ADAPTED FROM: PETER DAZELEY/GETTY

When Sharlayne Tracy showed up at the clinical suite in the University of Texas (UT) Southwestern Medical Center in Dallas last January, the bandage wrapped around her left wrist was the only sign of anything medically amiss. The bandage covered a minor injury from a cheerleading practice led by Tracy, a 40-year-old African American who is an aerobics instructor, a mother of two and a college student pursuing a degree in business. I feel like I'm healthy as a horse, she said.

Indeed, Tracy's well-being has been inspiring to doctors, geneticists and now pharmaceutical companies precisely because she is so normal. Using every tool in the modern diagnostic arsenal from brain scans and kidney sonograms to 24-hour blood-pressure monitors and cognitive tests researchers at the Texas medical centre have diagnostically sliced and diced Tracy to make sure that the two highly unusual genetic mutations she has carried for her entire life have produced nothing more startling than an incredibly low level of cholesterol in her blood. At a time when the target for low-density lipoprotein (LDL) cholesterol, more commonly called 'bad cholesterol', in Americans' blood is less than 100 milligrams per decilitre (a level many people fail to achieve), Tracy's level is just 14.

A compact woman with wide-eyed energy, Tracy (not her real name) is one of a handful of African Americans whose genetics have enabled scientists to uncover one of the most promising compounds for controlling cholesterol since the first statin drug was approved by the US Food and Drug Administration in 1987. Seven years ago, researchers Helen Hobbs and Jonathan Cohen at UT-Southwestern reported1 that Tracy had inherited two mutations, one from her father and the other from her mother, in a gene called PCSK9, effectively eliminating a protein in the blood that has a fundamental role in controlling the levels of LDL cholesterol. African Americans with similar mutations have a nearly 90% reduced risk of heart disease. She's our girl, our main girl, says Barbara Gilbert, a nurse who has drawn some 8,000 blood samples as part of Cohen and Hobbs' project to find genes important to cholesterol metabolism.

Of all the intriguing DNA sequences spat out by the Human Genome Project and its ancillary studies, perhaps none is a more promising candidate to have a rapid, large-scale impact on human health than PCSK9. Elias Zerhouni, former director of the US National Institutes of Health (NIH) in Bethesda, Maryland, calls PCSK9 an iconic example of translational medicine in the genomics era. Preliminary clinical trials have already shown that drugs that inhibit the PCSK9 protein used with or without statins produce dramatic reductions in LDL cholesterol (more than 70% in some patients). Half-a-dozen pharmaceutical companies all aiming for a share of the global market for cholesterol-reducing drugs that could reach US$25 billion in the next five years according to some estimates are racing to the market with drugs that mimic the effect of Tracy's paired mutations.

Stephen Hall talks about Sharlaynes unusual condition and whether similar cases might lead to a new line of drugs.

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Zerhouni, now an in-house champion of this class of drug as an executive at drug firm Sanofi, headquartered in Paris, calls the discovery and development of PCSK9 a beautiful story in which researchers combined detailed physical information about patients with shrewd genetics to identify a medically important gene that has made super-fast progress to the clinic. Once you have it, boy, everything just lines up, he says. And although the end of the PCSK9 story has yet to be written the advanced clinical trials now under way could still be derailed by unexpected side effects it holds a valuable lesson for genomic research. The key discovery about PCSK9's medical potential was made by researchers working not only apart from the prevailing scientific strategy of genome research over the past decade, but with an almost entirely different approach.

As for Tracy, who lives in the southern part of Dallas County, the implications of her special genetic status have become clear. I really didn't understand at first, she admits. But now I'm watching ads on TV [for cholesterol-lowering drugs], and it's like, 'Wow, I don't have that problem'.

Cardiovascular disease is and will be for the foreseeable future, according to the World Health Organization the leading cause of death in the world, and its development is intimately linked to elevated levels of cholesterol in the blood. Since their introduction, statin drugs have been widely used to lower cholesterol levels. But Jan Breslow, a physician and geneticist at Rockefeller University in New York, points out that up to 20% of patients cannot tolerate statins' side effects, which include muscle pain and even forgetfulness. And in many others, the drugs simply don't control cholesterol levels well enough.

The rest is here:
Genetics: A gene of rare effect

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