Patterns of pharmacogenetic variation in nine biogeographic groups

Area of Science:

• Pharmacogenomics
• Genetics
• Drug Metabolism

Background:

• Pharmacogenetic (PGx) variant frequencies differ substantially across global populations.
• Existing PGx literature often focuses on limited population groups or specific genes, using non-standardized definitions.
• This can lead to inequities in the application of PGx-guided drug selection.

Purpose of the Study:

• To compare population group sizes and allele frequencies of altered function alleles across nine biogeographic groups using curated data from Clinical Pharmacogenetic Implementation Consortium (CPIC) guidelines.
• To identify genes with significant frequency differences in altered function alleles across populations.

Main Methods:

• Extracted allele frequency data from 23 CPIC guidelines covering 19 pharmacogenetic genes.
• Analyzed and compared allele frequencies across nine defined biogeographic groups.
• Identified alleles present in underrepresented groups but not in the largest reference group.

Main Results:

• The European population group was the most represented in the curated literature for 16 out of 19 genes studied.
• American and Oceanian groups were the least represented.
• Nearly 200 alleles were detected in nonreference groups that were absent in the largest reference group.
• CYP2B6 and CYP2C9 showed higher frequencies of altered function alleles in nonreference groups, while CYP4F2, DPYD, SLCO1B1, and UGT1A1 showed lower frequencies.

Conclusions:

• Pharmacogenetic allele frequencies and functions exhibit substantial variation across nine biogeographic groups.
• Most biogeographic groups are underrepresented in the available PGx data.
• Increased efforts are needed to characterize global PGx variation to prevent exacerbating health disparities and ensure equitable implementation of PGx-guided therapies.