# Discovery of Pharmacogenomic Biomarkers for OATP1B1 and OATP1B3

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $599,475

## Abstract

Discovery of Pharmacogenomic Biomarkers for OATP1B1 and OATP1B3
In marked contrast to the plethora of genome-wide association studies (GWAS) focused on human disease,
there has been a dearth of GWAS focused on pharmacogenomic traits such as variation in drug response and
toxicity. Further, many of the pharmacogenomic GWAS have been underpowered and therefore few genetic
variants at genomewide levels of significance have been discovered. Among the world's most widely
prescribed drugs, sulfonylureas are associated with great inter-individual variation in response, with ~35% of
patients with type 2 diabetes failing therapy after 5 years and frequently needing insulin therapy to achieve
acceptable glycemic control. In exciting preliminary GWAS focused on response to sulfonylureas, we
discovered a strong association between change in glycated hemoglobin levels (HbA1c) on sulfonylureas and
a SNP in the SLCO1B1/1B3 locus encoding the transporters OATP1B1 and OATP1B3 at genome-wide levels
of significance (p=4.8×10-8, N = 5,479). The major goals of this competing renewal application are to
determine the pharmacologic mechanisms by which OATP1B1 and OATP1B3 associate with response
to sulfonylureas, discover and validate selective biomarkers for the transporters and discover other
genes that associate with response to sulfonylureas. To achieve our goals, we will use two large clinical
resources: MetGen PLUS, a large multi-ethnic international consortium, established during this granting period
and SUGAR-MGH, a rich deeply phenotyped consortium of healthy volunteers, which can be used to probe
clinical pharmacokinetic and pharmacodynamic mechanisms. Three specific aims are proposed. In aim 1, we
will employ a genome-wide approach in MetGen PLUS to identify common genetic variants in SLCO1B1/1B3
and other genes that impact response to sulfonylureas. In aim 2, we will identify the causal variants in the
SLCO1B1/1B3 locus associated with drug response, using a multi-tiered approach, beginning with targeted
resequencing of the SLCO1B3/1B1 locus and extending through detailed functional genomic studies in cells
and in samples obtained from healthy volunteers in SUGAR-MGH. Finally, in aim 3, we will discover and
validate metabolomic biomarkers of SLCO1B3 that can be used as tools to predict OATP1B3 activity including
OATP1B3-mediated drug-drug interactions for a wide range of prescription drugs that are substrates, inhibitors
or inducers of the transporter. Our proposed methods range from genomewide association and NextGen
sequencing studies and analyses in large cohorts of patients to high throughput functional genomic and
metabolomic studies in cellular assays to clinical pharmacokinetic studies in healthy volunteers. We postulate
that this comprehensive genomic, metabolomic and functional approach including deep clinical phenotyping
will serve as a blueprint for systematic evaluations of other drugs, paving the way for precision therapeutics.

## Key facts

- **NIH application ID:** 10228630
- **Project number:** 5R01GM117163-06
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** JOSE CARLOS FLOREZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $599,475
- **Award type:** 5
- **Project period:** 2015-09-25 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10228630

## Citation

> US National Institutes of Health, RePORTER application 10228630, Discovery of Pharmacogenomic Biomarkers for OATP1B1 and OATP1B3 (5R01GM117163-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10228630. Licensed CC0.

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