The Apportionment of Pharmacogenomic Variation: Race, Ethnicity, and Adverse Drug Reactions

Abstract

Fifty years ago, Richard Lewontin found that the vast majority of human genetic variation falls within (~85%) rather than between (~15%) racial groups. This result has been replicated numerous times since and is widely taken to support the notion that genetic differences between racial groups are trivial and thus irrelevant for clinical decision-making. The aim of this study was to consider how the apportionment of pharmacogenomic variation within and between racial and ethnic groups relates to risk disparities for adverse drug reactions. We confirmed that the majority of pharmacogenomic variation falls within (97.3%) rather than between (2.78%) the three largest racial and ethnic groups in the United States: Black, Hispanic, and White. Nevertheless, pharmacogenomic variants showing far greater within than between-group variation can have high predictive value for adverse drug reactions, particularly for minority racial and ethnic groups. We predicted excess adverse drug reactions for minority Black and Hispanic groups, compared to the majority White group, and considered these results in light of the apportionment of genetic variation within and between groups. For 85% within and 15% between group variation, there are 700 excess adverse drug reactions per 1,000 patients predicted for a recessive effect model and 300 for a dominant model. We found high numbers of predicted Black and Hispanic excess adverse drug reactions for widely prescribed platinum chemotherapy compounds, such as cisplatin and oxaliplatin, as well as controlled narcotics, including fentanyl and tramadol. Our results indicate that race and ethnicity, while imprecise proxies for genetic diversity, correlate with patterns of pharmacogenomic variation in a way that is clearly relevant to medical treatment decisions. The effects of this variation is particularly pronounced for Black and Hispanic minority groups, owing to genetic differences from the majority White group. Treatment decisions that are made based on (assumed) White pharmacogenomic variant frequencies can be harmful for minority groups. Ignoring clinically relevant genetic differences among racial and ethnic groups, however well-intentioned, will exacerbate rather than ameliorate health disparities.

Figure 1.. Race, ethnicity, and genomic variation.

(A) Genomic relationships among study participants compared to their SIRE: Black (blue), Hispanic (red), and White (orange). (B) Apportionment of genetic variation within (purple) and between (green) SIRE group pairs.

Figure 2.. SIRE group allele frequencies and the apportionment of genetic variation.

Pairwise comparison of Black and White group allele frequencies and the amount of genetic variation found within (above diagonal) and between (below diagonal) groups.

Figure 3.. Apportionment of genetic variation and adverse drug reactions.

Results are shown for a comparison of Black (minority) and White (majority) SIRE groups. The amount of within group genetic variation (y-axis) is compared to ranges of the predicted number of excess adverse drug reactions (x-axis) for the minority Black group. Results are shown for recessive (yellow) and blue (dominant) pharmacogenomic variant effect modes.