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The Genetics and Definition of Salt Sensitivity in Blacks THE GENETICS AND DEFINITION OF SALT SENSITIVITY IN BLACKS by KAINE CHAMBERLAIN ONWUZULIKE, M.D. Submitted in partial fulfillment of the requirements For the degree Doctor of Philosophy Dissertation Advisor: Christopher Whalen, M.D., M.S. Department of Epidemiology and Biostatistics CASE WESTERN RESERVE UNIVERSITY August, 2008 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of _____________________________________________________ candidate for the ______________________degree *. (signed)_______________________________________________ (chair of the committee) ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ (date) _______________________ *We also certify that written approval has been obtained for any proprietary material contained therein. Table of Contents List of Tables 3 List of Figures 5 Acknowledgements 6 List of Commonly Used Abbreviations 8 Abstract 9 Chapter 1: Introduction and Specific Aims 11 Chapter 2: Background and Significance 17 Chapter 3: Methods 28 Chapter 4: Statistical Definition of Salt Sensitivity 45 Chapter 5: Results 5.1 GSSH Results 55 5.2 Discussion 64 Chapter 6: Results 6.1 Association Analysis i. Background 67 ii. Methods 70 iii. Results 77 6.2 Summary 81 Chapter 7: Conclusion 7.1 Discussion 84 7.2 Future Direction 89 Table and Figures 92 Appendix A Candidate Genes 137 B GSSH Assessment Sheets 157 C Code for Statistical Analyses (R Package/S.A.G.E.) 177 Literature Cited 220 - 2 - List of Tables Table 1 List of candidate genes/regions 92 Table 2 Inclusion and Exclusion Criteria for GSSH Study 94 Table 3 GSSH Recruietment Strategy 95 Table 4 Expected power based on # of affected sib pairs 96 Table 5 Definition of SS in statistical analysis 97 Table 6 Statistical Performance -Different measures of SS 98 (Sierra et al) Table 7 Demographics of Study Participants (Preliminary Study-p450) 99 Table 8 Statistical SS Prevalence (Preliminary Study-p450) 100 Table 9 Min. MAP difference detected by statistical method 101 using 8 vs. 17 readings Table10 Verification of SS by statistical testing using 2-17 readings 102 Table 11 Evaluation of individual test performance 103 Table 12 SS prevalence based on both cliniclal and statistical critieria 104 Table 13 Clinically significant SS prevalence (8 vs 17 BP readings) 105 Table 14 Mean values of Δ Map Based on HTN status and 106 statistical definition Table 15 Mean values of Δ Map Based on HTN status and 107 clinical definition Table 16 Baseline Demographic Data GSSH 108 Table 17 Mulitivariate analysis (ignoring sibling correlation) 109 Table 18 Mulitivariate analysis (with sibling correlation) 110 Table 19 Fixed effects of ΔMAP 111 - 3 - Table 20 Significant SNP’s for ΔMAP 112 Table 21 Significant SNP’s for trait ΔMAP (chromosome, gene, 113 and function) Tabel 22 Fisher’s Exact and Pearson’s correlation (chromosome 2) 114 Tabel 23 Fisher’s Exact and Pearson’s correlation (chromosome 14) 115 Tabel 24 Fisher’s Exact and Pearson’s correlation (chromosome 16) 116 Table 25 Linkage Disequilibrium and deviations from HWE 117 (ch 2, 14, 16) - 4 - List of Figures Figure 1 Prevalence and percent of hypertension 118 Figure 2 Prevalence of Hypertension by Race (AHA 2007) 119 Figure 3 Prevalence of Hypertension in African & European 120 Origin Populations Figure 4 Physiological response to sodium intake (Menton et al) 121 Figure 5 Renal Mutations and polymorphisms affecting blood pressure 122 Figure 6 Randomization of study participants (Preliminary Study) 123 Figure 7 Baseline Distribution of Systolic Blood Pressure 124 Figure 8 Baseline Distribution of Diastolic Blood Pressure 125 Figure 9 Baseline Distribution of MAP Blood Pressure 126 Figure 10 Comparison by statistical testing of salt sensitivity prevalence 127 Figure 11 ΔMAP in AA and white subjects after high salt diet 128 Figure 12 Comparison of 8 vs 17 BP readings (statistical) 129 Figure 13 Average MAP on high salt diet AA and whites 130 Figure 14 Average MAP on low salt diet AA and whites 131 Figure 15 Average MAP of all participants on low salt diet 132 Figure 16 Flow chart of screened participants for GSSH study 133 Figure 17 Pair Plot (age vs. cardiovascular factors) 134 Figure 18 Number of new genetic association studies (1984-2002) 135 Figure 19 Frequency of published genetic association studies 136 (2000-2006) - 5 - Acknowledgements This work was made possible by the generous contributions of several people. First and foremost, I would like to extend my deepest gratitude to my dissertation committee for their time, knowledge, advice, and most notably their collective patience. Dr. Whalen’s (Committee Chair) expertise and insight has been