Aims: This PhD project was designed under two studies, the genetic association study to investigate a genetic component or a genetic pathway that might be associated with both schizophrenia and type-2 diabetes (T2D). The gene functional study to explore whether clozapine could affect expression of the genes associated with obesity and T2D. Methods: In genetic association study, a total of 17 single nucleotide polymorphisms (SNPs) were genotyped in the PPARG, PLA2G4A, PTGS2 and AKT1 genes in 221 British nuclear families. In the gene functional study, U937 cells were treated with clozapine (1g/ml and 2g/ml) for 48 hours and 96 hours. Quantitative real-time PCR analysis was used to measure the mRNA expression levels of the genes of interest in clozapine-treated and untreated cells. Results: Eight SNPs tested across the PPARG gene did not show allelic association with schizophrenia. An association was detected at rs2745557 in the PTGS2 locus (2=4.19, p= 0.041) and rs10798059 in the PLA2G4A locus (2=4.28, p=0.039), but these associations did not survive after 10,000 permutations (global p=0.246). Allelic association for the AKT1 gene was detected at rs1130214 (2=6.28, p=0.012) and at rs11847866 (2=4.64, p=0.031) only although the global p-value of overall associations for the AKT1 was 0.059 after 10,000 permutations. Haplotype analysis showed a disease association for the rs1130214-rs2494746-rs11847866 haplotypes (2= 10.18, df= 4, p=0.037), of which the T-G-A haplotype was excessively transmitted (2=6.93, p=0.008) and this haplotypic association survived the Bonferroni correction (p=0.04). The expression of the MTCH2 gene showed a significant decrease in mRNA expression (combined p=0.001) and that of the PPARG gene showed a significant increase (combined p=0.005) in the cells treated with 1g/ml clozapine for 96 hours. Conclusions: The present results support the AKT1 gene association with schizophrenia as reported in previous studies; both the MTCH2 and PPARG genes may be involved in the development of clozapine-induced obesity and in an increased risk of T2D.

by Annie Chi Kwan Lam. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2002. / Includes bibliographical references (leaves 112-119). / Abstracts in English and Chinese ; questionnaires also in Chinese. / Acknowledgements --- p.i / Abstract --- p.ii-vi / List of Figures --- p.vii / List of Tables --- p.vii-x / List of Abbreviations --- p.xi / Table of Contents --- p.xii-xvi / Chapter Chapter One: --- Background / Chapter 1.1 --- Diabetes Mellitus: A public health burden / Chapter 1.1.1 --- Definition and Health Consequences --- p.2 / Chapter 1.1.2 --- Prevalence of Type 2 Diabetes Mellitus in Asia --- p.3 / Chapter 1.1.3 --- Prevalence of Type 2 Diabetes Mellitus in the Hong Kong Chinese Population --- p.4 / Chapter 1.1.4 --- Medical Burden of Diabetes Mellitus in Hong Kong --- p.7 / Chapter 1.2 --- Clinical Intervention To Improve Glycemic Control / Chapter 1.2.1 --- The United Kingdom Prospective Studies (UKPDS) --- p.8 / Chapter 1.2.2 --- The Diabetes and Complications Trial (DCCT) --- p.9 / Chapter 1.2.3 --- Another Clinical Trial of Lifestyle Intervention --- p.10 / Chapter 1.2.4 --- Physical Activity in Diabetes Management --- p.12 / Chapter 1.3 --- Dietetic Situation in Hong Kong / Chapter 1.3.1 --- Survey of the Hong Kong Dietetics Situation --- p.15 / Chapter 1.3.2 --- Current Situation of Prince of Wales Hospital --- p.17 / Chapter 1.3.3 --- Diabetes Knowledge and Compliance Level in Hong Kong Patients --- p.22 / Chapter 1.4 --- Medical Nutrition Therapy and Practice Guidelines / Chapter 1.4.1 --- Definition --- p.24 / Chapter 1.4.2 --- Development of the Practice Guidelines --- p.24 / Chapter 1.4.3 --- Recommended Procedure for the Practice Guidelines in Type 2 Diabetic Patients --- p.28 / Chapter 1.5 --- Study Purpose and Objectives --- p.32 / Chapter Chapter Two: --- Study Design