Browsing by Subject "Gout"
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Item Pharmacogenetic Investigations Using Community-Based Participatory Research to Address Health Disparities in Minnesota Hmong(2017-08) Roman, YoussefIntroduction: Pharmacogenomics is an approach to personalizing therapy to help patients achieve their therapeutic goals with the least possible adverse events. This approach relies on the knowledge derived from large genetic studies that involve diverse populations to guide the development of treatment algorithms. The underrepresentation of select populations or unique sub-populations in genetic-based research presents as a gap in knowledge to create comprehensive genetic-based treatment algorithms and a missed opportunity to address health disparities within those unique populations. A prime example is the Minnesota Hmong. The Hmong is an Asian sub-population minimally represented in clinical or genetic-based research with a high prevalence of gout and gout-related comorbidities than non-Hmong. Methods: Using the principles of community-based participatory research and the establishment of the Hmong advisory board, assessment of the community’s perception of genetics and preparedness for engagement in research were conducted. Capitalizing on the findings from the first informational study, two Hmong genetic-based studies were conducted. The first study was to ascertain the frequency of select pharmacogenes and disease-risk genes in the Hmong, relative to non-Hmong. The second study was to quantify the effect of genetic variations within uric acid transportome and purine metabolizing genes on the pharmacokinetics and pharmacodynamics of allopurinol in Hmong adults with gout or hyperuricemia. Results: The informational study results indicated that most Hmong are willing to participate in research to help themselves and the Hmong community. Some of the genetic perceptions in the Hmong were not scientifically grounded and some concerns about privacy were reported while the return of genetic results to participants had mixed responses. The first genetic-based study indicated that more than 80% of Hmong participants were willing to store their DNA for future analyses and share their DNA with other scientists. Pharmacogenes risk allele frequencies of CYP2C19, CYP2C9, VKORC1, and CYP4F2 were higher in the Hmong relative to Caucasian. Disease risk allele frequencies of hyperuricemia and gout associated genes such as SLC2A9, SLC17A1, SLC22A11, SLC22A12, ABCG2, PDZK1, were also higher in the Hmong than Caucasian and Han-Chinese. The second genetic-based study indicated that the genetic variation within SLC22A12 (rs505803T>C) significantly affects the exposure to and the renal clearance of the active metabolite of allopurinol, oxipurinol. Additionally, the rs505802 was also significantly associated with the overall response to allopurinol. Conclusions: Engaging the Hmong in genetic-based research is a step forward to advance precision medicine while addressing health disparities within the Hmong community. The prevalence of pharmacogenes within the Hmong suggest that the Hmong will require a lower starting dose of warfarin and unlikely to benefit from clopidogrel. The prevalence of hyperuricemia and gout associated risk alleles in the Hmong are consistent with the higher prevalence of gout in the Hmong. Finally, the rs505802 T>C within SLC22A12 gene could predict the overall response to allopurinol.Item Toward Individualized Medicine in Understudied Populations using Personal Genome and Microbiome(2022-03) Wen, Ya-FengOn 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.