Organizations that provide accurate and credible personal genetic testing in a responsible manner to physicians and their patients are pioneering a new path to personalized healthcare.

When will personal genetic testing become integrated into standard medical care? The history of other clinical tests may give us an idea.

As we enter into the holiday season with visions of turkeys and hams, and the anticipation of pure gluttonous goodness with our families, a relevant example of this topic comes to mind: the cholesterol test. 

Many genetic tests are not used to diagnose disease, but rather to identify patients who may be predisposed to developing a disease or being poor responders to specific drugs. Similarly, the cholesterol test is used to identify patients at high risk of developing coronary heart disease.

Today, there is solid scientific evidence and universal agreement that elevated blood cholesterol is a major cause of coronary heart disease, heart attack and stroke, and most people today know about the fact that there is good cholesterol (HDL) and bad cholesterol (LDL). It is instructive to look at the long history of how the link between cholesterol and heart disease was established.

In 1913, Nikolai Nikolajewitsch Anitschkow, a young Russian pathologist, showed that rabbits fed purified cholesterol developed lesions that resembled those of human atherosclerosis. At the time, the discovery was not appreciated because the results could not be replicated in rats and dogs. But, it was not until much later that the researchers realized the reason for the discrepancy was that rats and dogs, unlike rabbits and humans, break down cholesterol very efficiently.

From that point on, the evidence associating cholesterol’s role with negative health impacts increased. In fact, in the 1930s and 1940s, researchers discovered genetic evidence linking families with a history of high blood cholesterol with a high incidence of premature heart attack. Strong epidemiological evidence for the link between high cholesterol and heart disease came from large population studies that began in the late 1940s. The Framingham Heart Study (FHS), which was initiated in 1948 and is still ongoing, sought to identify common factors in cardiovascular disease among 5,000 residents of Framingham, Massachusetts. In 1971, the FHS reported a positive correlation between serum cholesterol and coronary heart disease.

Another link between high cholesterol and negative health impacts came to light in 1958 when Dr. Ancel Keys, the father of the U.S. Army’s K-rations and the Mediterranean diet, analyzed the relationship between diet, lifestyle, serum cholesterol and the incidence of coronary heart disease. The study, famously called the Seven Countries Study, took place between 1958 and 1970 while Dr. Keys was a professor at the University of Minnesota and followed the lives of 12,000 men in Yugoslavia, Greece, Italy, Finland, Netherlands, Japan and the United States. Taking advantage of the different diets in the seven countries, it was possible to show a link between high cholesterol and coronary heart disease, as well as the influence of diet. The study concluded that the countries with diets higher in saturated fat intake had a higher incidence of coronary heart disease.

A third key study linking coronary heart disease to cholesterol levels was the Multiple Risk Factor Intervention Trial (MRFIT). Between 1973 and 1975 a total of 361,662 men between the ages of 35 to 57 with no prior history of heart attack were screened for cholesterol levels and followed for six years. This study showed an increased risk of coronary heart disease with progressively higher cholesterol levels and corroborated, on a much larger scale, the findings of the FHS that a 1 percent increase in cholesterol increased the risk of coronary heart disease by 2 percent.

In 1984, the National Institutes of Health (NIH) convened the Consensus Development Conference on lowering blood cholesterol to prevent disease. The conference panel consisting of physicians, epidemiologists, statisticians and preventive medicine experts examined years of research linking elevated blood cholesterol to coronary heart disease. They concluded that “elevated blood cholesterol level is a major cause of coronary artery disease” and that lowering blood cholesterol levels “will reduce the risk of heart attacks due to coronary heart disease.” This was the first official notice from the NIH that combined the results of various trials into a unified statement.

