May 2, 2003 A common version of a gene has been identified as a potent risk factor for early-onset atherosclerosis, report the Johns Hopkins scientists who first linked it to shorter life expectancy in humans. Their report appears in the May issue of the American Journal of Human Genetics.
Using information and samples from two earlier studies of people at high risk for heart disease, the team discovered that those with at least one copy of a specific version of this gene, called "klotho," are almost twice as likely to have undetected atherosclerosis than others. Startlingly, smokers with low amounts of "good" cholesterol had 10-fold greater risk if they also had this gene variant.
"If you knew you had this version of klotho, should you keep smoking? Should you exercise more? Eat better? Lose weight?" asks Hal Dietz, M.D., a Howard Hughes Medical Institute associate investigator and professor of pediatrics and molecular biology and genetics at Johns Hopkins. "This gene variant appears to be a potent risk factor for atherosclerosis.
"You have to be very careful with association-type studies like ours, but what we've seen here is not a subtle trend but a strong observation in two independent study populations," adds Dietz, also a member of Hopkins' McKusick-Nathans Institute for Genetic Medicine.
Atherosclerosis, or so-called hardening of the arteries, is a key risk factor for heart attack and stroke, two of the nation's top killers. Lifestyle changes, such as eating a healthier diet, quitting smoking, exercising more and taking certain drugs, can lower the risk of heart disease and death by reducing cholesterol levels and weight.
Everyone has two copies of the klotho gene (one inherited from each parent), but last year the Hopkins researchers found that, of several common versions of klotho, one was associated with earlier death from all causes. Moreover, they showed that roughly 2.5 percent of the population has two copies of this "bad" version, known as KL-VS, while another 25 percent carry one "bad" copy.
"While KL-VS may increase the risk of dying early, this new study suggests that it's possible to modify that risk by making lifestyle changes, which makes the possibility of genetic testing worth considering," says Dietz, who adds that no test is commercially available at this time.
Japanese scientists were the first to learn that variations in klotho, named after the Greek Fate purported to spin the thread of life, made mice age quickly and similarly to humans, developing conditions similar to atherosclerosis and osteoporosis that are practically unheard of in the furry critters.
Intrigued, Dietz and his colleagues, including Dan Arking, Ph.D., now a postdoctoral fellow, determined that KL-VS was more common in people who die before the age of 65. Searching for an explanation of how klotho could reduce life expectancy, the researchers turned to two Hopkins studies originally designed to check for undetected atherosclerosis in apparently healthy siblings of people hospitalized for cardiovascular disease before the age of 60.
More than 900 people between the ages of 39 and 59 were included in the new analysis. The scientists determined which klotho variants each participant had, and linked that to the person's clinical diagnosis and risk factors, which had been gathered as part of the older studies.
One of these studies, called SIBS-I, included 520 apparently healthy siblings of hospitalized patients, and 97 of them were discovered to have undetected atherosclerosis. The other, called SIBS-II, included only African Americans and found that 56 of 436 participants had undetected atherosclerosis.
For the SIBS-I group, roughly 15 percent of the 373 participants with two "good" copies of klotho had undetected atherosclerosis. Of the 135 people with one copy of the KL-VS version of klotho, about 25 percent had hidden coronary artery disease, as did about 40 percent of the 12 people with two copies of KL-VS. Similar results were seen for SIBS-II.
Overall, those with at least one copy of KL-VS had approximately twice the risk of having atherosclerosis than others. Start adding known risk factors to the presence of KL-VS, and risk really shot up, the researchers discovered.
For example, smokers with at least one KL-VS copy had more than seven times the risk of non-smokers without the gene variant. Smokers who had low (less than 40 mg/dl) "good" cholesterol, or HDL, and at least one copy of KL-VS had about 10 times the risk of comparable individuals without the variant. However, high levels of "good" cholesterol, known as HDL, significantly reduced the risk associated with the KL-VS variant.
"What is particularly exciting," says Arking, "is that we have demonstrated that modifiable risk factors, including hypertension, smoking and HDL cholesterol levels, can modulate the risk imposed by KL-VS."
How exactly klotho increases the risk of atherosclerosis, or exacerbates the effects of smoking, is still unknown. The klotho gene carries the blueprint for a protein that seems related to enzymes known as beta-glycosidases, but no specific target for the klotho protein has been identified. The KL-VS gene results in two changes in the protein's sequence that seem to influence how cells secrete the protein and how well it functions, say the researchers.
The work was funded by the Howard Hughes Medical Institute, the National Institutes of Health and The Johns Hopkins University School of Medicine General Clinical Research Center.
Authors on the report are Arking, Dietz, Diane Becker, Lisa Yanek, Daniel Judge, Taryn Moy and Lewis Becker, all of the Johns Hopkins School of Medicine; and Daniele Fallin of the Johns Hopkins Bloomberg School of Public Health.
Press release on klotho variant's link to earlier death: http://www.hopkinsmedicine.org/press/2002/JANUARY/020114.htm
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