Celera Publishes Three Papers Demonstrating that Carriers of a Gene Variant are at Elevated risk of Coronary Heart Disease Which is Virtually Eliminated by Statin Therapy
New studies in more than 30,000 individuals indicate that carriers of the KIF6 gene variant have up to a 55% increased risk of a coronary event
A laboratory-developed test is being validated at Berkeley HeartLab based on these research findings and is expected to be offered in the coming months
Alameda, CA - January 21, 2008
Celera (NYSE:CRA), an Applera Corporation business, today announced three publications reporting that a variant of the gene encoding kinesin-like protein 6 (KIF6) is associated with up to a 55% increased risk of primary and recurrent coronary heart disease (CHD) events. These research studies included a total of more than 30,000 individuals, among whom about 60% are carriers of this risk variant. These research studies also showed that the excess risk associated with the KIF6 variant was virtually eliminated by pravastatin (Pravachol®) therapy and that high-dose atorvastatin (Lipitor®) therapy reduced risk in carriers of the KIF6 risk variant more effectively than moderate-dose pravastatin therapy in acute coronary syndrome patients. These papers are expected to appear in the January 29, 2008 edition of Journal of the American College of Cardiology, and are currently available on the publication’s website at http://content.onlinejacc.org/in_press.dtl.
The increased risk of clinical events observed in KIF6 carriers and its reduction by statin therapy was independent of other well-known CHD risk factors, including smoking, hypertension, cholesterol level, age and sex, further supporting the conclusion that a KIF6 gene variant is a new, independent predictor of risk for CHD and clinical benefit from statin therapy.
“These findings make a compelling case for testing for KIF6 status in the substantial number of Americans considered to be at moderate risk of developing heart disease based on traditional risk factors such as cholesterol levels and blood pressure,” said Kathy Ordoñez, President of Celera. “Moreover, knowledge that the elevation in heart disease risk conveyed by the KIF6 gene variant can be virtually eliminated by statin therapy provides physicians with new genetic information in considering treatment options for their patients and also supports long-term therapy compliance among patients carrying the risk variant.”
Berkeley HeartLab, which was recently acquired by Celera, is expected to offer a laboratory-developed test for the KIF6 gene variant in the coming months. Celera plans to pursue regulatory registration for a diagnostic product based on the same research findings.
“Berkeley HeartLab is validating a laboratory-developed test based on these research findings to identify individuals carrying the KIF6 gene variant,” said Cleland Landolt, M.D., Chief Medical Officer at Berkeley HeartLab, a subsidiary of Celera. “This test will be based on Celera's consistently replicated discoveries as reported in multiple publications, and this is expected to be an important addition to our core competence in a personalized cardiovascular disease management program. ”
“ These studies indicate that carriers of the KIF6 gene variant are both at higher risk of coronary heart disease and this risk is reduced by statin therapy,” said Frank M. Sacks, M.D., Professor of Cardiovascular Disease Prevention , Harvard School of Public Health and Professor of Medicine, Brigham and Women’s Hospital and Harvard Medical School, and the senior author of one of the papers. “This is one of the first gene variants that has been associated with the pharmacodynamics of statin therapy in multiple studies , providing new genetic information that can assist physicians in making personalized cardiovascular treatment decisions for their patients. The important thing is that carriers are not only at greater risk but that statins lower the risk especially well compared to noncarriers. Since reduction in LDL does not explain the KIF6 effect on cardiovascular disease, a KIF6 test could give physicians new information to identify patients in whom statins work particularly well. This is really personalized medicine based on genetics for a common condition.”
“These findings provide us with a better understanding of genetic predisposition to coronary heart disease and should motivate further studies that explore the biological role of the kinesin motor encoded by KIF6 in the development of coronary heart disease,” said Professor James Shepherd, M.D., Ph.D., Chairman of the Department of Biochemistry, University of Glasgow and Glasgow Royal Infirmary, and a co-author of one of the papers.
The first paper demonstrates that a gene variant in the KIF6 gene predicts increased risk for recurrent CHD events (the CARE study) and primary CHD events (the WOSCOPS study) 1. This risk was virtually alleviated by statin therapy (pravastatin, or Pravachol) in those carrying the gene variant. In a second paper, a genetic sub-study of PROVE IT―TIMI 22 2 showed that high-dose atorvastatin (Lipitor) was more effective at reducing the risk of CHD events in carriers than in noncarriers. This differential response to treatment occurred despite similar reduction of lipid levels in carriers and noncarriers. These results show that the clinical benefit has a statin class effect rather than a specific drug effect since the two different statins tested had different characteristics: one hydrophilic and the other lipophilic. A third paper in the same issue of the journal reports that this gene variant (KIF6) was also associated with CHD events in the Women’s Health Study (WHS), a large prospective study of women 3.
The KIF6 gene variant has also predicted CHD in two other prospective studies that have been published in recent months by Celera and its collaborators. This gene variant was associated with increased risk for CHD in Caucasian and African American participants of the Atherosclerosis Risk in Communities (ARIC) study 4 (a study of 13,907 middle aged Americans) and it was associated with increased risk for myocardial infarction (MI) in the Cardiovascular Health Study (a study of 3,849 Americans, aged 65 or older) 5. Thus, this KIF6 gene variant has been associated with CHD events in studies of more than 49,000 people.
