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Genetic Contribution to Type 1 Diabetes Microvascular Complications Ettie

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Genetic Contribution to Type 1 Diabetes Microvascular Complications Ettie Genetic contribution to type 1 diabetes microvascular complications Ettie M. Lipner Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy under the Executive Committee of the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2013 ! ©2013 Ettie M. Lipner All rights reserved ! ABSTRACT Genetic contribution to type 1 diabetes microvascular complications Ettie M. Lipner Type 1 diabetes (T1D) is an autoimmune disease characterized by destruction of beta cells in the pancreas resulting in insulin deficiency, which leads to hyperglycemia and organ damage. T1D patients experience an increased risk of morbidity and mortality due to long-term complications, specifically retinopathy, nephropathy, and neuropathy. Studies demonstrating familial aggregation support the claim that a genetic contribution may influence the development of complications. This dissertation aims to identify genes/chromosomal regions that predispose T1D patients to, or protect them from, the expression of the chronic microvascular complications: retinopathy, neuropathy and nephropathy. In my first chapter, I introduce the history of type 1 diabetes and microvascular complications and their importance as a public health concern. Data show that the prevalence for T1D is increasing, and thus it is likely that the prevalence for the associated complications will also increase. Further, a large proportion of T1D patients develop at least one microvascular complication within 15 years of T1D diagnosis. By identifying risk alleles for the microvascular complications of T1D, the findings of this study could allow physicians to determine which patients are at greater/lesser risk for developing complications, help to develop interventions to delay or protect against the development of complications and thus reduce medical expenditure and suffering due to diabetes. In the second chapter, I provide the background for, and review the literature on, the genetics of T1D and microvascular complications. The genetic risk factors for T1D are well-established, but there is conflicting research on the question of whether T1D-predisposing HLA alleles may also be in part responsible for the occurrence of microvascular complications seen in T1D patients. We also investigate whether T1D HLA risk alleles are associated with all forms of microvascular complications or whether there are HLA alleles specifically associated with a given complication. In the work described, I address these questions by examining the relationship of HLA alleles to the risk for any complication and to the risk for some specific complication. In the third chapter, I perform case-control analysis and evaluate known type 1 diabetes HLA susceptibility alleles and their association with microvascular complications. I used data from the Human Biological Data Interchange (HBDI), which includes 425 Caucasian families (2,506 family members) with cases diagnosed with type 1 diabetes. Using a case-control study design nested on the cohort of the HBDI type 1 diabetes patients and their families, probands with at least one microvascular complication were considered cases, and the probands with T1D without microvascular complications (T1D only) were considered controls. Our findings suggest that the HLA class II DRB1*03:01 allele is a protective factor for complications, specifically for retinopathy, as is the DQA1*05:01-DQB1*02:01 haplotype. The DRB1*04:01 allele showed no evidence of association, except when the carriers of the protective DRB1*03:01 were removed from the analysis. Findings also showed a strong positive association between the HLA class I allele B*39:06 and complications. In the fourth chapter, using the same sample of HBDI type 1 diabetes families that I used in Chapter 3, I perform linkage analysis and test markers along chromosome 6 for co-segregation with microvascular complications. Using SNP data that were genotyped by the Center for Inherited Disease Research (CIDR), I performed linkage analysis examining 1) the phenotype of T1D itself, 2) the presence of any microvascular complication, 3) retinopathy alone, 4) nephropathy alone, and 5) neuropathy alone. Initially, we confirmed the linkage of the HLA locus to T1D. In subsequent analyses, using all complications as well as retinopathy alone as the phenotypes, we identified two linkage peaks; a linkage peak located at the HLA locus and another novel locus was telomeric to HLA. We did not find evidence for linkage for nephropathy alone or neuropathy alone. Findings from this dissertation show that both HLA and non-HLA regions are involved in the expression of complications with strong evidence of genetic influences specifically for retinopathy. ! TABLE OF CONTENTS 