and Method / Chapter 2.1 --- Research Design --- p.34 / Chapter 2.2 --- Sample Selection --- p.34 / Chapter 2.2.1 --- Method of Randomization --- p.35 / Chapter 2.2.2 --- Sample Size Calculation --- p.36 / Chapter 2.2.3 --- Inclusion Criteria --- p.37 / Chapter 2.2.4 --- Exclusion Criteria --- p.38 / Chapter 2.3 --- Summary of Patient Procedure --- p.38 / Chapter 2.3.1 --- Definition Of The Two Treatments --- p.41 / Chapter 2.3.2 --- Research Procedure For PGC Group --- p.43 / Chapter 2.3.3 --- Research Procedure For CC Group --- p.49 / Chapter 2.4 --- Outcome Measures / Chapter 2.4.1 --- Anthropometrics Variable --- p.50 / Chapter 2.4.2 --- Laboratory Data --- p.51 / Chapter 2.4.3 --- Pre-testing For Questionnaires --- p.51 / Chapter 2.4.4 --- Dietary Variables --- p.52 / Chapter 2.4.5 --- Measurement of Diabetes Knowledge --- p.53 / Chapter 2.4.6 --- Measurement of Barriers To Diet Compliance --- p.54 / Chapter 2.4.7 --- Measurement of Physical Activity --- p.54 / Chapter 2.4.8 --- Measurement of Barriers To Exercise Compliance --- p.54 / Chapter 2.4.9 --- Measurement of Overall Compliance in MNT --- p.55 / Chapter 2.5 --- Statistical Analysis --- p.57 / Chapter 2.6 --- Ethics --- p.58 / Chapter Chapter Three: --- Results / Chapter 3.1 --- Subjects and Response Rate --- p.60 / Chapter 3.1.1 --- Baseline Characteristics of the PGC and CC Group --- p.61 / Chapter 3.2 --- Results of Intervention Process Between PGC and CC Group / Chapter 3.2.1 --- Attendance Rate --- p.67 / Chapter 3.2.2 --- Total Patient-Dietitian Contact Time --- p.67 / Chapter 3.2.3 --- Satisfaction With Dietetic Services --- p.68 / Chapter 3.2.4 --- Other Alternatives Treatment --- p.69 / Chapter 3.2.5 --- Changes In Medical Therapy After Intervention --- p.69 / Chapter 3.2.6 --- Hospital Admission --- p.71 / Chapter 3.3 --- Outcomes - Questionnaires Results Between PGC and CC Group / Chapter 3.3.1 --- Food Frequency Questionnaire --- p.72 / Chapter 3.3.2 --- Physical Activity Questionnaire --- p.72 / Chapter 3.3.3 --- Diabetes Knowledge --- p.72 / Chapter 3.3.4 --- Barrier To Diet Compliance --- p.72 / Chapter 3.3.5 --- Barrier To Exercise Compliance --- p.73 / Chapter 3.3.6 --- Overall Medical Nutrition Therapy Compliance --- p.78 / Chapter 3.4 --- Outcomes - Anthropometry Results Between PGC and CC Group --- p.79 / Chapter 3.5 --- Outcomes - Laboratory Results Between PGC and CC Group / Chapter 3.5.1 --- Glycemic Control --- p.83 / Chapter 3.5.2 --- Lipid --- p.84 / Chapter Chapter four: --- Discussion and Conclusion / Chapter 4.1 --- Enrollment / Chapter 4.1.1 --- Response Rates --- p.91 / Chapter 4.1.2 --- Behavior Change Model --- p.92 / Chapter 4.1.3 --- Participation of Subjects --- p.93 / Chapter 4.1.4 --- Randomization --- p.93 / Chapter 4.2 --- Measurements / Chapter 4.2.1 --- Questionnaire --- p.94 / Chapter 4.2.2 --- Blinding Process --- p.94 / Chapter 4.2.3 --- Laboratory --- p.94 / Chapter 4.3 --- Outcomes / Chapter 4.3.1 --- Questionnaire Outcomes --- p.95 / Chapter 4.3.2 --- Anthropometry Outcomes --- p.100 / Chapter 4.3.3 --- Glycemic Outcomes --- p.102 / Chapter 4.3.4 --- MNT Process Outcomes --- p.103 / Chapter 4.3.5 --- Limitations --- p.104 / Chapter 4.4 --- Clinical Significance and Implications --- p.104 / Chapter 4.5 --- Conclusions and Recommendations --- p.110 / References --- p.112 / Appendices --- p.120

Zhao Hailu. / "June 2002." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2002. / Includes bibliographical references (p. 192-210). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

Leung Yun Shing Wilson. / "May 2003." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2003. / Includes bibliographical references (p. 157-184). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest dissertations and theses, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Washington, 1995. / Vita. Includes bibliographical references (leaves [188]-209).

