Comprehensive Allele Genotyping in Critical Pharmacogenes Reduces Residual Clinical Risk in Diverse Populations

Abstract

Genomic-guided pharmaceutical prescribing is increasingly recognized as an important clinical application of genetics. Accurate genotyping of pharmacogenomic (PGx) genes can be difficult, owing to their complex genetic architecture involving combinations of SNPs and structural variation.Here we introduce the Helix PGx database, an open-source star allele, genotype, and resulting metabolic phenotype frequency database for CYP2C9, CYP2C19, CYP2D6, and CYP4F2, based on short-read sequencing of >86,000 unrelated individuals enrolled in the Helix DNA Discovery Project.The database is annotated using a pipeline that is clinically validated against a broad range of alleles and designed to call CYP2D6 structural variants with high (98%) accuracy. We find that CYP2D6 has greater allelic diversity than the other genes, manifest in both a long tail of low-frequency star alleles as well as a disproportionate fraction (36%) of all novel predicted loss-of-function variants identified.Across genes, we observe that many rare alleles (<0.1% frequency) in the overall cohort have 10x higher frequency in one or more subgroups with non-European genetic ancestry. Extending these PGx genotypes to predicted metabolic phenotypes, we demonstrate that >90% of the cohort harbors a high risk variant in one of the four pharmacogenes. Based on the recorded prescriptions for >30,000 individuals in the Healthy Nevada Project, combined with predicted PGx metabolic phenotypes, we anticipate that standard-of-care screening of these four pharmacogenes could impact nearly half of the general population.

Characterization of pharmacogenomic variants in a Brazilian admixed cohort of elderly individuals based on whole-genome sequencing data

“…Several initiatives have used NGS to analyze PGx markers in diverse populations, using large genomic databases ( Reisberg et al, 2019 ; Luo et al, 2021 ; McInnes et al, 2021 ; Taliun et al, 2021 ) or databases from specific populations ( Cohn et al, 2017 ; Al-Mahayri et al, 2020 ; Mauleekoonphairoj et al, 2020 ). The advances in genomic analyses by NGS have enabled scientists to investigate the contribution of rare variants to complex diseases and PGx.…”

A Call for Increased Inclusivity and Global Representation in Pharmacogenetic Testing

“…Pharmacogenetic (PGx) testing can be employed to optimize drug selection and dosing by factoring in genetic in uences on drug metabolism and response, reducing side effects and enhancing therapeutic outcomes compared to a generic "one-size-ts-all" treatment approach 1,2 . Pharmacogenes, such as the family of cytochrome P450 (CYP) enzyme-encoding genes are highly polymorphic, with signi cant variation observed across various racial and ethnic groups [3][4][5] . Rare variants account for roughly 30-40% of functional PGx variation 6 .…”

Global perspectives on CYP2D6 associations with primaquine metabolism and Plasmodium vivax radical cure

“…CYP2D6 is the most polymorphic of the CYP genes ( Zhou et al, 2017 ). Currently, there are 145 known major “star” (*) alleles and multiple sub-alleles that include at least 128 unique SNPs (upstream non-coding and coding region), 7 insertions (one to multiple nucleotides or duplicated nucleotides), 7 deletions (1 to multiple nucleotides), 5 gene deletions, gene duplication, conversion or hybridization variations that can together generate more than 1,220 unique genotypes ( Gaedigk et al, 2018b ; Luo et al, 2021 ) (ongoing updates can be followed at https://www.pharmvar.org/gene/CYP2D6 ). Many of the mutations are quite rare (e.g.…”

“…Many of the mutations are quite rare (e.g. occurring in single individuals or isolated populations ( Luo et al, 2021 ) and a significant number of resulting * alleles occur at frequencies less than 0.25%, and hence do not substantially affect drug metabolism at the population-level. That said, we have shown, in a study of CYP2D6 in a Malagasy population, that the unexpected appearance of some alleles associated with diverse populations, including new alleles, new allele frequency patterns, genotype combinations and genotype proportions may reveal population level patterns of special relevance to malaria treatment ( Mehlotra et al, 2021 ; Chan et al, 2022 ).…”