Association study of transcription factors regulating insulin secretion and action in type 2 diabetes in Chinese.

Abstract

Ho Sin Ka Janice.Thesis (M.Phil.)--Chinese University of Hong Kong, 2008.Includes bibliographical references (leaves 105-119).Abstracts in English and Chinese.Chapter CHAPTER 1. --- IntroductionChapter 1.1. --- Epidemiology of Type 2 Diabetes --- p.1Chapter 1.2. --- Risk factors contributing to Type 2 Diabetes --- p.3Chapter 1.2.1. --- Environmental and physiological factors --- p.3Chapter 1.2.2. --- Genetic factors --- p.3Chapter 1.3. --- Disruption of energy homeostasis in the pathogenesis of type 2 diabetes --- p.6Chapter 1.3.1. --- Clinical spectrum of diabetes --- p.6Chapter 1.3.2. --- Insulin as a key regulator of energy homeostasis --- p.7Chapter 1.3.3. --- Insulin secretion and glucose metabolism --- p.8Chapter 1.3.4. --- Insulin action and lipid metabolism --- p.9Chapter 1.3.5. --- Lipotoxicity and glucotoxicity --- p.12Chapter 1.3.6. --- Role of transcription factors as metabolic switch --- p.13Chapter 1.4. --- Candidate genes implicated in type 2 diabetes susceptibility --- p.15Chapter 1.4.1. --- Candidate genes involved in insulin secretion pathway --- p.15Chapter 1.4.1.1. --- HNF4A --- p.15Chapter 1.4.1.2. --- HNF1A --- p.16Chapter 1.4.1.3. --- PDX1/PBX1 --- p.17Chapter 1.4.1.4. --- NEUROD1 --- p.17Chapter 1.4.1.5. --- GCK --- p.17Chapter 1.4.1.6. --- KCNJ11/ABCC8 --- p.18Chapter 1.4.2 --- Candidate genes involved in insulin action pathway --- p.19Chapter 1.4.2.1. --- PPARG --- p.19Chapter 1.4.2.2. --- PPARA --- p.20Chapter 1.4.2.3. --- PPARGC1A --- p.20Chapter 1.4.2.4. --- ADIP0Q --- p.21Chapter 1.4.2.5. --- LPL --- p.21Chapter 1.4.2.6. --- UPC --- p.22Chapter 1.5. --- Hypothesis and objectives of the study --- p.23Chapter CHAPTER 2. --- Materials and methodsChapter 2.1. --- Study design --- p.25Chapter 2.1.1. --- Two-stage candidate gene association design --- p.25Chapter 2.1.2. --- Power calculation --- p.27Chapter 2.2. --- Study cohort --- p.29Chapter 2.2.1. --- Subject recruitment --- p.29Chapter 2.2.2. --- Clinical and biochemical measurements --- p.30Chapter 2.2.3. --- Clinical definitions --- p.31Chapter 2.3. --- Genetic study --- p.32Chapter 2.3.1. --- Candidate gene selection --- p.32Chapter 2.3.2. --- SNP selection --- p.32Chapter 2.3.3. --- DNA sample preparation --- p.35Chapter 2.3.4. --- Genotyping methods --- p.36Chapter 2.3.4.1. --- Allele specific Tm shift assay --- p.36Chapter 2.3.4.2. --- Mass spectrometry assay --- p.40Chapter 2.4. --- Data quality control --- p.42Chapter 2.4.1. --- Stage 1 --- p.42Chapter 2.4.2. --- Stage 2 --- p.42Chapter 2.5. --- Statistical analysis --- p.45Chapter 2.5.1. --- Stage 1 analysis --- p.45Chapter 2.5.2. --- Stage 2 analysis --- p.45Chapter 2.5.3. --- Stage 1 and 2 combined analysis --- p.46Chapter CHAPTER 3. --- ResultsChapter 3.1. --- Clinical characteristics of subjects in stages 1 and 2 studies --- p.48Chapter 3.2. --- Case-control associations in stage 1 --- p.51Chapter 3.2.1. --- Association with T2D --- p.51Chapter 3.2.2. --- Association with T2D subset by metabolic syndrome --- p.54Chapter 3.3. --- Case-control associations in stage 2 --- p.60Chapter 3.3.1. --- SNP selection for genotyping --- p.60Chapter 3.3.2. --- Association with T2D --- p.63Chapter 3.3.3. --- Association with T2D subset by metabolic syndrome --- p.64Chapter 3.4. --- Case-control associations in combined stages 1 and 2 --- p.66Chapter 3.4.1. --- Association with T2D --- p.66Chapter 3.4.2. --- Association with T2D subset by metabolic syndrome --- p.70Chapter 3.4.3. --- Association with T2D subset by age at diagnosis --- p.74Chapter 3.4.4. --- Association with T2D subset by gender --- p.76Chapter 3.4.5. --- Genetic epistasis for T2D association --- p.79Chapter 3.5. --- Metabolic traits associations in control subjects in combined stages 1 and 2 studies --- p.83Chapter CHAPTER 4. --- Discussion --- p.86Chapter 4.1. --- Role of insulin secretion genes in type 2 diabetes --- p.87Chapter 4.2. --- Role of insulin action genes in type 2 diabetes --- p.92Chapter 4.3. --- Combined genetic effects on risk for type 2 diabetes --- p.97Chapter 4.4. --- Summary --- p.98Chapter 4.5. --- Limitation of this study and future direction --- p.101REFERENCES --- p.104APPENDICES --- p.119Chapter Appendix 1: --- Gene structure and linkage disequilibrium of genotyped SNPs of candidate genes --- p.119Chapter Appendix 2: --- Information of SNPs genotyped in stage 1 --- p.130Chapter Appendix 3: --- T2D association results (additive model) of 152 SNPs for stage 1 case- control samples --- p.137Chapter Appendix 4: --- T2D association results (additive model) of 152 SNPs for stage 1 case- control samples subset by metabolic syndrome status in cases --- p.144Chapter Appendix 5: --- T2D association results (additive model) of 22 SNPs for stage 2 case- control samples --- p.151Chapter Appendix 6: --- T2D association results (additive model) of 22 SNPs for stage 2 case- control samples subset by metabolic syndrome status in cases --- p.15