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Association of Three Biomarkers of Nicotine As Pharmacogenomic Indices of Cigarette Consumption in Military Populations DISSERTA

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Association of Three Biomarkers of Nicotine As Pharmacogenomic Indices of Cigarette Consumption in Military Populations DISSERTA Association of Three Biomarkers of Nicotine as Pharmacogenomic Indices of Cigarette Consumption in Military Populations DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By William Arthur Matcham Graduate Program in Nursing The Ohio State University 2014 Dissertation Committee: Professor Karen L. Ahijevych, PhD, Advisor Professor Donna L. McCarthy, PhD Professor Kristine Browning, PhD Professor Yvette Conley, PhD Copyright by William Arthur Matcham 2014 ABSTRACT Tobacco-related diseases have reached epidemic proportions. There is no risk-free level of tobacco exposure. In the United States, tobacco use is the single largest preventable cause of death and disease in both men and women. Cigarette smoking alone accounts for approximately 443,000 deaths per year (one fifth of total US deaths) costing a staggering $193 billion per year in avoidable healthcare expenses and lost productivity. Literature shows military populations have rates of tobacco use two to three times higher than the civilian population. Military personnel returning from deployment in conflict areas can exceed 50% smoking prevalence. Research shows that genetic factors account for 40-70% of variation in smoking initiation and 50-60% of variance in cessation success. In the U.S., tobacco is responsible for more deaths than alcohol, AIDS, car accidents, illegal drugs, murders and suicides combined. This descriptive, cross-sectional study examined three of the biological markers used in tobacco research: the α4β2 brain nicotinic receptors (nAChR) that contribute to genetic risk for nicotine dependence, nicotine metabolite ratio (NMR) as a phenotypic marker for CYP2A6 activity, and bitter taste phenotype (BTP) to determine their impact on cigarette consumption in military populations. Sociodemographic and military variables were examined to determine if they impacted biomarker relationships. The availability of reliable biomarkers will facilitate development of personalized smoking cessation therapies for military personnel. ii The first chapter reviewed the state of the science related to the nicotine metabolism in the human body, nicotine acetylcholine receptor in the brain and perception of bitter taste as they apply to nicotine and smoking research. An in-depth description of CYP2A6 genetics and phenotype measurement is presented including identification of gene variation, problems with standardizing genetic testing, naming conventions and classifications. The function of nicotine acetylcholine receptor is reviewed with a detailed description of the rs16969968 single nucleotide polymorphism used to characterize risk of nicotine dependence. Bitter taste phenotype is reviewed in the context of cigarette smoking. The second chapter provided an overview of recruitment techniques used with military personnel. A timeline of recruitment activities was followed by a review of internal and external environmental influences that affected recruitment. An analysis of lessons learned is presented with a summary of strategies to overcome recruitment challenges which can be applied to broader populations than military personnel. The third chapter presents the method and procedures of the study. Inadequate subject accrual resulted in only 15 of the expected 160 participants completing the study. The results of the study were analyzed with biserial and Kendall’s tau coefficients but overall were not significant. The planned prediction modeling and interaction analysis could not be conducted due to low participant enrollment. Results did show some interesting relationships between military and sociodemographic variables. This study has provided valuable data to characterize the diverse individuals in the military and provides evidence for inclusion of this important group in future studies. iii To my wife Ann for inspiring me to dream iv ACKNOWLEDGMENTS I would like to express sincere gratitude to Dr. Karen Ahijevych for her unwavering support and mentorship in my academic pursuits and professional development as a scholar. I would like to thank Dr. Donna McCarthy, Dr. Kristine Browning and Dr. Yvette Conley for their expertise and continued support throughout my doctoral education. I appreciate your time and energy to provide comments and edits on my documents and always being available for consultation. I would also like to thank Dr. von Sadovszky for her support, guidance and mentorship as I transition into a faculty role. Special thanks to Dr. Christopher Bartlett for volunteering to represent the Graduate Faculty during my dissertation defense. Most importantly I would like to thank my wife Ann for her endless patience and unwavering support. This research was supported by a generous financial award from the Epsilon Chapter of Sigma Theta Tau at the Ohio State University College of Nursing. v VITA June 1989 .......................................................Elyria West High School 1998 ...............................................................A.A.S Nursing, Lorain County Community College 2003 ...............................................................A.A.S Technical Studies – Electronic Communication Technology / Digital Instrumentation Systems, Excelsior College 2007 ...............................................................B.S.N. Nursing, Capital University 2011 ...............................................................Fellowship Summer Genetics Institute, National Institutes of Health, National Institute of Nursing Research 2012 ...............................................................M.S. Nursing Science, The Ohio State University 2012 ...............................................................Graduate Interdisciplinary Specialization in University and College Teaching, The Ohio State University 1999 to 2000 .................................................Registered Nurse, Perioperative Services, University Hospitals of Cleveland 2000 to 2005 .................................................Registered Nurse, Traveling Nurse Perioperative Services, RN Network vi 2005 to 2009 .................................................Registered Nurse, Intensive and Cardiac Care Unit, Doctor’s Hospital West 2004 to 2012 .................................................Registered Nurse, Disaster Medical Assistance Team OH-5, National Disaster Medical System, U.S. Department of Health and Human Services 2008 to 2009 .................................................Graduate Teaching Associate, College of Nursing, The Ohio State University 2009 to Present ..............................................Graduate Administrative Associate, College of Nursing Information Technology, The Ohio State University 2011 to Present ..............................................Graduate Research Associate, College of Nursing, The Ohio State University Fields of Study Major Field: Nursing vii Table of Contents Abstract ............................................................................................................................... ii Acknowledgments............................................................................................................... v Vita ..................................................................................................................................... vi List of Tables ................................................................................................................... xiii List of Figures ................................................................................................................... xv Chapter 1: Three Biomarkers of Tobacco Use: State of the Science ................................. 1 Introduction ..................................................................................................................... 1 Nicotine Metabolism ....................................................................................................... 3 Nicotine ....................................................................................................................... 3 Metabolism .................................................................................................................. 4 Nicotine Metabolism Genetics .................................................................................... 6 Genetic Grouping Nomenclature ............................................................................... 11 Phenotypic Measurement of Nicotine Metabolism ................................................... 15 NMR Phenotype Group Nomenclature ..................................................................... 17 NMR Phenotype Ethnic Variation ............................................................................. 18 Nicotine Dependence .................................................................................................... 20 viii Nicotine Acetylcholine Receptors ............................................................................. 21 Nicotine Receptor Genetic Variation ........................................................................ 22 RS16969968 Genetic Variant of α4β2α5 Receptors ................................................. 24 RS16969968 as proxy for Nicotine Dependence ...................................................... 25 Bitter Taste Perception .................................................................................................. 30 Bitter taste genetics ...................................................................................................
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