DNA tests typically identify risk for a clinical outcome, but often do not correlate 100% with that outcome. Identification of the most common 2C19 variants does correlate with likely failure of standard clopidogrel dosing, and some preliminary evidence-based treatment guidelines have been developed. However, the clinical importance of some of the rarer variants is not well enough understood.
Furthermore, a normal 2C19 result doesn’t guarantee adequate response to clopidogrel. The test could miss a rare but significant variant, or any of several other factors listed above could contribute to treatment failure.
The primary benefit of 2C19 testing is that it can help guide specific medication choices, not only for platelet inhibition, but also for any of the other drugs metabolized by this enzyme.
The benefits and limitations of functional vs. DNA tests are not limited to platelet function and clopidogrel metabolism. The same principles apply to most genetic questions.
For example, transferrin saturation is the best test to identify iron overload, but as a functional test it cannot distinguish secondary iron overload from hereditary hemochromatosis, nor identify which of several genes might be causing hemochromatosis in that particular patient. Genetic testing of the most common human hemochromatosis (HFE) gene can identify mutations that increase the risk of hemochromatosis, but most patients with mutations in this gene never develop clinical iron overload and don’t require any medical intervention.
Similarly, testing of the apo E gene can identify variants associated with increased risk of Alzheimer disease, but it takes functional neuropsychiatric testing to diagnose dementia, plus additional testing to differentiate the various causes of dementia.
In general, functional tests are good for initial diagnostic evaluation. When results fall within the normal (or desired) range, typically no further investigation is necessary, unless there is a genetic reason to suspect future disease, or something changes that might alter the clinical characteristic of interest. DNA tests offer predictive value, and can be helpful in elucidating the differential diagnosis when a functional test is abnormal.
This column, "Genetics in Your Practice," appears regularly in Internal Medicine News, an Elsevier publication. Dr. Levy is at the division of general internal medicine and the McKusick-Nathans Institute of Genetic Medicine of Johns Hopkins University, Baltimore. He reports having no conflicts of interest.