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Roman Umn 0130E 18396.Pdf (2.096Mb Application/Pdf) Pharmacogenetic Investigations Using Community-Based Participatory Research to Address Health Disparities in Minnesota Hmong A Dissertation SUBMITTED TO THE FACULTY OF UNIVERSITY OF MINNESOTA BY Joseph Malak Roman IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY Adviser: Robert J Straka, Pharm.D., F.C.C.P. August 2017 © Joseph Malak Roman 2017 Acknowledgements This dissertation would not have been completed unless I had the support from a multitude of individuals from the Experimental and Clinical Pharmacology (ECP) Department and the College of Pharmacy at the University of Minnesota. First and foremost, I’m beyond grateful to my advisor, Dr. Robert Straka, for all his support, guidance and patience that he offered me throughout my training. Looking back on where I started and who I’m today, professionally, I realize that my career development was the result of continuous feedback and ongoing assessment of my work during the graduate school. I also want to thank Dr. Kathleen Culhane-Pera for being an outstanding community collaborator and support to my success. Indeed, she is an example to look up to when working with special and underserved communities. Finally, I want to thank the Hmong board members for their important role in making the university-community partnership very successful, the GOUT-H study volunteers, the study participants and the ECP faculty and staff. iii Dedication This dissertation is dedicated to my dad and grandmother whom I miss dearly. iv Abstract 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. v 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. vi Table of Contents List of Tables ..................................................................................................................................................xi List of Figures ............................................................................................................................................... xii Chapter 1 ......................................................................................................................................................... 1 Chapter Overview ........................................................................................................................................ 2 The History and Demographics of the Hmong ............................................................................................. 2 Gout Prevalence across Racial Groups ......................................................................................................... 5 Gout Prevalence in Minnesota Hmong ......................................................................................................... 7 Hmong Perceptions of Managing Chronic Diseases .................................................................................... 8 Dietary and Lifestyle Practices of the Hmong and Risk of Gout ............................................................... 11 Hmong and Minorities in Clinical Genetics Research ............................................................................... 15 Clinical Genetic Research Challenges and Opportunities .......................................................................... 16 Implementing Community-Based Participatory Research Model in Minnesota Hmong ........................... 18 Background: .......................................................................................................................................... 18 Approach: .............................................................................................................................................. 19 Results and Discussion: ......................................................................................................................... 21 Future Research Opportunities and Cultural Perspectives ......................................................................... 22 Chapter Summary ....................................................................................................................................... 24 Chapter 2 ....................................................................................................................................................... 33 Chapter Overview ...................................................................................................................................... 34 Gout: The Disease of Distinction ............................................................................................................... 34 Epidemiology of Hyperuricemia and Gout ................................................................................................ 36 Economic Impact of Managing Patients with Gout .................................................................................... 38 Pathogenesis of Hyperuricemia and Gout .................................................................................................. 39 Genetics of Hyperuricemia and Gout ......................................................................................................... 42 Risk Factors for Hyperuricemia ................................................................................................................. 43 Secondary Hyperuricemia .......................................................................................................................... 46 Drug-Induced Hyperuricemia ............................................................................................................... 46 Disease-Induced Hyperuricemia ........................................................................................................... 51 vii Hyperuricemia Secondary to Renal Insufficiency.................................................................................. 52 Uric Acid Reference Levels Confounders .................................................................................................. 52 Age and sex ............................................................................................................................................ 53 Race and genetics .................................................................................................................................. 53 Pregnancy .............................................................................................................................................
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