About the CARE and WOSCOPS studies1
The first of the three papers was based on two prospective, randomized clinical trials that assessed the effect of pravastatin on the prevention of CHD events: the Cholesterol and Recurrent Events (CARE) study and the West of Scotland Coronary Prevention Study (WOSCOPS). The association between increased risk of coronary events and the Arg variant of the KIF6 Trp719Arg polymorphism in both CARE and WOSCOPS was independent of traditional CHD risk factors, which was also true for the other studies mentioned in this press release. Further, the increased risk of MI and CHD associated with this polymorphism was significantly reduced in individuals who were treated with pravastatin, a lipid-lowering compound with anti-inflammatory properties.
The genetic association studies were performed among 2,715 patients of the CARE trial and among 1,561 patients of a nested case-control study of the WOSCOPS trial. Carriers of the 719Arg allele of the KIF6 gene had 50% higher incidence of MI in CARE and 55% higher risk of CHD in WOSCOPS, compared with noncarriers. This genetic information appears to complement traditional risk factors because these risk estimates are adjusted for traditional risk factors including subject’s age, baseline LDL-C (“bad” cholesterol) level, baseline HDL-C levels (“good” cholesterol) level, and history of smoking, hypertension, and diabetes.
The CARE study was led by Frank M. Sacks, M.D. and by Eugene Braunwald, M.D., Distinguished Hersey Professor of Medicine, Harvard Medical School. The WOSCOPS study was led by Professor James Shepherd. Olga A. Iakoubova, M.D., Ph.D., Principal Investigator at Celera, was the lead author of this genetic study into CARE and WOSCOPS, which was conducted with collaborators at Brigham and Women’s Hospital, Harvard Medical School and Harvard School of Public Health, Boston, MA, University of Glasgow and Royal Infirmary, Glasgow, United Kingdom, and Bristol-Myers Squibb Pharmaceutical Research Institute.
About the PROVE IT-TIMI 22 study2
The second paper tested 1,778 acute coronary syndrome patients within the Pravastatin and Atorvastatin Evaluation and Infection Therapy - Thrombosis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial and found that benefit from intensive, compared with moderate, statin therapy wassignificantlygreater in the 59% of the cohort who were carriers of KIF6 719Arg than in noncarriers. Therefore, only 10 carriers of the KIF6 719Arg variant needed to be treated with intensive statin therapy to prevent one CHD event; in contrast, the number needed to treat for noncarriers was 125 . The benefit of intensive therapy in carriers was significant as early as day 30 of therapy.
The PROVE-IT-TIMI 22study was led by Christopher P. Cannon, M.D., Associate Professor of Medicine at Harvard Medical School and senior investigator of the Thrombolysis in Myocardial Infarction (TIMI) Study Group and by Eugene Braunwald, M.D., C hairman of the TIMI Study Group. Olga A. Iakoubova, M.D., Ph.D., was the lead author of this genetic study, which was conducted with the collaborators at the TIMI Study Group at the Brigham and Women's Hospital, and other collaborators at the TIMI Study Group, Cardiovascular Division, at Brigham and Women’s Hospital, Harvard Medical School, and Bristol-Myers Squibb Pharmaceutical Research Institute.
About the Women’s Health Study3
The third paper investigated the association between the KIF6 variant and risk of CHD among 25,283 initially healthy Caucasian women, age 45 and over. These women were part of the Women’s Health Study, and were prospectively followed over a 12 year period for incident cardiovascular events. Carriers of the 719Arg variant had a 34% higher risk of MI and 24% higher risk of CHD compared with noncarriers. Dov Shiffman, Ph.D., Principal Investigator at Celera, and Daniel I. Chasman, Ph.D., Associate Geneticist, Brigham and Women's Hospital and Assistant Professor of Medicine, Harvard Medical School Boston, MA., were the lead authors and contributed equally to this study. The senior author of this study was Paul M. Ridker, M.D., Director of the Center for Cardiovascular Disease Prevention, Division of Cardiology, at Brigham and Women’s Hospital and Harvard Medical School , Boston , MA.
About Coronary Heart Disease
Coronary heart disease includes acute myocardial infarction (MI) and other acute ischemic (coronary) heart disease. This year an estimated 700,000 Americans will have a new coronary attack. About 500,000 will have a recurrent attack (ARIC, 1987–2000, NHLBI]. It is estimated that an additional 175,000 silent first heart attacks occur each year.) Coronary heart disease caused 1 of every 5 deaths in the United States in 2006. CHD is the largest killer of American males and females. Every 26 seconds an American will suffer a coronary event, and every minute someone will die from one. About 41 percent of those who experience a coronary attack will die within a year.
About Applera Corporation and Celera
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1Iakoubova, OA, et al (2007). Association of the Trp719Arg polymorphism in kinesin-like protein 6 with myocardial infarction and coronary heart disease in two prospective studies: CARE and WOSCOPS. JACC, In press.
2Iakoubova, OA, et al (2007). Polymorphism in KIF6 gene and benefit from statins after acute coronary syndromes. JACC , In press.
3Shiffman, D, Chasman, D, et al (2007) A kinesin family member 6 (KIF6) variant is associated with coronary heart disease in the Women’s Health Study, JACC, In press.
4Bare et al., (2007) Five common gene variants identify elevated genetic risk for coronary heart disease. Genetics in Medicine 9:682-689
5Shiffman D. et al., (2007) Association of gene variants with incident myocardial infarction in the Cardiovascular Health Study. Arteriosclerosis, Thrombosis, and Vascular Biology - November, 2007.
David Speechly, Ph.D.
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