However, national screening guidelines were not developed until 1988. In response to the findings of Consensus Development Conference, the National Heart, Lung and Blood Institute (NHLBI) launched the National Cholesterol Education Program (NCEP) in 1985. The goal of the NCEP was to educate both physicians and the public about the link between high blood cholesterol and the risk of coronary heart disease and the benefits of lowering blood cholesterol, with the overall aim of reducing illness and death due to coronary heart disease. In 1988 the NCEP released their first Adult Treatment Panel (ATP) report. The ATP included criteria for ‘normal’ cholesterol levels, and guidelines for screening, physician follow-up and treatment based on screening results. ATP I recommended that total cholesterol be measured in all adults over the age of 20, and again every five years after that. Subsequent ATP reports modified these recommendations. The American College of Physicians has also recommended screening guidelines.

Despite these recommendations, as recently as 20 years ago, there were still a few experts who disagreed. For example, in September of 1989, the The Atlantic ran a feature article called “The Cholesterol Myth” by acclaimed author Thomas J. Moore, proclaiming that “lowering your cholesterol is next to impossible with diet, and often dangerous with drugs — and it won’t make you live any longer.”

More than 80 years after the initial rabbit study, the definitive proof that convinced the skeptics and closed the door on debate finally arrived in 1994 in the form of the Scandinavian Simvastatin Survival Study, also called 4S,which clearly depicted that mortality rates from heart disease could be lowered by using a newly discovered drug, statin, to lower the level of blood cholesterol in a manner that was not possible by diet alone.

Just as the simple practice of testing a person’s cholesterol was once debated, the utility of genetic testing is currently being contested.

Much of the media debate has centered on genetic testing for complex diseases, such as prostate cancer or coronary artery disease. Pathway Genomics has selected genetic variants for testing which have been shown in multiple studies to be significantly associated with a person’s predisposition to develop diseases and traits. While there are not yet studies showing improved clinical outcomes for patients who have been tested for these variants, there is evidence to support the use of such tests as a motivational tool to promote healthful lifestyle changes (Kaufman et al., 2010, McBride et al., 2010).

Pathway also offers tests which are supported by strong scientific evidence, some of which are already well accepted by physicians. Our carrier status test includes mutations that are recommended for screening by the American College of Medical Genetics (ACMG) and the American Congress of Obstetricians and Gynecologists (ACOG) in prospective parents of Ashkenazi Jewish descent. Our drug response test includes genetic markers that are recommended for testing on the FDA-approved drug labels of common medications, such as warfarin and Plavix.

Based on the history of one clinical test, the cholesterol test, it is reasonable to extrapolate that personal genetic testing could take a long time before being accepted into standard medical practice, even with evidence of benefit. The debate about the strength of evidence needed to establish clinical utility has and will lead to well-designed clinical studies that will define the uses of the more controversial aspects of personal genetic testing.  In the mean time, there are many genetic tests that are useful today.

Pathway believes that you should not need to wait until the community is in unanimous agreement about the usefulness of genetic testing to find out what information is held within your DNA.

We look forward to being part of the discussion.

Further Reading

Steinberg D. The cholesterol controversy is over. Why did it take so long? Circulation. 1989 Oct;80(4):1070-8. Review. PubMed PMID: 2676235.

Steinberg D. Thematic review series: the pathogenesis of atherosclerosis. An interpretive history of the cholesterol controversy: part I . J Lipid Res. 2004 Sep;45(9):1583-93. Epub 2004 Apr 21. PubMed PMID: 15102877.

Steinberg D. Thematic review series: the pathogenesis of atherosclerosis. An interpretive history of the cholesterol controversy: part II: the early evidence linking hypercholesterolemia to coronary disease in humans . J Lipid Res. 2005 Feb;46(2):179-90. Epub 2004 Nov 16. Review. PubMed PMID: 15547293.

Steinberg D. Thematic review series: the pathogenesis of atherosclerosis. An interpretive history of the cholesterol controversy, part V: the discovery of the statins and the end of the controversy . J Lipid Res. 2006 Jul;47(7):1339-51. Epub 2006 Apr 3. Review. PubMed PMID: 16585781.

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