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Open Access Publications from the University of California

Scholarly Works (5 results)

  • Thesis
  • Peer Reviewed
UC San Francisco Electronic Theses and Dissertations (2015)

Precision medicine is quickly rising as an influential field of clinical practice and investigation, with new discoveries being published and recent governmental interest. A major area of research for precision medicine is pharmacogenomics, or how genetic factors influence both therapeutic and adverse drug response. Transporters are an important class of proteins in pharmacogenomics research, as they control how pharmaceuticals enter, circulate, distribute and exit the body. As such, this thesis has focused on research related to the pharmacogenetic effects of transporters using computational methods.

An online database was created for researchers to easily access information on transporters. This has become a regularly used tool for the academic, industrial and regulatory research communities. A genome-wide association study (GWAS) was conducted examining selective serotonin reuptake inhibitors, SSRIs, which target the transporter SLC6A4, and the genetic determinants of their therapeutic and adverse drug response. Suggestive associations for therapeutic response were detected for genetic variants in TENM4 and SNTG2, and a variant in CLEC12A was associated at genome-wide significance levels with sexual dysfunction, an adverse effect of SSRIs. A GWAS of baseline serum uric acid levels, which is known to strongly associate with genetic variants in transporters, in a multi-ethnic cohort was also conducted. An analysis in Asians revealed little association with the transporter SLC2A9, a difference when compared to any other ethnicity or even previous Asian studies. A subsequent genome-wide association analysis of the pharmacogenomics of allopurinol, the main treatment for hyperuricemia, revealed a novel association with the transporter ABCG2, which had not been reported to be play a role in the absorption, disposition, or response to allopurinol. Subsequent experiments proved that ABCG2 transports allopurinol and its active metabolite oxypurinol. Together, this dissertation research has expanded our knowledge of the pharmacogenomics of transporters and transporter related drugs.

    Cover page: Computational Approach to Studying the Pharmacogenetics of Transporters
    • Thesis
    • Peer Reviewed
    UC San Francisco Electronic Theses and Dissertations (2009)

    As an active transporter of anionic molecules in the kidney, OAT3 plays a role in

    the renal elimination of many drugs and is also thought to be involved in drug-drug

    interactions in the kidney. A number of drugs have been identified as substrates or

    inhibitors of OAT3 including several non-steroidal anti-inflammatory drugs (NSAIDs)

    and various antibiotics. To date, most studies of drug interactions with OAT3 have

    focused on a few compounds or at most, a small panel of structural analogs. The goal of

    the current study was to identify FDA approved drugs that interact with OAT3 using a

    high-throughput screening approach. A library of 937 FDA approved drugs was screened

    using a cell-based fluorescence assay. A total of 55 drugs were identified as hits

    including NSAIDS, anti-diabetic agents, and macrolide antibiotics not previously known

    to interact with OAT3. Kinetics profiles were generated for a selection of drugs as

    validation for the screen.

      Cover page: Drug Interactions with the Human Organic Anion Transporter 3, OAT3
      • Article
      • Peer Reviewed
      UC San Francisco Previously Published Works (2016)

      Purpose

      Vesicular monoamine transporters 1 and 2 (VMAT1 and VMAT2) are thought to mediate MIBG uptake in adult neuroendocrine tumors. In neuroblastoma, the norepinephrine transporter (NET) has been investigated as the principal MIBG uptake protein, though some tumors without NET expression concentrate MIBG. We investigated VMAT expression in neuroblastoma and correlated expression with MIBG uptake and clinical features.

      Methods

      We evaluated VMAT1 and VMAT2 expression by immunohistochemistry (IHC) in neuroblastoma tumors from 76 patients with high-risk metastatic disease treated in a uniform cooperative group trial (COG A3973). All patients had baseline MIBG diagnostic scans centrally reviewed. IHC results were scored as the product of intensity grading (0 - 3+) and percent of tumor cells expressing the protein of interest. The association between VMAT1 and VMAT2 scores and clinical and biological features was tested using Wilcoxon rank-sum tests.

      Results

      Patient characteristics were typical of high-risk neuroblastoma, though the cohort was intentionally enriched in patients with MIBG-nonavid tumors (n = 20). VMAT1 and VMAT2 were expressed in 62% and 75% of neuroblastoma tumors, respectively. VMAT1 and VMAT2 scores were both significantly lower in MYCN amplified tumors and in tumors with high mitotic karyorrhectic index. MIBG-avid tumors had significantly higher VMAT2 scores than MIBG-nonavid tumors (median 216 vs. 45; p = 0.04). VMAT1 expression did not correlate with MIBG avidity.

      Conclusion

      VMAT1 and VMAT2 are expressed in the majority of neuroblastomas. Expression correlates with other biological features. The expression level of VMAT2 but not that of VMAT1 correlates with avidity for MIBG.
        Cover page: Vesicular monoamine transporter protein expression correlates with clinical features, tumor biology, and MIBG avidity in neuroblastoma: a report from the Children’s Oncology Group
        • Article
        • Peer Reviewed
        UC San Francisco Previously Published Works (2015)

        Purpose

        (131)I-metaiodobenzylguanidine (MIBG) is a radiopharmaceutical with activity in neuroblastoma. Vorinostat is a histone deacetylase inhibitor that has radiosensitizing properties. The goal of this phase I study was to determine the MTDs of vorinostat and MIBG in combination.

