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The Genetics of Nontraditional Glycemic Biomarkers of Type 2 Diabetes

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The Genetics of Nontraditional Glycemic Biomarkers of Type 2 Diabetes THE GENETICS OF NONTRADITIONAL GLYCEMIC BIOMARKERS OF TYPE 2 DIABETES by Stephanie J. Loomis, MPH A dissertation submitted to The Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland May, 2018 © 2018 Stephanie J. Loomis All rights reserved Abstract Type 2 diabetes is a major public health problem that affects over 10% of the US adult population. It is associated with substantially increased risks of mortality and serious clinical outcomes such as heart disease, stroke, kidney disease and retinopathy. Diabetes is defined by hyperglycemia, or elevated glucose concentrations in the blood, which are commonly measured by fasting glucose and hemoglobin A1c (HbA1c), but these have limitations. As a result, nontraditional glycemic biomarkers, fructosamine, glycated albumin and 1,5-anhydroglucitol (1,5-AG) are gaining interest. While it is established that genetics play a role in type 2 diabetes, fasting glucose, and HbA1c, the genetics of fructosamine, glycated albumin, and 1,5-AG have not been well explored. This dissertation sought to determine the amount of variation in each biomarker due to genetics through heritability estimation, and to determine the specific genetic variants associated with each biomarker though genome wide association study (GWAS) analysis, multivariate phenotype analysis, and exome sequencing analysis. Heritability estimates showed a substantial portion of fructosamine, glycated albumin and 1,5-AG variation was due to genetics, which is likely comprised of both common and rare variants. GWAS identified common variants associated with fructosamine and glycated albumin including a known diabetes variant and a likely nonglycemic variant. Exome sequencing did not identify variants associated with fructosamine and glycated albumin, but multivariate phenotype analysis identified a potentially interesting region in a gene that alters bilirubin levels that may affect fructosamine in a nonglycemic manner. Exome sequencing identified rare, coding variants with large effect size in a glucose transporting gene associated with 1,5-AG ii which inform the biology and may impact the clinical interpretation of 1,5-AG. Analyzing the genetics of nontraditional glycemic biomarkers of type 2 diabetes has increased the understanding of these biomarkers, including their underlying biology, and may aid in decisions about their clinical implementation. Dissertation Readers Priya Duggal, PhD, MPH (Advisor) Associate Professor of Epidemiology and International Health Elizabeth Selvin, PhD, MPH Professor of Epidemiology and Medicine Rasika Mathias, ScD Associate Professor of Medicine Ni Zhao, PhD Assistant Professor of Biostatistics iii Acknowledgements I would like to thank a number of people who have helped me along the way to pursuing a PhD. Firstly, I would like to thank Priya Duggal, who has been an excellent advisor. She has given me so much of her time and helped guide me through each step of the PhD process. She has challenged me to move beyond the methods and results to really grasp the “but why does it matter?” aspect of my work. I would also like to thank Liz Selvin, for venturing into the genetics world as my co-advisor. She gives so much to her students and is incredibly patient with multiple rounds of revisions to make sure my work is the best it can be. I would also like to thank the other members of my dissertation committee, Joe Coresh and Adrienne Tin for their helpful insight. My coauthors on this work have given thoughtful and useful comments. In particular, Anna Köttgen has provided guidance on much of this work. Even from across the Atlantic, she is ready with prompt replies with knowledgeable answers to may many emails. Debashree Ray has been especially helpful with the multivariate phenotype analysis project. I would also like to thank my dissertation readers, Priya Duggal, Liz Selvin, Rasika Mathias and Ni Zhou. The members of my epidemiology PhD doctoral cohort have been such a wonderful aspect of my time at Hopkins. They are great friends and colleagues, and have been so supportive, listening to practice talks, preparing for oral exams, and letting me randomly walk into their offices to bounce ideas off of them. I would like to thank the faculty and students in the genetic epidemiology track, who are incredibly knowledgeable and were always willing to do discuss methods and share code. The members of Priya’s iv research group have been so helpful in providing excellent feedback, particularly at the early stages of this work. Finally, I would like to thank my incredibly supportive family and friends, who have been there for the good, bad, and everything in-between during this PhD process. v Table of Contents Abstract………………………………………………………………………....