Pharmacogenomics studies how our genome influences medication responses, affecting both drug effectiveness and the likelihood of adverse reactions  (Gurwitz & Motulsky, 2007). Observing occurrences of adverse drug reactions (ADRs) at different rates in diverse populations can provide evidence for a genetic component to variability. These observations often originate from differences in the frequencies of specific gene alleles involved in drug metabolism or action pathways (Gurwitz & Motulsky, 2007). An identified challenge in applying pharmacogenomics at a clinical level is that much of the foundational research identifying relevant genetic variants was conducted primarily using populations of European ancestry. This narrow focus can create disparities, limiting the effectiveness and equity of pharmacogenomic testing when applied to individuals from other ancestral backgrounds (Lu, Lewis, & Traylor, 2017).

The field of pharmacogenetics was conceptualized decades ago, yet its routine integration into clinical practice to guide prescribing medications has progressed somewhat slowly. ADRs are a problem in healthcare, revealing a continuing need for strategies to improve medication safety (Gurwitz & Motulsky, 2007). While some ADRs can be explained by variants in single genes, many drug responses likely arise from complex interactions involving multiple genes plus environmental influences. Early observations regarding population differences in drug responses stressed the importance of the genetic component. Applying pharmacogenetic insights more broadly in patient care promises to enhance drug safety and effectiveness (Gurwitz & Motulsky, 2007).

The rise of Direct-to-Consumer (DTC) genetic testing companies, like 23andMe (RIP), now provides individuals direct access to some pharmacogenetic information, circumventing traditional healthcare intermediaries (Lu, Lewis, & Traylor, 2017). The study by Lu, Lewis & Taylor in 2017 evaluated DTC pharmacogenetic tests offered in the UK market, comparing them against established clinical guidelines and covering tests related to drug responses (Lu, Lewis, & Traylor, 2017). A principal finding was that the clinical usefulness and validity of these DTC tests varied substantially, with their applicability often strongly dependent on the user’s ancestral background because allele frequencies and local linkage disequilibrium (LD) patterns differ significantly across global populations (Lu, Lewis, & Traylor, 2017).

The population differences have direct clinical relevance. For instance, CYP2C19 poor metabolizer alleles are more common in East Asian populations (~14%) than in European (~2%) or African (~4%) populations (Lu, Lewis, & Traylor, 2017). These findings imply standard clopidogrel doses may fail more often in East Asians, which emphasizes the need for population-aware guidance. Another example involves testing for abacavir hypersensitivity risk associated with HLA-B57:01*. Some tests use a tagging SNP that works well in Europeans but is uninformative in Africans and has variable accuracy in Asians due to differing LD patterns, necessitating direct HLA-B57:01* testing or population-specific tags (Lu, Lewis, & Traylor, 2017). Similarly, common variants in CYP2C9 and VKORC1 that influence warfarin dosing show different frequencies across populations suggesting dosing algorithms developed mainly in Europeans may require adjustments for other groups (Lu, Lewis, & Traylor, 2017).

The findings reported by the Lu study emphasize the need for pharmacogenomic research to include diverse global populations to ensure findings are broadly applicable. Relying on genetic markers identified primarily in one ancestral group can lead to tests lacking accuracy or relevance for others (Lu, Lewis, & Traylor, 2017). Establishing comprehensive population-specific reference data and ensuring test reports and guidelines incorporate information about population-specific performance are needed for accurate clinical interpretation worldwide. While DTC testing can raise awareness, navigating these intricacies often benefits from guidance from knowledgeable healthcare professionals (Lu, Lewis, & Traylor, 2017). Addressing population diversity issues is important for the equitable use of pharmacogenomics to improve medication outcomes for everyone (Gurwitz & Motulsky, 2007).

The frequencies of alleles influencing drug response vary among different human populations. Research focusing on European ancestry groups has led to potential gaps and inequities when applying genomic information across diverse populations (Lu, Lewis, & Traylor, 2017). Realizing the full potential of pharmacogenomics responsibly and equitably requires continued research in diverse populations, refining testing strategies, and developing ancestry-aware clinical resources (Gurwitz & Motulsky, 2007).

References

Gurwitz, D., & Motulsky, A. (2007). ‘Drug Reactions, Enzymes, and Biochemical Genetics‘: 50 years Later. Pharmacogenomics, 8(11), 1479-1484; https://doi.org/10.2217/14622416.8.11.1479.

Lu, M., Lewis, C., & Traylor, M. (2017). Pharmacogenetic testing through the direct-to-consumer genetic testing company 23andMe. BMC Medical Genomics, 10(47). , https://doi.org/10.1186/s12920-017-0283-0.