A version of a gene common in many populations 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 was presented Oct. 19 at the annual meeting of the American Society for Human Genetics in Baltimore.
Using information and samples from two earlier studies of people at high risk for cardiovascular disease, the team discovered that those with at least one copy of a specific variation of this gene, called klotho, are almost twice as likely to have undetected atherosclerosis than others. Startlingly, smokers had an additional fourfold increase in the risk of having atherosclerosis 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, 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," he says.
"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 earlier this year the Hopkins researchers found that several common varieties exist. Moreover, they showed that roughly 2-1/2 percent of the population has two copies of the "bad" version, known as KL-VS, while another 25 percent carries one "bad" copy and one copy of another version.
"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," Dietz says. "That crucial information makes the possibility of genetic testing worth considering."
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 like atherosclerosis and osteoporosis that are practically unheard of in the furry critters.
Intrigued, Dietz and his colleagues, including Dan Arking, now a postdoctoral fellow, determined that the KL-VS version of the gene 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, and more than 40 percent of the 12 people with two copies of KL-VS did, too. 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. Smokers with at least one KL-VS copy had more than seven times the risk of nonsmokers without the gene variant. However, high levels of "good" cholesterol, known as HDL, significantly reduced the risk associated with the KL-VS variant.
"What is particularly exciting," Arking says, "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, the researchers say.
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.