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Computational Approach to Studying the Pharmacogenetics of Transporters

  • Author(s): Wen, Christopher Chun-Hong
  • Advisor(s): Giacomini, Kathy M
  • et al.
Abstract

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.

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