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INTRODUCTION

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Precision medicine is being applied in several areas of cardiovascular disease. Various tests are available to identify individuals with hereditary predisposition to familial hypercholesterolemia, inherited thrombophilia, arrhythmias, cardiomyopathy, and other rare genetic heart defects. Pharmacogenomic tests are being considered for commonly prescribed drugs including clopidogrel, warfarin, and simvastatin. What are the indications for these tests? Are they clinically valid and useful? Where can you learn more?

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CORONARY ARTERY DISEASE

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Coronary artery disease, the most common manifestation of cardiovascular disease, has long been suspected to have an inherited component, especially when it occurs prematurely. However, despite best efforts in the field of genomics to identify high-risk genetic variants underlying the disease, few such variants exist. Most genetic variants for coronary artery disease discovered to date are common variants with very small effects (low-risk variants).

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Common variants

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Common genetic variants in over 33 gene regions, including the APOE gene and the genomic region 9p21, have been reproducibly shown to be associated with coronary artery disease risk (Table 7-1). Most (70%) of these genetic variant associations are independent of known risk factors[1]. The average magnitude of increased risk associated with each variant is very small, on average 1.18-fold. For example, if the average population risk of coronary artery disease is 25%, carriers of one of these low-risk variants would be at about 29.5% risk. Clinical validity of these common low-risk genetic variants has not been demonstrated and no current guidelines support genetic testing[2]. Researchers have tried to develop aggregate risk prediction scores from multiple common low-risk variants, but none of these have yet been validated in prospective studies[3].

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Table Graphic Jump Location
Table 7-1.Characteristics of common genetic variants associated with risk of coronary artery disease.
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Familial hypercholesterolemia (FH)

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FH is one exception of a genetic risk factor for coronary artery disease, where rare variants in one of three genes, LDLR, APOB, and PCSK9, are associated in an autosomal dominant fashion with severely elevated low-density lipoprotein (LDL) cholesterol levels and high risk of premature myocardial infarction. FH is common, affecting approximately 1:200 to 1:500 people, but the prevalence varies by population[...

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