37, 38 Determining the function of 9p21 is further complicated by the observation that the risk variant is not present in the mouse P450 inhibitor genome, the favorite animal model for assessing gene function. Harismendy et al. had suggested that interferon-gamma may mediate the risk of 9p21 for CAD.39 However, we have recently shown that interferon-gamma acts independently of the 9p21 risk variant.40 All studies have consistently shown Inhibitors,research,lifescience,medical that the 9p21 risk variant is associated with atherosclerosis

and not with MI.30, 41-43 Several studies have also indicated that the 9p21 risk variant is associated with progression of coronary atherosclerosis as suggested by the correlation between the number of vessels involved and the number of copies of the 9p21 risk variant.41, 43 However, there are other

studies that have not confirmed the correlation between 9p21 and progression of CAD.42, 44, 45 Genetic Risk Variants and Management of CAD Where do these genetic risk variants fit in the management of CAD? Currently, the answer would be that they do Inhibitors,research,lifescience,medical not. One might argue that until there is some therapy to alter their risk, why Inhibitors,research,lifescience,medical would one screen for these genetic risk variants? If one has to await the development of drug therapy, it could certainly be 10 years away other than what has already been identified for PCSK9 or antiplatelet therapy for blood groups A and B. One approach to incorporating independent genetic risk variants such as 9p21 into the management Inhibitors,research,lifescience,medical of CAD is on the basis of increased burden of risk as outlined by the Adult Treatment Panel III (ATP III). Currently, the ATP III recommends that LDL-C ≥ 190 mg/dL be reduced in individuals with one other risk factor and Inhibitors,research,lifescience,medical that LDL-C ≤ 160 mg/dL be reduced in those with two other risk factors. One of these other risk factors could be an independent genetic risk factor such as 9p21, since there is universal agreement that

9p21, like the 34 other genetic risk factors, is independent of conventional risk factors. The ATP panel could then assess whether individuals positive for one or more of these genetic risk variants should have LDL-C treated since it provides for an independent risk factor. It is important to note that in individuals with Unoprostone premature CAD, 9p21 is associated with a 2-fold increased risk—greater than the risk from smoking or that associated with a moderate increase in blood pressure or plasma LDL-C. The Hope for the Future The challenge for the next decade will be to identify the molecular mechanisms mediating the risk of those genetic risk variants that do not act through known conventional risk factors. There is good evidence that several of these genetic risk variants predispose to CAD through inflammatory pathways.19, 46 This would appear to be a major pathway in keeping with previous epidemiological suggested evidence.