Introduction: 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.
University of Minnesota Ph.D. dissertation. August 2017. Major: Experimental & Clinical Pharmacology. Advisor: Robert Straka. 1 computer file (PDF); xii, 237 pages.
Pharmacogenetic Investigations Using Community-Based Participatory Research to Address Health Disparities in Minnesota Hmong.
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