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Mutation Linked to Early-Onset Atherosclerosis May Prompt Increased Statin Use; No Dx Exists


Researchers at Howard Hughes Medical Institute and Johns Hopkins School of Medicine said a common gene mutation may be a “potent risk factorEfor early-onset atherosclerosis.

Their discovery, if validated, may prompt the development of a molecular diagnostic for atherosclerosis Ewhich would in turn draw the mutations into the market for hyperlipidemia drugs, a popular therapeutic option of atherosclerosis. That market, which is heaving from competition among big pharma, is expected to exceed $16 billion this year, according to most estimates [See SNPtech Reporter, Jan. 31, 2003].

Using data from two earlier studies of people at high risk for heart disease, the Howard Hughes scientists, led by associate investigator Hal Dietz, found that individuals with at least one copy of a specific version of a gene called klotho are “almost twice as likelyEas others to have undetected atherosclerosis.

“This gene variant appears to be a potent risk factor for atherosclerosis,E said Dietz, who is also a professor of molecular biology and genetics at Johns Hopkins and a member of the school’s McKusick-Nathans Institute for Genetic Medicine.

Humans have two copies of the klotho gene, but last year Dietz’s team found that one of several common versions of it was linked to early death from all causes. The researchers also showed that approximately 2.5 percent of the population has two copies of this version, known as KL-VS, while 25 percent carry one 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,Esaid Dietz, who adds that no test is commercially available today.

In 1997, scientists in Japan were the first to learn that variations in klotho caused mice to age quickly and to develop conditions similar to atherosclerosis and osteoporosism Econditions that “are practically unheard ofEin mice.

Piqued by this finding, Dietz and his colleagues determined that KL-VS is “more commonEin people who die before the age of 65. Searching for an explanation of how klotho could reduce life expectancy, the researchers turned to two ongoing Hopkins studies ESIBS-I and SIBS-II Eoriginally designed to check for undetected atherosclerosis in apparently healthy siblings of people hospitalized for cardiovascular disease before the age of 60.

Through these studies, Dietz’s team analyzed data from more than 900 people aged 39 to 59. The researchers looked into which klotho variants each participant had and linked them to the individual’s clinical diagnosis and risk factors, which had been gathered as part of the older studies.

The first study, SIBS-I, included 520 ”apparently healthyEsiblings of hospitalized patients, 97 of whom were found to have undetected atherosclerosis. In this group, of 373 participants with two so-called good copies of klotho, roughly 15 percent were found to have undetected atherosclerosis. Of the 135 people with one copy of the KL-VS version of the gene, about 25 percent had the condition. Furthermore, of the 12 people with two copies of KL-VS, roughly 40 percent were found with undetected atherosclerosis.

The SIBS-II group, meantime, found that 56 of 436 participants had undetected atherosclerosis. Similar results were seen in SIBS-II patients as was found in the SIBS-I group. Results of the study appear in this month’s issue of the American Journal of Human Genetics.

The results have led the team to believe that a molecular diagnostic can become a realistic endpoint Ea step that would likely spur even greater use of statins and other drugs prescribed to treat components of atherosclerosis. In fact, after anti-platelet therapies, statins are the second-most-prescribed class of drugs in atherosclerotic patients, according to British pharmaceutical research firm LeadDiscovery.

Plus, raising HDL levels Ea function of statins Emay protect against the “detrimental effectsEof the klotho mutation, according to Dan Arking, a study co-author.

“For this particular type of mutation, a molecular diagnostic test is readily achievable,EArking told SNPtech Reporter. “The technology already exists; it’s a matter of simply taking the time and infrastructure to do a high-throughput, high-accuracy method.EToday, physicians rely on a combination of symptoms, arteriography, or Doppler ultrasonography to diagnose atherosclerosis.

Grain of Salt

To be sure, researchers don’t know how klotho increases the risk of atherosclerosis. What is known is that the klotho gene expresses a protein that “seems relatedE to beta-glycosidases. According to Arking, these enzymes, which are thought to be involved with cell signaling and protein trafficking, have been shown to incite the klotho gene to regulate angiotensin-converting enzyme and plasminogen-activator inhibitor Ewhich are involved in a number of cardiovascular phenotypes. The KL-VS gene is found to trigger two changes in the protein’s sequence that seem to influence how cells secrete the protein and how well it functions, the researchers said. However, no specific target for the klotho protein has been found.

“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,Esaid Dietz.

Arking said that “an important next stepEwould be to organize a prospective, double-blind study “to see whether there is a specific protective effect of raising HDL levels. I think this would be therapeutically extremely relevant.E



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