1.0 Chapter 1 1.1. Introduction 1 1.2. Type 1 Diabetes – A brief history 2 1.3. Microvascular complications as a Significant Public Health Concern 3 1.3.1. Financial burden due to diabetes and microvascular complications 4 1.4. References 5 2.0 Chapter 2: Literature Review 2.1. Type 1 Diabetes 7 2.1.1. Epidemiology of Type 1 Diabetes 7 2.1.2. Pathogenesis of Type 1 Diabetes 9 2.1.3. Clinical diagnosis of Type 1 Diabetes 10 2.1.4. Symptoms of Type 1 Diabetes 11 2.1.5. Risk factors for Type 1 Diabetes 12 2.1.6. Genetic risk factors for Type 1 Diabetes 13 2.1.7. Geographic distribution of HLA and Genetic Susceptibility to Type 1 Diabetes 14 2.2. Microvascular complications 19 2.2.1. Origin and clinical diagnoses of microvascular complications 19 A. Retinopathy 19 B. Nephropathy 19 ! i! C. Neuropathy 20 2.2.2. Factors implicated in the development of microvascular complications 20 A. Risk factors for microvascular complications 20 i. HbA1c as a risk factor for microvascular complications 20 ii. Other risk factors for microvascular complications 23 B. Genetic risk factors 24 i. Familiality of microvascular complications 24 C. Evidence for microvascular complications with specific genes 24 i. Retinopathy 25 ii. Nephropathy 27 iii. Neuropathy 28 2.3. Does the risk for one complication increase the risk for a second complication? 29 2.4. Summary and Conclusion 31 2.5. References 32 3.0. Chapter 3: HLA Class I and II Alleles are Associated with Microvascular Complications of Type 1 Diabetes 3.1. Abstract 49 3.2. Introduction 50 3.3. Materials and methods 51 3.3.1. Family identification and data collection 51 3.3.2. HBDI data 52 ! ii! 3.3.3. Assessment and definition of diabetes and diabetic complications 52 3.3.4. Type 1 diabetes subjects and complications 53 3.3.5. Study design 53 3.3.6. HLA genotyping 54 3.3.7. Statistical analysis 54 3.3.8. Multiple Testing 55 3.4. Results 56 3.4.1. Patient characteristics 56 3.4.2. MHC Class II genes analyses 56 3.4.3. MHC Class I genes analyses 58 3.5. Discussion 59 3.5.1. MHC Class II genes and complications risk: Current study and past work 59 3.5.2. Effect of DRB1*03:01 vs. DRB1*04:01 62 3.5.3. MHC Class I genes 62 3.5.4. Effect of age-of-onset of type I diabetes 63 3.6. Advantages and limitations 64 3.7. Conclusion 65 3.8. References 66 4.0. Chapter 4: Linkage Analysis: Genomic Regions Contributing to the Expression of Type 1 Diabetes Microvascular Complications 4.1. Abstract 75 ! iii! 4.2. Introduction 77 4.3. Methods 78 4.3.1. Family recruitment and data collection 78 4.3.2. HBDI data 79 4.3.3. Assessment and definition of diabetes and diabetic complications 79 4.3.4. Type 1 diabetes subjects and complications 80 4.3.5. Genotyping 80 4.3.6. Phenotype definitions 80 4.3.7. Analysis Overview 81 4.3.8 Linkage analysis 82 4.3.9 Pedigree stratification for high-risk alleles using T1D with complications as the phenotype 82 4.4. Results 83 4.4.1. Distribution of affected and unaffected individuals within families 83 4.4.2. Linkage analysis with type 1 diabetes as the phenotype 83 4.4.3. Linkage analysis with ‘presence of any complication’ as the phenotype 84 4.4.4. Linkage analysis with retinopathy alone as the phenotype 85 4.4.5. Linkage analysis with nephropathy alone & neuropathy alone as the phenotypes 85 4.4.6. Stratification by HLA-DRB1 alleles among probands 85 i. Linkage analysis with the presence of any complication as the phenotype 85 ! iv! ii. Linkage analysis with retinopathy alone as the phenotype 88 iii. Linkage analysis with nephropathy alone & neuropathy alone as the phenotypes 90 4.5. Discussion 90 4.5.1 Other linkage analyses 97 4.6. Conclusion 99 4.7. References 101 5.0. Chapter 5: Summary and Conclusions 114 5.1. Summary of Findings 116 5.2. Strengths and limitations 119 5.3. Strengths of the study 120 5.4. Weaknesses of the study 120 5.5. Future research directions 121 5.2. References 122 6.0. Appendices 6.1. Appendix 1: Supplemental figures for Chapter 4 123 6.2. Appendix 2: Supplemental figures for Genome-wide linkage analyses 126 ! v! LIST OF TABLES AND FIGURES Chapter 2: Literature Review Figure 1. Geographical distribution of type 1 diabetes 7 Table 1. Diagnostic criteria for type 1 diabetes 11 Table 2. Studies investigating predisposing (or protective) genes/loci with Retinopathy 42 Table 3. Studies investigating predisposing (or protective) genes/loci with Nephropathy 45 Table 4. Studies investigating predisposing (or protective) genes/loci with Neuropathy 47 Chapter 3: HLA Class I and II Alleles are Associated with Microvascular Complications of Type 1 Diabetes Table 1. Characteristics of type 1 diabetes by numbers of total probands cases and controls 70 Table 2. Distribution of microvascular complications among probands with Type 1 diabetes 71 Table 3. Results of logistic regression models for one or more microvascular complications among probands with type 1 diabetes 72 Table 4.
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