Pharmacogenomics and race: Can heritage affect drug disposition?

The still-emerging field of pharmacogenomics is the study of how genes affect an individual’s response to drugs. Through this study, we know that different races and ethnicities can have varying responses to medications. While some of this is attributable to known genes, the cause of some race- or ethnicity-specific reactions is still unknown.

How widely is the pharmacogenomics of race considered?

In a recent review on this topic by Ramamoorthy, et al (Clin Pharmacol Ther. 2015;97(3):263-273), the authors stated that approximately 20% of the new drugs approved in the past several years have known racial/ethnic differences in disposition.

The impact of race/ethnicity on drug disposition is understood to some extent by clinicians when making treatment decisions. I've seen clinicians consider this when deciding on whether or not to use an ACE inhibitor to treat hypertension, for example. However, I've also heard many express surprise at learning of some of the race- or ethnicity-specific warnings or dose limits that are present in some drug labeling.

Information in the labeling is important since it automatically carries some degree of authority. However, such statements in labeling rarely come with much detail or explanation. I suspect clinicians vary widely in how they view the importance, credibility, and value of such label statements.

With the relative simplicity of what can be communicated by labeling and still developing research on pharmacogenomics in general, let alone as it relates to race, ethnicity, and even region of one’s birth or heritage, genetic testing can become key to unlocking potential concerns for patients.

Recent data indicate that providers predict patient genomic data is going to be one of the most useful healthcare data sources within the next five years. The testing industry is helping drive this development through the marketing of genetic testing services aimed at patients themselves. The marketing and availability of such tests have likely played a significant role in making patients (and healthcare providers) more aware of the potential role that genetics may play in drug response. This then contributes to patients asking more from their providers regarding genetic testing and individualized drug and dose selection. Similarly, healthcare professionals are helping to push this by asking for and using this privately obtained testing information more frequently in practice.

Common drug disposition issues

One of the most well-known race-specific pharmacogenetic responses involves G6PD deficiency, which is more common in individuals of African or Mediterranean heritage. It has been associated with a high risk for hemolysis with potentially significant consequences when these individuals are exposed to any of dozens of specific medications, including many antimalarial medications, sulfa drugs, and other medications, including possibly aspirin.

Some others that are less common, but have received some attention in drug labeling include:

• Risk for severe skin reactions due to carbamazepine in patients of Asian heritage, associated with the presence of HLA-B*15:02
• Risk for death due to the excessive conversion of codeine into morphine, which is thought to vary by ethnicity, but is associated with the presence of multiple functional copies of the gene encoding CYP2D6

But there are some race-specific reactions for which causal genes are not fully known, and therefore cannot be tested.

One of the best examples of this is probably the reduced response to ACE inhibitors, angiotensin II receptor antagonists, and beta-blockers in African Americans. This seems to reflect that hyperactivation of the renin-angiotensin-aldosterone system is less significant in these patients than in patients from some other racial/ethnic populations. Because of these common reactions, the FDA approved the combination drug isosorbide dinitrate and hydralazine just for patients who self-identify as African Americans.

When we encounter differences in drug response for which we don't know the specific gene or genes responsible, race and ethnicity are the best markers of response that we have. In those instances, the social concept of race/ethnicity is very helpful for clinicians. Similarly, in situations for which we know a certain genetic variation is much more common in some racial or ethnic groups, this concept can help identify when testing is more important.

However, in some instances, relying on race/ethnicity can be somewhat misleading. The carbamazepine labeling, for example, recommends testing for the presence of HLA-B*15:02 in patients of Asian heritage prior to use. While this variant is common in many Asian populations, it is present in less than 1% of Koreans and Japanese.

Similarly, the frequency of individuals with extra copies of the CYP2D6 gene (and consequently greater risk for excessive response to codeine and lesser response to many other medications) is greater in individuals of North African heritage than among many of sub-Saharan African heritage. Yet we don't often go beyond the broader designations of African or African American when inquiring about a patient’s race or ethnicity. These issues all become even more complex when trying to account for individuals who identify as being multiracial.

The growth of genetic testing, the expansion of pharmacogenomics research, and clear communication with patients regarding their racial/ethnic identity and heritage will help clinicians deepen their knowledge of these issues to help make effective and safe drug therapy decisions for their patients.