Empowering prevention*

The effect of the identified genetic risk variants on chromosome 9 appears to be in addition to and independent of other known risk factors such as obesity, hypertension, diabetes or elevated blood cholesterol.When it comes to coronary heart disease and MI, understanding risk is the first step in empowering prevention.

Heart disease is the leading cause of death for both women and men in western societies and coronary heart disease is the principal type of heart disease. Worldwide, coronary heart disease kills more than 7 million people each year.  In the US alone 494,392 people died from coronary heart disease in 2002. In 2002, age–adjusted death rates for diseases of the heart were also found to be 30% higher among African Americans than among Caucasians. In 2006, heart disease in the US was projected to cost more than $258 billion, including health care services, medications, and lost productivity.  According to numbers for the years 1999 – 2002 the prevalence of the leading known, but at the same time manageable risk factors for coronary heart disease among persons 20 years and older, were:

In 2003, approximately 37% of adults reported having two or more of the above six risk factors of cardiovascular diseases.  Studies among people with heart disease have shown that lowering high blood cholesterol and high blood pressure can reduce the risk of dying of heart disease, having a nonfatal heart attack, or needing heart bypass surgery or angioplasty.

The Third Report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III, September 2003) explicitly provides a role for emerging risk factors in adjusting the risk assessment as described above.

In a large clinical utility study by Ballantyne’s group showed that adding the deCODE MI™ 9p21 risk variant to traditional risk factors in the ARIC cohort significantly increased the accuracy of MI risk prediction; 18 percent of patients in the intermediate and intermediate-high risk categories were reclassified into higher or lower risk categories, changing their LDL cholesterol target (10).  A study by Humphries group investigating 2742 men in the prospective NPHS trial in the UK showed that the 9p21 risk marker significantly increased the accuracy of MI risk prediction when added to the Framingham risk score (LR  p = 0.01) and 22% of patients changed risk categories (11).

For the purposes as described above the10 year risk estimates of established risk assessment tools such as the Framingham the Reynold’s, or the ARIC score may be multiplied by the relative genetic risk result of the deCODE MI™ test to derive a more complete risk for the next 10 year interval since the genetic risk test is independent of the components used by those tools.

Irrespective if the deCODE MI™ risk results moves a patient between risk categories, you as a physician are likely to have numerous patients with well known risk factors for coronary heart disease, who need to stop smoking, lose weight, get more exercise, improve their diet, and comply with your recommended blood lipid and/or blood pressure lowering medication. Moreover, your efforts to get your patients to change their lifestyle and address known risk factors for coronary heart disease are most likely not always successful. Additional information on which of your patients might also be at increased genetic risk gives your advice added weight and relevance. For your patients the information should increase their incentive to implement and stick to lifestyle modification regimens and prescribed medications that can reduce their chances of getting MI. It can be argued that it is the patient's right to know about all of his/her relevant risk factors. This is especially relevant in light of the difficulties patients are having with adhering to diet and weight recommendations and because of the physician's role in reminding them of the importance of compliance to his/her recommendations.  It is in this context where knowledge of the presence of the extra genetic risk is most important for both parties.

deCODE MI™ provides an important new means of identifying those who are at elevated inherited risk of developing coronary heart disease and MI independent of other risk factors and can be used to modify patient’s 10 year risk estimated derived by conventional risk assessment tools such as the Framingham, the Reynold’s, or the ARIC. deCODE MI™ detects versions of  SNPs (single nucleotide polymorphism) – single letter variations in the sequence of the genome on chromosome 9 and have been linked to increased risk of MI. These risk variants are the first widely-replicated, common genetic variants ever found to associate with substantially increased risk of coronary heart disease and MI as public health problems.

In deCODE’s study, published in Science in June 2007, and which has been validated in 10 independent populations covering thousands of people, 20-22% of the general population have been shown to carry two copies of the risk variants.  In other words, having two copies of the risk variant has been shown to correspond to an approximate 1.6 fold increase in likelihood of early onset MI and 1.3 fold risk for MI regardless of age of onset, i.e. over the general population risk. The risk variants tested for by deCODE's MI test are the “G” allele of SNP rs10757278 and the "C" allele in SNP rs1333049 located in the vicinity of the tumor suppressor genes CDKN2A and CDKN2B on chromosome 9p21, whose proteins encoded called p16INK4a, ARF, and p15INK4b - play a critical role in regulating cell proliferation, cell aging and senescence, and apoptosis in many cell types. These are all important features of atherogenesis, the underlying cause of coronary heart disease and MI. Despite their vicinity to these genes the mechanism whereby the genetic variants exert their effects in the pathogenesis of MI and if that is even through the protein products of CDKN2A and CDKN2B, remains to be elucidated.

Despite our current lack of understanding how the deCODE MI variant mediates its effect the deCODE MI™ test provides a new risk factor that can and should be taken in account when physicians evaluate their patients’ overall risk of developing myocardial infarction according to established risk modelling tools, such as the Framingham, the Reynold’s, or the ARIC. The implications are that some patients should be treated more aggressively through lifestyle change and/or through drug treatment for lower cholesterol targets and for associated risk conditions where as others may be reclassified to lower risk categories.

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