Health disparity in pharmacogenomics: African American SNPs and drug metabolism

Project: Research project

Project Details

Description

As pharmacogenomics moves from bench-top to bed-side, African Americans have been left out of the
advances personalized medicine holds. To date, African Americans have been largely absent from the
numerous pharmacogenetic studies that identify predictive single nucleotide polymorphisms (SNPs) that are
being used clinically to improve care. As we move toward more comprehensive bioinformatics and highthroughput
methods of evaluating the genome for functionally relevant SNPs that affect drug phenotypes, we
are also producing a growing health disparity in the translation of these findings into the clinic for African
Americans. Current genomic methods are trying to reach beyond genome–wide association in hopes of
finding biological plausibility to genetic findings. This search has led to the use of expression quantitative trait
loci (eQTLs) as a tool in pharmacogenetic association studies. SNPs labeled as eQTLs have intrinsic
biological plausibility since they are significantly associated with changes in gene expression. However, no
liver eQTL studies have been conducted in African Americans. By using liver-specific eQTLs, we will discover
SNPs that affect drug metabolizing enzymes (DMEs), which will have wide-spread scientific and clinical
impact; given that most drugs currently prescribed undergo some form of hepatic metabolism. Because of the
increase genetic diversity found in African Americans, they may carry population specific SNPs can never be
found by pharmacogenomics studies in populations of European-descent alone. Without African American
focused pharmacogenomics studies we risk excluding African Americans from personalized medicine. We
plan to use primary hepatocytes to conduct gene expression studies both before and after drug enzyme
induction to identify genes that are differentially expressed. Drug enzyme induction is driven by increased
gene transcription; therefore, by focusing on the genes that are differentially expressed after induction we can
pin-point the drivers (i.e. genes) that regulate drug metabolizing enzymes. We will then look at SNPs within
and in close proximity to these genes to determine if any are associated with differences in gene expression
(dubbed DI-eQTLs). We will then look to see if these DI-eQTLs are associated with pharmacokinetic
measures in the same set of cell cultures, affectedly preforming a pharmacokinetic and a pharmacogenetic
study in the same individual. We hypothesize that drug enzyme induction will provide us with DI-eQTLs that
are strongly associated to drug pharmacokinetics, a clinically relevant phenotype. To validate these findings
we will query publically available data to look for an enrichment of our DI-eQTLs within the most strongly
associated SNPs in pharmacogenomic GWAS data. The association between genotype, gene expression and
drug pharmacokinetics in African Americans has never been conducted before and will provide an invaluable
resource for pharmacogenomics and clinical pharmacology, as well as clinical translation in this understudied
population.
StatusFinished
Effective start/end date1/13/174/30/20

Funding

  • National Institute on Minority Health and Health Disparities (5R01MD009217-05 REVISED)

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