Toward Individualized Medicine in Understudied Populations using Personal Genome and Microbiome
2022-03
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Toward Individualized Medicine in Understudied Populations using Personal Genome and Microbiome
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2022-03
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On January 30, 2015, the US President Barak Obama first announced the Precision Medicine Initiative cohort program in his State of Union address. This program emphasized the critical need for creative approaches to precision medicine and use the evidence to guide clinical practice. Following this announcement, All of Us network was established in July 2016 with a target of enrolling at least 1 million persons with diverse ethnic backgrounds to discover genetic and environmental factors that correlated with disease, to improve predictions of therapeutic safety and efficacy, to discover disease biomarkers, to improve understanding of health disparities, to return data to participants, and many others. These themes with the All of Us initiative resonate with our goals to actively include diverse populations in research programs. This thesis demonstrates research projects which enrolled an understudied population in clinical studies with various objectives, including 1) identify and quantify commonly tested and novel genetic variants within very important pharmacogenes; 2) develop a genotype-guided strategy for allopurinol dose selection in patients with gout to increase attainment of treatment success; and 3) design a clinical study to quantitatively examine how genetics and microbiome can impact the serum-lowering effect of vitamin C. We found significant differences in allele frequencies between the Hmong and East Asians for 23% (5/22) of the CPIC actionable variants tested. These pharmacogenes include CYP2C9*3A, CYP2C19*2, CYP2C19*3, CYP4F2*3, and SLCO1B1*5. Additionally, a higher portion of Hmong participants (50%) are predicted to have an intermediate metabolizer phenotype for CYP2D6 compared to other East Asians which range between 27%-44%. The differences significantly influenced predicted medication usage recommendations in warfarin, simvastatin, and phenytoin, and many other drugs metabolized by CYP2D6 between Hmong and East Asians. Three novel suballeles within CYP2D6 (*10.007, *36.004, and *75.002) were also identified in the Hmong population. Our findings underscore the importance of thoroughly interrogating unique subpopulations to accurately predict a patient’s metabolizer status for key drug metabolizing enzymes and transporters. Combining the knowledge of pharmacogenes and population pharmacokinetics and pharmacodynamics, we proposed an allopurinol dosing guide based on fat-free mass, renal function, and SLC22A12 and PDZK1 genotype to achieve target serum urate, a critical biomarker for gout in the Hmong. This observation is significant due to the high prevalence and disease burden of gout observed in this population. Finally, we designed and conducted a prospective open-labelled clinical trial to quantify the impact of vitamin C on serum urate in Hmong adults with and without hyperuricemia and/or gout, and to identify associations between vitamin C, transporter genomics, gut microbiome, and consequent serum urate level. The development an individualized strategy combining knowledge of pharmacogenes, microbiota, and patients’ characteristics to select optimal therapies that can safely and effectively tailor treatment represents a promising approach to select the right medication with the right dose in the Hmong patients. The research strategies demonstrated in this these are expected to positively impact the severity of illness, mortality, and healthcare costs for Hmong and other understudied populations with many other related diseases.
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University of Minnesota Ph.D. dissertation .March 2022. Major: Experimental & Clinical Pharmacology. Advisor: Robert Straka. 1 computer file (PDF); xiii, 126 pages.
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Wen, Ya-Feng. (2022). Toward Individualized Medicine in Understudied Populations using Personal Genome and Microbiome. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/254116.
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