markers that were discovered more than two years ago. Since
then, the field has moved on to studying larger populations of patients
— sometimes on the order of tens of thousands — using genome-wide
screens for subtle genetic differences.
But
despite the larger data sets, Ioannidis points out that some of these
studies have also been difficult to reproduce. Possible genetic risk
factors for Parkinson's disease, for example, were later knocked down
by follow-up studies.
All
of this highlights the importance of spending the time and money to
validate initial results before they are transported to the clinic,
says Morgan. "We need to value validation as much as we value the
discovery process," he says. "I was told by some that I was wasting my
time going back over things that were already known."
Meanwhile,
the availability of genetic tests that have not been clinically
verified could harm consumers, says Ioannidis. "If you are given the
wrong information, you can really go down the wrong path," he says.
"You can get deeper into having medical tests and medical care and
perhaps even treatment that you might not need."
References
- Morgan T. M., Krumholz H. M., Lifton R. P. & Spertus J. A. J. Am. Med. Assoc.,
297
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1551
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1561
(2007).
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