Genetic and Environmental Factors Influencing Circulating Concentration of Vitamin D Metabolites and Odds of Colorectal Neoplasia Item Type Electronic Dissertation; text Authors Hibler, Elizabeth Anne Publisher The University of Arizona. Rights Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. Download date 05/10/2021 11:50:32 Link to Item http://hdl.handle.net/10150/145300 GENETIC AND ENVIRONMENTAL FACTORS INFLUENCING CIRCULATING CONCENTRATION OF VITAMIN D METABOLITES AND ODDS OF COLORECTAL NEOPLASIA. by Elizabeth Anne Hibler ______________________ A Dissertation Submitted to the Faculty of the MEL AND ENID ZUCKERMAN COLLEGE OF PUBLIC HEALTH In Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY WITH A MAJOR IN EPIDEMIOLOGY In the Graduate College THE UNIVERSITY OF ARIZONA 2011 2 THE UNIVERSITY OF ARIZONA GRADUATE COLLEGE As members of the Dissertation Committee, we certify that we have read the dissertation prepared by Elizabeth Anne Hibler entitled GENETIC AND ENVIRONMENTAL FACTORS INFLUENCING CIRCULATING CONCENTRATION OF VITAMIN D METABOLITES AND ODDS OF COLORECTAL NEOPLASIA. and recommend that it be accepted as fulfilling the dissertation requirement for the Degree of Doctor of Philosophy _______________________________________________________________________ Date: 3/21/2011 Elizabeth Jacobs, Ph.D. _______________________________________________________________________ Date: 3/21/2011 Maria Elena Martinez, Ph.D. _______________________________________________________________________ Date: 3/21/2011 Chengcheng Hu, Ph.D. _______________________________________________________________________ Date: 3/21/2011 Eugene Gerner, Ph.D. _______________________________________________________________________ Date: 3/21/2011 Patricia Thompson, Ph.D. Final approval and acceptance of this dissertation is contingent upon the candidate’s submission of the final copies of the dissertation to the Graduate College. I hereby certify that I have read this dissertation prepared under my direction and recommend that it be accepted as fulfilling the dissertation requirement. ________________________________________________ Date: 3/21/2011 Dissertation Director: Elizabeth Jacobs, Ph.D. 3 STATEMENT BY AUTHOR This dissertation has been submitted in partial fulfillment of requirements for an advanced degree at the University of Arizona and is deposited in the University Library to be made available to borrowers under rules of the Library. Brief quotations from this dissertation are allowable without special permission, provided that accurate acknowledgment of source is made. Requests for permission for extended quotation from or reproduction of this manuscript in whole or in part may be granted by the head of the major department or the Dean of the Graduate College when in his or her judgment the proposed use of the material is in the interests of scholarship. In all other instances, however, permission must be obtained from the author. SIGNED: Elizabeth Anne Hibler 4 ACKNOWLEDGEMENTS There are many individuals who supported me through this dissertation work and the years leading up to it. Dr. Howell and the staff of the Indiana State Department of Health showed me what it really means to work in public health and pushed me to take the next step. The staff of the supplement trial provided critical support and I could not have completed it without the help of Sibeso Namakando, Chad Wagoner, Marty Cisneroz, and the dedicated staff of the CaTS center at the University of Arizona. Bess LeRoy and Erin Ashbeck were central to my learning R and the statistical methods used for the genetic analysis. I am especially thankful for having had a committee that was so supportive of my ideas and tolerant of my questions. Thank you all for being so patient and always willing to help. I am grateful for the unwavering support of my family and friends, who tolerated my ramblings about vitamin D with patience and generous smiles. Shivani, thank you for always being ready with a pep talk and providing the words that I needed to stay focused. To my Tucson family, thank you for your willingness to help me whenever I need it and making sure that I stayed sane throughout this process. To my Indiana family, thank you for giving me the strength to fly the coop. To my sisters, thank you for the words of encouragement and always listening when I needed a break. To my father, thank you for always telling me how “smart” you think I am and for having the generous and kind spirit that taught me the value of choosing a career focused on helping others. Finally, to my mother, thank you for always insisting that your girls would go to college, making sure I had the confidence to make it through, and buying me my first microscope. 5 DEDICATION To Monnie Hibler and Jeff Peterson, who remind me every day of why I do this… 6 TABLE OF CONTENTS LIST OF TABLES .............................................................................................................. 8 LIST OF FIGURES……………...………………………………………………………10 ABSTRACT ...................................................................................................................... 11 I. INTRODUCTION ......................................................................................................... 13 A. EXPLANATION OF THE PROBLEM ............................................................................... 13 B. GOALS AND OBJECTIVES .......................................................................................... 14 C. ROLE OF THE AUTHOR IN THE RESEARCH .................................................................. 15 D. BACKGROUND .......................................................................................................... 17 1. Vitamin D: synthesis and metabolism ................................................................. 17 2. Vitamin D Receptor and Mechanism of Action ................................................... 22 3. Vitamin D and Calcium Homeostasis ................................................................... 27 4. Vitamin D deficiency ............................................................................................ 30 5. Epidemiology of vitamin D deficiency and factors influencing circulating concentrations of 25(OH)D....................................................................................... 32 6. Summary of evidence for effectiveness of cholecalciferol supplementation ...... 45 7. Evidence for the role of selected genes in etiology of vitamin D deficiency ...... 52 8. Vitamin D and cancer ........................................................................................... 59 9. Genetic variation in CASR and GC and colorectal neoplasia outcomes ............... 67 E. SUMMARY OF THE INTRODUCTION ............................................................................ 70 II. PRESENT STUDY ...................................................................................................... 72 A. INTRODUCTION ......................................................................................................... 72 B. VITAMIN D SUPPLEMENT CLINICAL TRIAL ................................................................ 72 1. Methods................................................................................................................. 72 2. Results .................................................................................................................. 80 C. ASSOCIATION BETWEEN POLYMORPHIC VARIATION IN VDR, RXR, GC, AND CASR AND CIRCULATING CONCENTRATIONS OF 25(OH)D ....................................................... 91 1. Methods for Aims 2 and 3 .................................................................................... 91 2. Results ................................................................................................................. 103 D. ASSOCIATION BETWEEN GENETIC VARIATION IN GC AND CASR AND ODDS OF METACHRONOUS COLORECTAL NEOPLASIA. ................................................................. 124 1. Methods............................................................................................................... 124 2. Results ................................................................................................................ 124 III. DISSERTATION CONCLUSIONS AND FUTURE DIRECTIONS ...................... 132 A. DISCUSSION AND CONCLUSIONS ............................................................................. 132 1. Specific Aim 1: pilot study to assess whether over-the-counter vitamin D supplements affect circulating concentrations of 25(OH)D in the blood. .............. 133 2. Specific aim 2: association between genetic variation in VDR, RXR, GC, and CASR and circulating concentrations of 25(OH)D ................................................ 139 7 TABLE OF CONTENTS- Continued 3. Specific aim 3: association between genetic variation in GC and CASR and odds of metachronous colorectal neoplasia ..................................................................... 147 4. Statistical methods for genetic analysis ............................................................. 152 5. Strengths and Limitations ..................................................................................