invaluable throughout this process and he has combined a sincere perspective with balanced outlook, culminating in the successful opportunity to defend my work. I would like to thank Dr. Rimm (Immediate Past Chair, Epidemiology & Biostatistics) for his timely and honest assessment of my progress and work, and for continuous motivation to “just get it done”. He has been more than accommodating with respect to his time and even more generous in the dissemination of applicable epidemiological methodology. Dr. Luo’s (Committee Member) statistical expertise helped form the basis of much my initial investigations in this project. She constantly challenged me to think critically and efficiently both as a teacher during my years in the Genetic & Molecular Epidemiology tract, and later as committee member on this project. I have further honed some of my most valuable investigative techniques under her tutelage. Perhaps the greatest inspiration towards the completion of this project came from both Drs. Robert Haynie (Committee Member), and Jackson Wright (Research Advisor). They each possess unique and admirable traits that have made them quite successful in their own right, including outstanding work ethic, poise, aptitude and commitment. In attempting to follow directly in their footsteps by becoming a notable Black M.D./Ph.D. clinician and academician, they allowed me great autonomy in this work and provided a - 6 - stern yet reassuring sense of confidence that anything was possible with proper planning and execution. My investigative skills and critical thinking abilities were sharply developed in working with Dr. Wright. Over the past decade, he has been instrumental in my progression from a budding medical student researcher during my junior years of medical school, to now feeling dedicated and confident in my ability as recommended by the American College of Epidemiology for doctoral trainees to be able upon graduation, to carry out all aspects of molecular epidemiological research, from primary data collection, to the analysis, interpretation and reporting of key findings. I would also like to thank Sungho Won for his statistical prowess in completing the first round of analysis of the GSSH project. It is because of our commiseration that I developed my ‘code’ writing ability which I employed throughout this project. I would be remiss if I did not acknowledge perhaps the most important people involved throughout this process. They are my mother, sister and brother who have been pivotal in my continuing success, and have often put my needs before their wants and desires. They have instilled in me the 4 D’s (Dedication, Discipline, Determination and Desire) to success which I carry with me for eternity. Lastly, I would like to thank my wife Sophia for her kindness, patience and support. She has blessed me with a wonderful star of unending radiance in our daughter, my life, Zoe Jasmin of whom I ultimately dedicate this and all future work. Thank God for all of you, for without him strategically placing you all in my life, I would not be here today! - 7 - List of Commonly Used Abbreviations AA: Black ABPM: Ambulatory Blood Pressure Measurement AHA: American Heart Association BP: Blood Pressure DBP: diastolic blood pressure ERSD: End-Stage-Renal-Disease Etoh: Alcohol GSSH: Genetics of Salt Sensitivity and Hypertension HTN: Hypertension HWE: Hardy-Weinberger Equilibrium LD: Linkage Disequilibrium MAP: Mean Arterial Pressure Na+: Sodium NE: Norepinephrine SBP: systolic blood pressure SNP’s: Single Nucleotide Polymorphisms SS: Salt sensitive VAMC: Veteran Affair’s Medical Center - 8 - The Genetics and Definition of Salt Sensitivity in Blacks Abstract by KAINE CHAMBERLAIN ONWUZULIKE, M.D. Essential hypertension is a multifactorial disorder whose prevalence, morbidity, and mortality are disproportionately high in the Black population. Blacks are also reported to display amplified increase in blood pressure compared to other populations in response to salt, although much of this observed difference may be based on unmatched patient selection. The cellular and molecular mechanisms of salt sensitive hypertension in humans remain poorly defined, and our knowledge of potential genetic mechanisms remains incomplete. Blacks have significantly higher intracellular Na and depressed activity of the Na pump as compared to Whites suggesting that these may be important phenotypic markers of salt sensitive hypertension. An increase in intracellular Na is positively correlated with increases in systolic blood pressure following one week of low salt vs. one week of high salt diet in Blacks but not in Whites. Moreover, this inverse relationship was noted
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