Personal Genomics for Preventive Cardiology

Genome wide association studies (GWAS) have identified over 1000 disease associated SNPs,
including many related to cardiovascular disease (CVD). Associations have been found for most
traditional risk factors including lipids, blood pressure /hypertension, weight/body mass
index, smoking behavior, and diabetes. Importantly, GWAS have also identified susceptibility
variants for coronary heart disease/ myocardial infarction (CHD/MI), many of which are
independent of traditional risk factors and thus cannot currently be assessed by surrogate
measures. The first, and so far the strongest, of these signals was found in the 9p21.3 locus
and are associated with a 20-40% increase in the relative risk of coronary heart disease
among Caucasian and East Asian populations. Like most of the associations identified to date,
the function of the non-coding 9p21.3 chromosomal region remains unclear. These markers
predict disease and can modesty improve reclassification indices. For instance, in a very
recent example, 13 SNPs previously identified in GWAS as associated with CHD/MI were
incorporated into a multilocus model to estimate the association of a genetic risk score with
incident CHD/MI in several large prospective studies. Even after adjusting for family history
and traditional risk factors, individuals in the top quintile were at 1.66 times increased
risk compared with those at the bottom quintile 36. There was a significant improvement in
reclassification of intermediate risk patients. The use of these markers has not yet been
shown to outperform models including traditional risk factors and family history. This
shortcoming is probably because the vast majority of heritable risk remains undiscovered. The
basis for this heritability gap remains unclear but is the focus of intense investigation.
Despite the heritability gap, it is still possible that the use of known genetic risk factors
may improve patient outcomes. For instance, genetic testing can improve patient adherence and
risk factor reduction for Mendelian forms of coronary disease like familial
hypercholesterolemia (FH). However, for "garden variety" coronary disease, there has never
been a clinical trial that indicates that using genetic markers improves outcomes. There are
strong signals from the NIH, the US Preventive Services Task Force and other independent
prevention centers that genetic screening will be highly scrutinized until such trials exist.
Currently, both the Evaluation of Genomic Applications in Practice and Prevention (EGAPP)
Working Group and the ACC/AHA Taskforce on Practice Guidelines recommend against genetic
testing for coronary disease 39,40 because there is no clinical trial data supporting their
use. Despite these recommendations, and lack of efficacy data, there are huge financial
pressures to increase genetic testing by "direct-to-consumer" companies. In this context,
there is a perfect opportunity to develop well-designed clinical trials to test these
variants.

Inclusion Criteria:

- Adults age > 18

- Patient seeking cardiovascular risk evaluation

- At intermediate (6-20%) or high risk (> 20%) over 10 years of CAD as defined by
Framingham 10 year risk score AND/OR at > 20% risk of CAD over 30 years using the
Framingham 30 year risk calculator

- The genetic risk factors have been evaluated predominantly in white/European subjects.
However, there is considerable overlap in the genetic architecture of South Asians and
Hispanic/Latino populations. Therefore, we will limit our initial studies to these
three race/ethnicity groups.

Exclusion Criteria:

- History of myocardial infarction, angina, stroke, peripheral arterial disease, PCI, or
CABG

- Already on lipid lowering therapy

- Anticipated survival <1 year (e.g. metastatic cancer)

- Serious conditions that would limit ability to adhere to recommendations (inability to
take statins, exercise)

- Already had genetic testing

- Concurrent enrollment in another clinical trial

- Pregnant or breastfeeding