Hypertension and type two diabetes mellitus (Type 2 DM) are serious chronic illnesses that impact on the lives of millions of people around the world. Various epidemiological studies have shown a relationship between early life events such as intrauterine growth retardation (IUGR) resulting in low birth weight and the development of these chronic illnesses in adult life. To explain the link between these two events, it has been suggested that an ‘insult’ at a critical time point of development can ‘program’ alterations in gene expression, organ size, and cell number. This has been termed “the early life origins of disease’. There is also evidence that these programmed effects are not limited to the first generation but can also be passed to subsequent generations. With changes in lifestyle in modern society, the prevalence of obesity is increasing, in association with problems such as type 2 DM, hypertension, fatty liver, atherosclerosis and the metabolic syndrome. Obesity during pregnancy is linked to problems such as gestational diabetes, hypertension and early miscarriage as well as a higher risk of congenital malformations. Maternal obesity has also been recognised as one of the factors capable of ‘programming’ the offspring, increasing the risk of childhood and adult disorders such as obesity and hypertension. In this thesis I have used two animal models to explore the underlying mechanisms of programming and its intergenerational effects: i) a rat model of prenatal glucocorticoid over-exposure (the dexamethasone-programmed rat) and ii) a mouse model of obesity during pregnancy. Using the dexamethasone-programmed rat, I have shown that prenatal glucocorticoid overexposure reduces fetal and placental weight in the first generation (F1) offspring, in association with alterations in gene expression in placenta and liver. In addition, I have shown effects on fetal and placental weights and gene expression in the second generation (F2) offspring. The observed changes in gene expression in the F2 offspring differ from those in the first generation. Thus, although effects on fetal growth are seen in both generations, the underlying mechanisms appear to be different. We also observed marked parent of origin effects on fetal and placental growth and gene expression in the second generation. In the mouse model of maternal obesity, birth weight was decreased in the F1 offspring. At weaning, the offspring of obese mothers were heavier than controls, however this difference in weight was not persistent. At three months of age, F1 female offspring of obese mothers showed altered expression of hepatic genes important in lipid regulation and metabolism. More striking changes were seen in the F2 generation in which there was an effect of paternal exposure to maternal obesity to decrease birth weight. There were also parent of origin effects on organ weights and insulin levels at six months of age. These results provide evidence for the transmission of programming effects to a second generation in two different programming models and suggest that the mechanisms leading to these effects differ between generations.

Type 2 diabetes (T2D) is a metabolic disease that results from complex interactions between the environment, the genetic variation and epigenetic regulation of gene expression in individuals. Beta-cell dysfunction and insulin resistance are regarded as the hallmarks of the disease as the common presentation of T2D is the inability of beta-cells to adequately respond to the insulin demands of the body. The prevalence of T2D in Africa, and particularly South Africa, is on the rise. This is very likely the result of the combination of genetic susceptibility with increasing availability and accessibility of relatively cheap, highly palatable, calorie-dense meals with no corresponding lifestyle adjustment. This study aims