Abstract
BackgroundPharmacogenomic (PGx) variants mediate how individuals respond to medication, and response differences among racial/ethnic groups have been attributed to patterns of PGx diversity. We hypothesized that genetic ancestry (GA) would provide higher resolution for stratifying PGx risk, since it serves as a more reliable surrogate for genetic diversity than self-identified race/ethnicity (SIRE), which includes a substantial social component. We analyzed a cohort of 8628 individuals from the United States (US), for whom we had both SIRE information and whole genome genotypes, with a focus on the three largest SIRE groups in the US: White, Black (African-American), and Hispanic (Latino). Our approach to the question of PGx risk stratification entailed the integration of two distinct methodologies: population genetics and evidence-based medicine. This integrated approach allowed us to consider the clinical implications for the observed patterns of PGx variation found within and between population groups.ResultsWhole genome genotypes were used to characterize individuals’ continental ancestry fractions—European, African, and Native American—and individuals were grouped according to their GA profiles. SIRE and GA groups were found to be highly concordant. Continental ancestry predicts individuals’ SIRE with > 96% accuracy, and accordingly, GA provides only a marginal increase in resolution for PGx risk stratification. In light of the concordance between SIRE and GA, taken together with the fact that information on SIRE is readily available to clinicians, we evaluated PGx variation between SIRE groups to explore the potential clinical utility of race and ethnicity. PGx variants are highly diverged compared to the genomic background; 82 variants show significant frequency differences among SIRE groups, and genome-wide patterns of PGx variation are almost entirely concordant with SIRE. The vast majority of PGx variation is found within rather than between groups, a well-established fact for almost all genetic variants, which is often taken to argue against the clinical utility of population stratification. Nevertheless, analysis of highly differentiated PGx variants illustrates how SIRE partitions PGx variation based on groups’ characteristic ancestry patterns. These cases underscore the extent to which SIRE carries clinically valuable information for stratifying PGx risk among populations, albeit with less utility for predicting individual-level PGx alleles (genotypes), supporting the concept of population pharmacogenomics.ConclusionsPerhaps most interestingly, we show that individuals who identify as Black or Hispanic stand to gain far more from the consideration of race/ethnicity in treatment decisions than individuals from the majority White population.
Highlights
Pharmacogenomic (PGx) variants mediate how individuals respond to medication, and response differences among racial/ethnic groups have been attributed to patterns of PGx diversity
Perhaps most interestingly, we show that individuals who identify as Black or Hispanic stand to gain far more from the consideration of race/ethnicity in treatment decisions than individuals from the majority White population
Self-identified race/ethnicity (SIRE) and genetic ancestry (GA) in the United States (US) We compared self-identified race/ethnicity (SIRE) to GA for a cohort of 8628 individuals characterized as part of the Health and Retirement Study (HRS), for whom both SIRE information and whole genome genotypes were available (Table 1)
Summary
Pharmacogenomic (PGx) variants mediate how individuals respond to medication, and response differences among racial/ethnic groups have been attributed to patterns of PGx diversity. A 2015 review found that 20% of drugs approved over the previous 6 years showed response differences among racial/ethnic groups, and these differences are often translated into group-specific prescription recommendations that are issued on FDA-approved drug labels [7]. Examples of such recommendations include contraindication of Rasburicase, a medication used to clear uric acid from the blood in patients undergoing chemotherapy, for individuals of African or Mediterranean ancestry, and a toxicity warning for the anticonvulsant Carbamazepine in Asian patients. Despite the inclusion group-specific recommendations in a number of drug labels, the utility of racial and ethnic categories in biomedical research, and their relevance to clinical decision making, remain a matter of substantial controversy [9,10,11,12]
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