Results of research study on the expression of KIF6 in mouse model

Celera Corporation (NASDAQ:CRA) and its collaborators at The University of Washington, WA, and Indiana University, IN, today announced the presentation of data from a research study that investigated the expression of KIF6 in a mouse Celera Corporation model. A key finding was that KIF6 was specifically expressed in macrophages and chondrocytes in mouse atherosclerotic lesions, but not in normal arteries. These data suggest a potential role for KIF6 in inflammatory processes of atherosclerotic lesions, processes that can result in the development of vulnerable plaques that may rupture, leading to coronary events. The research study results were presented on Saturday, April 10, at the 2010 Arteriosclerosis, Thrombosis and Vascular Biology Annual Conference under the auspices of the American Heart Association in San Francisco, CA.

“We believe these findings provide valuable insight into a potential mechanism for the role of KIF6 in CHD.”

KIF6 encodes a kinesin, and the kinesin superfamily of proteins is involved in microtubule-mediated intracellular transport. Previous research has shown that a variant of the KIF6 gene is associated with up to a 55% increased risk of primary and recurrent coronary heart disease (CHD) events in the placebo arms of pravastatin clinical trials, and that this increased risk is virtually eliminated with statin therapy. The current study was designed to investigate the potential roles of KIF6 in atherosclerosis.

"Multiple independent studies have replicated the association of KIF6 with risk for coronary heart disease and event reduction during treatment, but this is the first biological function study that links the KIF6 protein to atherosclerosis," said Thomas White, Ph.D., Chief Scientific Officer at Celera. "We believe these findings provide valuable insight into a potential mechanism for the role of KIF6 in CHD."

Study Details

ApoE-deficient mice develop advanced atherosclerotic lesions in arteries that have many of the morphological features of advanced human atherosclerotic lesions. These advanced lesions are prone to rupture, resulting in a heart attack. Immunostaining of these mouse artery lesions with rabbit antibodies against KIF6 revealed that KIF6 was expressed in macrophages and by chondrocyte-like cells in the lesions. In human lesions from carotid endarterectomy specimens, KIF6 was also found in macrophages in human atherosclerotic lesions.

This study was led by Professor Michael Rosenfeld of the University of Washington, School of Public Health, Seattle, WA, in collaboration with Professor Claire Walczak from Indiana University, Bloomington, IN, and scientists from Celera.

Other research on KIF6

The association between KIF6 and event reduction during pravastatin (Pravachol®) therapy has been demonstrated previously in three prospective, placebo-controlled randomized clinical trials on the prevention of CHD events: the secondary prevention Cholesterol and Recurrent Events (CARE) study; the primary prevention West of Scotland Coronary Prevention Study (WOSCOPS); and the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study. Additionally, a genetic study of PROVE IT-TIMI 22 reported that in patients after an acute coronary syndrome (ACS), high-dose atorvastatin (Lipitor®), compared with standard dose pravastatin, was significantly more effective at reducing CHD events in KIF6 carriers than in noncarriers. To date, the benefits of statin therapy for KIF6 carriers has only been demonstrated with atorvastatin and pravastatin therapy.

The KIF6 gene variant has also been reported to predict risk of CHD in prospective population studies. This gene variant was associated with increased risk of CHD in Caucasian and African American participants of the Atherosclerosis Risk in Communities (ARIC) study (a study of 12,556 middle aged Americans), and with increased risk for myocardial infarction (MI) in both the Cardiovascular Health Study (a study of 4,522 Americans, aged 65 or older), and the Women's Health Study (a study of 25,283 women older than 45 years without a previous history of CHD). Thus, this KIF6 gene variant has been investigated in studies that included a total of approximately 55,000 people.

In a case-control analysis of subjects in the Ottawa Heart Study, no association was found between KIF6 and >50% coronary artery narrowing, which is a different clinical endpoint than the acute CHD event end point examined in the other KIF6 studies referenced above. Furthermore, 89% of the cases in the Ottawa Study were on statin therapy, which Celera believes may have suppressed the excess risk of KIF6 carriers.

The increased risk of CHD events observed in KIF6 carriers has been shown to be independent of other well-known CHD risk factors, including smoking, hypertension, cholesterol level, age, and sex, further supporting the conclusion that the KIF6 gene variant is an independent predictor of risk for CHD.