Celera Corporation announced the publication of a review article on the KIF6 gene variant as a predictor of risk of coronary heart disease (CHD) and reduction of CHD events from statin therapy.

This review of multiple studies of over 50,000 people included a meta-analysis of 7 prospective studies showing that a variant of the KIF6 gene is strongly associated with increased risk of CHD (P value = 1×10-6). These included the results of genetic studies of 4 landmark prospective, randomized clinical trials, the gold standard for clinical research, in which it was found that statin therapy significantly reduced CHD events in KIF6 719Arg carriers, but not in noncarriers. This review has been published ahead of print in the American Journal of Cardiology, and is currently available on the publication’s Web site.

The article summarized multiple independent studies conducted over several years that involved collaborations with a number of academic institutions. Results from prospective studies showing that the KIF6 gene variant was an independent predictor of risk of CHD were reviewed. These studies included the Atherosclerosis Risk in Communities (ARIC) study of 12,556 middle-aged Caucasians and African Americans, the Cardiovascular Health Study of 4,552 Americans aged 65 or older, and the Women’s Health Study of 25,283 initially healthy women older than 45 years. The increased risk of CHD events observed in KIF6 carriers was independent of other well-known CHD risk factors, including age, sex, smoking, hypertension, and cholesterol.

The review also summarized results that indicated statin therapy significantly reduced coronary events in carriers of the KIF6 719Arg variant, but not in noncarriers. Three of these clinical trials assessed the effect of pravastatin (Pravachol®) on the prevention of CHD events: the 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). 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 have only been demonstrated with atorvastatin and pravastatin therapy.

The review article further detailed findings that the number of people needed to be treated with a statin to prevent one CHD event was 10 to 20 in KIF6 carriers compared to >80 in noncarriers, suggesting that KIF6 carriers could obtain greater benefit from statin therapy.

“We are pleased with the publication of this comprehensive summary of our KIF6 findings,” said John Sninsky, Ph.D., Vice President of Discovery Research at Celera. “Recently, questions have been raised regarding the substantial investment in genetic studies, including large scale genome-wide association studies (GWAS), and whether these studies have been successful in impacting medicine to date. We believe that part of the explanation for why these studies have not discovered more markers for both disease risk and drug response is that such studies often use a design that includes case and control subjects who may be undergoing drug therapy that mitigates the relevant disease risk. For example, if one were to conduct a case-control study to identify gene variants associated with elevated blood pressure among patients on anti-hypertensive drugs, we believe it is unlikely that such risk variants would be found, and indeed this has been shown by Tobin et al1.

“In typical case-control studies such as the Ottawa Heart Study, some of the cases had taken a statin prior to their event,” added Dr. Sninsky. “In that study, no association was found between KIF6 and arteriographic evidence for a >50% coronary artery narrowing, which is a different clinical phenotype than the clinical events of CHD examined in the previous KIF6 studies referenced above. Of note, 89% of the cases in the Ottawa study were on statin therapy, which Celera believes may have had an effect on the lack of an association with risk in KIF6 carriers.

“The investigation of the KIF6 variant described in the review article differs from most of the recent GWAS case-control studies in two important ways,” added Dr. Sninsky. “First, the association between the KIF6 variant and risk of CHD was investigated in the placebo group of randomized clinical trials of statin therapy, thereby preventing statin use from masking the risk associated with this gene variant. Second, the association between the KIF6 variant and risk of CHD was further replicated in multiple prospective population-based studies, a type of study that minimizes the ascertainment biases that frequently occur in case-control study designs.”

“Like most other genetic variants recently associated with complex diseases, the precise role KIF6 plays in the pathophysiology of disease is still being delineated,” said James Devlin, PhD, Senior Director of Cardiovascular Diseases at Celera.

“The KIF6 gene encodes a member of the molecular motor protein kinesin family; data presented earlier this year suggest a potential role for KIF6 in the inflammatory cells of atherosclerotic lesions, lesions that can develop into vulnerable plaques that may rupture and cause CHD events. We believe these findings provide initial insight into a potential mechanism for the role of KIF6 in CHD.”

Source: Celera