Are Asians at higher genetic risk of serious adverse events to common medications?
Last Updated on March 31, 2020 by Joseph Gut – thasso
In a new study recently published in Clinical Translational Science, researchers from the University of Britisch Columbia and from Stanford University reveal just how prevalent and serious some of these adverse events can be and how patients with Asian decency have heightened risks for some of the most prominent and serious, if not lifetreathening forms of these effects. They examined existing literature in the field of pharmacogenomics, i.e., the study of how genes affect a person’s response to drugs, in combination with guidelines and statistics from the American Food and Drug Administration (FDA) and the Clinical Pharmacogenetics Implementation Consortium (CPIC), summarizing some of these adverse effects and how they in fact are affected by genetics.
Asian people often suffer from severe skin reactions, such as Steven Johnson Syndrome (SJS) or even Toxic Epidermal Necrolysis (TEN), when treated with Carbamazepine (Tegretol), an anti-convulsant drug and primarily used in the treatment of epilepsy and neuropathic pain. The underlying genetic risk factor is the HLA-B*15:02 allele, whose Odds ratios for the development of SJS or TEN in people who carry this allele can be in the double, triple or even quadruple digits, depending on the population studied. HLA-B*1502 occurs almost exclusively in people with ancestry across broad areas of Asia, but has a very low or absent frequency in European (i.e. Caucasian), Japanese, Korean and African populations. In contrast, however, in these latter populations, the HLA-A*31:01 allele has been shown to be a strong predictor of both mild and severe adverse reactions, such as the DRESS syndrome form of severe cutaneous reaction to Carbamazepine.
A similar situation presents with the anti-gout medication Allopurinol (Zyloprim). Here, the HLA-B*5801 allele is a strong genetic marker for Allopurinol-induced severe cutaneous adverse reactions, including SJS and TEN. The frequency of the HLA-B*5801 allele varies between ethnicities: Han Chinese and Thai populations have HLA-B*5801 allele frequencies of around 8%, as compared to European and Japanese populations, who have allele frequencies of around 1.0% and 0.5%, respectively. The increase in risk for developing allopurinol-induced SJS or TEN in individuals with the HLA-B*5801 allele (as compared to those who do not have this allele) is very high, ranging from a 40-fold to a 580-fold increase in risk, depending on ethnicity.
The examples of Carbamazepine and Allopurinol show one of the enduring challenges facing pharmacogenomics and its application in personalised and/or precision medicine: the appreciation for granularity of differences between related populations, From the examples here, it is important to remember that ethnic groups we colloquially refer to as “Asian” can have quite different genetic backgrounds and can range specific populations such as “Han Chinese” to much broader populations like “South Asian.” Moreover, we need to understand that adverse clinical endpoints such as SJS, TEN, or DRESS can be associated with the treatment of a variety of medications in individuals, who may carry different genetically predisposing constellations (e.g., allelic variants), similarly occurring in a number of ethnicities, at very different frequencies, however. In any case, it remains challenging to refer to “Asians”, “Africans”, “Caucasians”, “African Americans”, or “Latinos”, etc., when it comes to pharmacogenomics.
Given this real life granularity in genetic predisposition for adverse events in combination with large inter-ethnic variation in frequency of allelic variants, genetic testing will have a huge impact on clinical practice. Patients who have experienced serious adverse events to medications may be tested for the underlying genetic variants or can bring into the physicians office or the clinic their own genetic test results for interpretation. For physicians all over the world, recognizing that certain effects may be more prevalent in certain populations than in others can be very helpful in their daily practice and their decision making for treatment options.
Already today, genetic testing is mandatory bevor prescribing certain drugs to patients. For a review, one might consult the Drug Label Annotations overview table provided by PharmGKB, the pharmacogenomics knowledge resource that encompasses clinical information including clinical guidelines and drug labels, potentially clinically actionable gene-drug associations and genotype-phenotype relationships. This resource details on how Health Authorities such as the American Food and Drug Administration (FDA), the European Medicines Agency (EMA), the Swiss Agency of Therapeutic Products (Swissmedic), the Pharmaceuticals and Medical Devices Agency, Japan (PMDA), and Health Canada (Santé Canada) (HCSC) request genetic testing in their drug labels for selected medications.
Overall, it will always be the frequency of an (offending, i.e., being the root cause for an adverse drug event) allele in the population that dictates if a population (more precisely, an ethnic group) is more affected by adverse events with a given medication than others, as it is very nicely illustrated in the example here with “Asian” populations, the HLA-B*15:02 allele, and the resulting SJS occurence under Carbamazepine.
See here a short sequence on SJS and TEN: