ASHG Abstract Presented by Xiao Jiang, AstraZeneca, Cambridge, United Kingdom
Researchers have found a scarcity of genomic data for individuals of non-European ancestry as well as limited information about how specific drugs are metabolized among these populations after studying how an important pharmacogene, CYP2D6, metabolizes drugs. These limitations mean that it is difficult to provide evidence-based advice about drug dose and treatment options for those with non-European ancestries. The research was done using 490,558 genomes from the United Kingdom Biobank. Prescription drug data was available for 222,068 participants and showed that 24.5% had been prescribed codeine, with 1.6% of those classified as either poor metabolizers (PMs) or ultra-rapid (UM) metabolizers for this gene. Further analysis revealed that those who are normal metabolizers (NM) or UMs had a higher risk of allergy to narcotics compared to PMs, while intermediate metabolizers (IMs), NMs, and UMs were associated with a higher risk for kidney stones. These findings illustrate the value of pharmacogenetic data and point to the need for more information from underrepresented groups and about specific drugs, which would in turn lead to more data about clinical outcomes.
– The researchers observed 95 distinct star alleles, patterns in the CYP2D6 gene that indicate potential differences in protein activity. Among these alleles, 51% had unknown effects on function, meaning that individuals with these patterns could not be placed into one of the categories described below.
– Four categories of metabolic function were used: normal metabolizers (NMs), intermediate metabolizers (IMs), ultra-rapid metabolizers (UMs), and poor metabolizers (PMs). The limited data on underrepresented groups meant that between 5 and 6% of African American, biracial, and South Asian individuals could not be assigned into any one of these categories, compared to about 2% of those from Europe and East Asia.
– In multi-ancestry analyses, NMs and UMs had a higher risk of allergy to narcotics compared to PMs, and IMs, NMs, and UMs were associated with a higher risk of kidney stones.
– The associations between gene categories and clinical outcomes are significant and illustrate the value of this kind of information.
– Future research will include identification of associations between drug dose and treatment outcomes across a wider range of ancestries and metabolized medicines.