        Experimental design

        Patients ≤ 30 years with relapsed/refractory MIBG-avid neuroblastoma were eligible. Patients received oral vorinostat (dose levels 180 and 230 mg/m(2)) daily days 1 to 14. MIBG (dose levels 8, 12, 15, and 18 mCi/kg) was given on day 3 and peripheral blood stem cells on day 17. Alternating dose escalation of vorinostat and MIBG was performed using a 3+3 design.

        Results

        Twenty-seven patients enrolled to six dose levels, with 23 evaluable for dose escalation. No dose-limiting toxicities (DLT) were seen in the first three dose levels. At dose level 4 (15 mCi/kg MIBG/230 mg/m(2) vorinostat), 1 of 6 patients had DLT with grade 4 hypokalemia. At dose level 5 (18 mCi/kg MIBG/230 mg/m(2) vorinostat), 2 patients had dose-limiting bleeding (one grade 3 and one grade 5). At dose level 5a (18 mCi/kg MIBG/180 mg/m(2) vorinostat), 0 of 6 patients had DLT. The most common toxicities were neutropenia and thrombocytopenia. The response rate was 12% across all dose levels and 17% at dose level 5a. Histone acetylation increased from baseline in peripheral blood mononuclear cells collected on days 3 and 12 to 14.

        Conclusions

        Vorinostat at 180 mg/m(2)/dose is tolerable with 18 mCi/kg MIBG. A phase II trial comparing this regimen to single-agent MIBG is ongoing.
          Cover page: Phase I Study of Vorinostat as a Radiation Sensitizer with 131I-Metaiodobenzylguanidine (131I-MIBG) for Patients with Relapsed or Refractory Neuroblastoma
          • Article
          • Peer Reviewed
          UC San Francisco Previously Published Works (2021)

          Objective

          Sulfonylureas, the first available drugs for the management of type 2 diabetes, remain widely prescribed today. However, there exists significant variability in glycemic response to treatment. We aimed to establish heritability of sulfonylurea response and identify genetic variants and interacting treatments associated with HbA1c reduction.

          Research design and methods

          As an initiative of the Metformin Genetics Plus Consortium (MetGen Plus) and the DIabetes REsearCh on patient straTification (DIRECT) consortium, 5,485 White Europeans with type 2 diabetes treated with sulfonylureas were recruited from six referral centers in Europe and North America. We first estimated heritability using the generalized restricted maximum likelihood approach and then undertook genome-wide association studies of glycemic response to sulfonylureas measured as HbA1c reduction after 12 months of therapy followed by meta-analysis. These results were supported by acute glipizide challenge in humans who were naïve to type 2 diabetes medications, cis expression quantitative trait loci (eQTL), and functional validation in cellular models. Finally, we examined for possible drug-drug-gene interactions.

          Results

          After establishing that sulfonylurea response is heritable (mean ± SEM 37 ± 11%), we identified two independent loci near the GXYLT1 and SLCO1B1 genes associated with HbA1c reduction at a genome-wide scale (P < 5 × 10-8). The C allele at rs1234032, near GXYLT1, was associated with 0.14% (1.5 mmol/mol), P = 2.39 × 10-8), lower reduction in HbA1c. Similarly, the C allele was associated with higher glucose trough levels (β = 1.61, P = 0.005) in healthy volunteers in the SUGAR-MGH given glipizide (N = 857). In 3,029 human whole blood samples, the C allele is a cis eQTL for increased expression of GXYLT1 (β = 0.21, P = 2.04 × 10-58). The C allele of rs10770791, in an intronic region of SLCO1B1, was associated with 0.11% (1.2 mmol/mol) greater reduction in HbA1c (P = 4.80 × 10-8). In 1,183 human liver samples, the C allele at rs10770791 is a cis eQTL for reduced SLCO1B1 expression (P = 1.61 × 10-7), which, together with functional studies in cells expressing SLCO1B1, supports a key role for hepatic SLCO1B1 (encoding OATP1B1) in regulation of sulfonylurea transport. Further, a significant interaction between statin use and SLCO1B1 genotype was observed (P = 0.001). In statin nonusers, C allele homozygotes at rs10770791 had a large absolute reduction in HbA1c (0.48 ± 0.12% [5.2 ± 1.26 mmol/mol]), equivalent to that associated with initiation of a dipeptidyl peptidase 4 inhibitor.

          Conclusions

          We have identified clinically important genetic effects at genome-wide levels of significance, and important drug-drug-gene interactions, which include commonly prescribed statins. With increasing availability of genetic data embedded in clinical records these findings will be important in prescribing glucose-lowering drugs.
            Cover page: Genome-Wide Meta-analysis Identifies Genetic Variants Associated With Glycemic Response to Sulfonylureas
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