to utilize available data from GWAS and gene expression arrays to identify potential variants that likely influence T2D susceptibility in African populations. Two public data repositories were mined – the National Center for Biotechnology Information’s (NCBI) Gene Expression Omnibus (GEO) and the National Human Genome Research Institute’s (NHGRI) GWAS Catalog. The criteria for selecting the studies for inclusion were based on ten descriptive T2D-related terms taken from the GWAS catalog’s pre-defined search categories. These terms were also applied to the selection of gene expression studies in GEO. These terms are: “fasting glucose-related traits”, “fasting insulin-related traits”, “fasting plasma glucose”, “insulin resistance/response”, “insulin traits”, “diabetes-related insulin traits”, “pro insulin levels” “Type 2 diabetes”, “type 2 diabetes and 6 quantitative traits” and “type 2 diabetes and other traits”. Ten Affymetrix platform-based studies in human tissues were chosen from GEO using these criteria. A Benjamin-Hochberg adjusted p-value of 0.05 was set as a cut-off for significant differentially expressed genes (7,887 genes) with 497 genes occurring in two or more studies, based on tissue- or array-type, considered candidates for downstream analysis. The GWAS catalogue presented 175 “reported” genes and 218 SNPs from 51 studies matching the set T2D-related criteria. Functional analyses done with the Database for Annotation, Visualization and Integrated Discovery (DAVID) on both the GWAS and expression studies genes lists,

by Mui Kin Tung. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1993. / Includes bibliographical references (leaves 97-113). / Chapter CHAPTER 1: --- INTRODUCTION --- p.1 / Chapter CHAPTER 2: --- LITERATURE REVIEW --- p.5 / Chapter 2.1 --- ION TRANSPORT SYSTEMS IN HUMAN ERYTHROCYTES --- p.6 / Chapter 2.1.1 --- "Sodium Pump (Na+,K+-ATPase)" --- p.6 / Chapter 2.1.2 --- Passive Sodium Transport Systems --- p.9 / Chapter 2.1.2.1 --- Sodium-potassium-chloride cotransport system --- p.9 / Chapter 2.1.2.2 --- Sodium-lithium Countertransport --- p.13 / Chapter 2.1.3 --- Ouabain- and Frusemide-Resistant Passive Effluxes --- p.17 / Chapter 2.2 --- ERYTHROCYTE SODIUM TRANSPORT SYSTEMS IN ESSENTIAL HYPERTENSION --- p.17 / Chapter 2.2.1 --- "Sodium Pump (Na+, K+-ATPase) in Essential Hypertension" --- p.18 / Chapter 2.2.2 --- Sodium-Potassium-Chloride Cotransport in Essential Hypertension --- p.20 / Chapter 2.2.3 --- Sodium-Lithium Countertransport in Essential Hypertension --- p.23 / Chapter 2.2.4 --- Passive Ion Fluxes in Essential Hypertension --- p.26 / Chapter 2.2.5 --- Intracellular Sodium Concentration in Essential Hypertension --- p.26 / Chapter 2.3 --- ERYTHROCYTE SODIUM TRANSPORT SYSTEMS IN DIABETES MELLITUS --- p.27 / Chapter CHAPTER 3: --- MATERIALS & METHODS --- p.29 / Chapter 3.1 --- MATERIALS --- p.30 / Chapter 3.1.1 --- Choline Wash Solution (CWS) --- p.30 / Chapter 3.1.2 --- Lithium Loading Solution --- p.31 / Chapter 3.1.3 --- Choline Wash Solution with Ouabain (CWS-O) --- p.31 / Chapter 3.1.4 --- Sodium Containing Medium (SCM) --- p.31 / Chapter 3.1.5 --- Sodium Free Medium (SFM) --- p.31 / Chapter 3.1.6 --- Sodium Free Medium with Bumetanide (SFM-B) --- p.32 / Chapter 3.1.7 --- Preservation Solution --- p.32 / Chapter 3.2 --- STUDY POPULATION --- p.32 / Chapter 3.2.1 --- Control Subjects --- p.35 / Chapter 3.2.2 --- Patients with Essential Hypertension --- p.35 / Chapter 3.2.3 --- Diabetic Patients --- p.35 / Chapter 3.3 --- DETERMINATION OF ERYTHROCYTE INTRACELLULAR SODIUM AND POTASSIUM CONCENTRATIONS (Naic/Kic --- p.36 / Chapter 3.3.1 --- Preparation of Erythrocytes --- p.36 / Chapter 3.3.2 --- Preparation of Haemolysates --- p.38 / Chapter 3.3.3 --- Determination of Sodium and Potassium Concentrations in Haemolysates --- p.38 / Chapter 3.3.4 --- Determination of Haemoglobin