…………ii Acknowledgements…………….………………………………………………....………iv Table of Contents……………………………………………………….…………...……vi List of Tables………………………………………...………………….………….….…ix List of Figures………………………………….……………………………………...…xii Chapter 1: Introduction……………………………………………………………….…...1 1.1 Type 2 diabetes is an important public health concern……......…………..…..1 1.2 Environmental and genetic factors increase risk of type 2 diabetes……..........1 1.3 Type 2 diabetes results in elevated blood glucose levels, measured by biomarkers……..............................………………………………………………..2 1.4 Nontraditional biomarkers of hyperglycemia are gaining interest…….….…..3 1.5 Genetics of traditional hyperglycemia biomarkers have been well-studied…..4 1.6 Little is known of the genetics of nontraditional hyperglycemia biomarkers............……………………………………………………..............…..5 1.7 Dissertation specific aims…....……………………….…………..............…...6 1.8 Tables and Figures...........……………………………….………..............….10 Chapter 2: Heritability analysis of nontraditional hyperglycemia biomarkers in the Atherosclerosis Risk in Communities (ARIC) Study……………………….…………...14 2.1 Abstract………………………………………………………….…………..15 2.2 Introduction…………………………………….………………….………...15 2.3 Methods…………………………………………………………….………..18 2.4 Results…………………………………………………….………….……...23 2.5 Discussion……………………………………………………………….…..25 2.6 Tables and Figures…………………………………………...……………...28 vi Chapter 3: Genome-wide association study of serum fructosamine and glycated albumin in adults without diagnosed diabetes: results from the Atherosclerosis Risk in Communities Study………………………………………………………….…………...34 3.1 Abstract……………………………………………………………………...36 3.2 Introduction…………………………………….………………..…….…….37 3.3 Methods………………………………………………………….…….…….38 3.4 Results…………………………………………………….………..…….….43 3.5 Discussion…………………………………………………………………...48 3.6 Tables and Figures…………………………………………...……………...54 Chapter 4: Multivariate phenotype analysis of hyperglycemia biomarkers, fructosamine and glycated albumin ………………………………………………………….….…......84 4.1 Abstract……………………………………………………………………...85 4.2 Introduction…………………………………….………………….………...86 4.3 Methods……………………………………………………………..…….....87 4.4 Results…………………………………………………….………….……...90 4.5 Discussion…………………………………………………………………...93 4.6 Tables and Figures…………………………………………...……………...96 Chapter 5: Rare variants in SLC5A10 associated with 1,5-AG in the Atherosclerosis Risk in Communities (ARIC) Study…………………….……………………….….……….107 5.1 Abstract…………………………………………………………………….108 5.2 Introduction…………………………………….………………….……….110 5.3 Methods…………………………………………………………………….111 5.4 Results…………………………………………………….……….……….116 5.5 Discussion………………………………………………………………….120 5.6 Tables and Figures…………………………………………...…………….123 vii Chapter 6: Conclusions…………………………………………...…………………….134 6.1 Summary of Key Findings…………………………...……….…………….134 6.2 Strengths and Limitations…………………………...………….….……….136 6.3 Future Directions…………………………...…………………...............….139 6.4 Public Health Significance…………………………....…………………….141 References........................................................................................................................143 Chapter 1 References…………….……..............………………………………143 Chapter 2 References…………….……..............………………………………150 Chapter 3 References…………….……..............………………………………156 Chapter 4 References…………….……..............………………………………163 Chapter 5 References…………….……..............………………………………167 Chapter 6 References…………….……..............………………………………170 Curriculum Vitae……………….…...………………………………………………….171 viii List of Tables Table 2.1. Demographic and clinical characteristics in unrelated and first-degree relative study participants………………………………....………………………….…….…….28 Table 2.2. SNP-based ( )and narrow-sense ( ) heritability estimates for glycemic biomarkers………………………………………………………………2 2 ....……….…….29 ℎ ℎ Supplemental Table 2.1. Bivariate heritability results………………………….…...….31 Table 3.1. Genome-wide significant loci for fructosamine and percent glycated albumin…………………………………………………............................……….…….54 Table 3.2. Genome-wide significant loci for fructosamine and percent glycated albumin and their association with total glycated albumin, fasting glucose and HbA1c in ARIC.…………. ………………………………………………………….………….….55 Table 3.3. Significance of associations between fasting glucose known genetic determinants and fructosamine and percent glycated albumin in ARIC……….…….….56 Table 3.4. Significance of associations between HbA1c known genetic determinants and fructosamine and percent glycated albumin in ARIC………………………………...….57 Supplemental Table 3.1. Characteristics of participants included in the GWAS….…...61 Supplemental Table 3.2. Power for replication of ARIC genome-wide significant results in CARDIA
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