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=4.810-8, 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.
Organic anion transporters, OATPs, play important roles in the transport of many prescription drugs into the liver where they may be inactivated. People have different genetic forms of OATPs, and therefore may inactivate drugs at different rates, leading to differences in drug response. This research will focus on discovering the genetic forms of OATPs that influence response to many drugs, and in particular to drugs used in the treatment of diabetes in order to improve selection and dosing of drugs.
Showing the most recent 10 out of 16 publications