Concentration in Haemolysates --- p.38 / Chapter 3.3.5 --- Evaluation of Erythrocyte Intracellular Sodium and Potassium Concentrations --- p.39 / Chapter 3.4 --- DETERMINATION OF ERYTHROCYTE PASSIVE POTASSIUM EFFLUX --- p.39 / Chapter 3.4.1 --- Determination of Potassium Concentrations in Supernatant --- p.40 / Chapter 3.4.2 --- Evaluation of Passive Potassium Efflux --- p.40 / Chapter 3.5 --- DETERMINATION OF ERYTHROCYTE SODIUM-LITHIUM COUNTERTRANSPORT (SLC) AND LITHIUM-POTASSIUM COTRANSPORT (LPC) --- p.41 / Chapter 3.5.1 --- Lithium Loading --- p.42 / Chapter 3.5.2 --- Determination of Haematocrit --- p.42 / Chapter 3.5.3 --- Preparation of Haemolysates --- p.42 / Chapter 3.5.4 --- Determination of the Lithium Concentration in Haemolysates --- p.43 / Chapter 3.5.5 --- Determination of Lithium Efflux --- p.43 / Chapter 3.5.6 --- Evaluation of Lithium Efflux Rate --- p.43 / Chapter 3.5.7 --- Evaluation of Intracellular Lithium Concentration --- p.44 / Chapter 3.6 --- VALIDATION OF METHODOLOGY FOR DETERMINATION OF ERYTHROCYTE SODIUM TRANSPORT SYSTEMS --- p.45 / Chapter 3.6.1 --- Effect of Time Course of Lithium Efflux --- p.45 / Chapter 3.6.2 --- Intracellular Potassium Concentration and Its Effect on Ouabain- and Frusemide-Resistant Passive Potassium Efflux --- p.45 / Chapter 3.7 --- PRESERVATION OF ERYTHROCYTES FOR DETERMINATION OF SODIUM TRANSPORT SYSTEMS --- p.51 / Chapter 3.8 --- PRECISION OF THE METHOD --- p.51 / Chapter 3.9 --- STATISTICS --- p.52 / Chapter CHAPTER 4: --- RESULTS --- p.56 / Chapter 4.1 --- POPULATION CHARACTERISTICS --- p.57 / Chapter 4.2 --- ERYTHROCYTE INTRACELLULAR LITHIUM CONCENTRATIONS AFTER LITHIUM LOADING --- p.57 / Chapter 4.3 --- RELATIONSHIP BETWEEN ERYTHROCYTE ION TRANSPORT PARAMETERS AND OTHER VARIABLES --- p.58 / Chapter 4.4 --- ERYTHROCYTE SODIUM TRANSPORT SYSTEMS IN ESSENTIAL HYPERTENSION --- p.64 / Chapter 4.5 --- ERYTHROCYTE SODIUM TRANSPORT SYSTEMS IN PATIENTS WITH DIABETES MELLITUS --- p.64 / Chapter 4.5.1 --- NIDDM Patients without Hypertension --- p.64 / Chapter 4.5.2 --- NIDDM Patients with Hypertension --- p.65 / Chapter 4.5.3 --- NIDDM Patients with and without Hypertension --- p.65 / Chapter 4.6 --- ERYTHROCYTE SODIUM TRANSPORT SYSTEMS IN DIABETES MELLITUS PATIENTS WITH PROTEINURIA --- p.65 / Chapter 4.6.1 --- Clinical Features and Biochemistry Indices --- p.69 / Chapter 4.6.2 --- Ion Transport Systems and NIDDM Patients with Proteinuria --- p.69 / Chapter 4.7 --- EFFECTS OF TREATMENTS ON ERYTHROCYTE ION TRANSPORT SYSTEMS IN DIABETIC HYPERTENSIVE PATIENTS --- p.70 / Chapter 4.7.1 --- Effects of Diuretic Therapy --- p.70 / Chapter 4.7.2 --- Effects of Enalapril and Nifedipine Therapy --- p.74 / Chapter 4.7.3 --- Effects of Enalapril Therapy --- p.74 / Chapter 4.7.4 --- Effects of Nifedipine Therapy --- p.75 / Chapter 4.7.5 --- Comparison of the Effects of Enalapril and Nifedipine Therapy --- p.75 / Chapter CHAPTER 5: --- DISCUSSION --- p.81 / Chapter 5.1 --- SODIUM TRANSPORT IN ESSENTIAL HYPERTENSION --- p.82 / Chapter 5.1.1 --- Erythrocyte Sodium-Lithium Countertransport in Essential Hypertension --- p.82 / Chapter 5.1.2 --- Erythrocyte Sodium-Potassium Cotransport in Essential Hypertension --- p.86 / Chapter 5.1.3 --- Erythrocyte Intracellular Concentration of Sodiumin Essential Hypertension --- p.87 / Chapter 5.1.4 --- Erythrocyte Passive Potassium Efflux in Essential Hypertension --- p.90 / Chapter 5.2 --- SODIUM TRANSPORT SYSTEMS IN NON-INSULIN- DEPENDENT DIABETES MELLITUS (NIDDM) --- p.91 / Chapter 5.2.1 --- Sodium-Lithium Countertransport in Non-Insulin-Dependent Diabetes Mellitus --- p.91 / Chapter 5.2.2 --- Erythrocyte Lithium-Potassium Cotransport and Intracellular Sodium Concentration in Non-Insulin-Dependent Diabetes Mellitus --- p.93 / Chapter 5.3 --- EFFECT OF ANTIHYPERTENSIVE AGENTS ON ERYTHROCYTE SODIUM TRANSPORT SYSTEMS --- p.95 / REFERENCES --- p.98