Thesis Title Exploring new methodologies to identify disease-associated variants in African populations through the integration of patient genotype data and clinical phenotypes derived from routine health data: A case study for Type 2 Diabetes Mellitus patients in the Western Cape Province, South Africa. Abstract Introduction There is poor knowledge on the genetic drivers of disease in African populations and this is largely driven by the limited data for human genomes from sub-Saharan Africa. While the costs of generating human genomic data have gone down significantly, they are still a barrier to generating large scale African genomic data. This project is therefore a proof-of-concept pilot study that demonstrates the implementation of a cost-effective, scalable genotyped virtual cohort that can address population level genomic questions. Methods We optimised a tiered informed consent process that is suitable for the cohort study design and adapted it to conducting human genomic research in the African context. We used an existing dataset to explore statistical methods for modelling longitudinal routine health data into a standardised phenotype for genome wide association studies (GWAS). We then conducted a feasibility study and piloted the tiered informed consent process, DNA collection by buccal swab and DNA extraction from buccal swabs and peripheral blood samples. DNA samples were genotyped for approximately 2.2 million variants on the Infinium™ H3Africa Consortium Array V2. Genotyping quality control (QC) was done in Plink 1.9 and genome wide imputation on the Sanger Imputation Service. We demonstrated successful variant calling and provide aggregate statistics for known aetiological variants for type 2 diabetes and severe COVID-19 as well as demonstrating the feasibility of running nested case-control GWAS with these data. Results We demonstrate the use of routine health data to provide complex phenotypes to link to genotype data for both non-communicable diseases (diabetes) and infectious diseases (Tuberculosis, HIV and COVID-19). 459 participants consented to providing a DNA sample and access to their routine health data and were included in the feasibility study. A total of 343 DNA samples and 1782023 genotyped variants passed quality control and were available for further analysis. While most of the cohort population clustered with the 1000 genomes African population, principal component analysis showed extensive population admixture. For the COVID-19 analysis, we identified 63 cases of severe COVID-19 and 280 controls, and for the type 2 diabetes analysis we identified 93 cases and 250 controls using the routine health data of participants in the cohort. While the sample sizes were insufficient for a GWAS we were able to evaluate known type 2 diabetes mellitus and COVID-19 variants in the study population. Conclusion We have described how we conceptualised and implemented a genotyped virtual population cohort in a resource constrained environment, and we are confident that this design and implementation are appropriate to scale up the cohort to a size where novel health discoveries can be made through nested case-control studies. In the interim we demonstrate the analysis and validation of aetiological variants identified in other studies and populations.

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Thesis (M Med (Family Medicine))--University of Limpopo (Medunsa Campus), 2010. / Introduction: Diabetes Mellitus still remains an important non- communicable disease globally. The burden of the disease continues to rise even in the sub-Saharan Africa. Aim: The study aimed to assess and describe the dietary practices and the prevalence of obesity among type 2 diabetic patients seen at Scott Hospital. Methods: A descriptive cross- sectional study was conducted among type 2 diabetic patients at Scott Hospital, Morija, Lesotho. A simple random sample of 50 participants was selected and each completed an interviewer administered questionnaire. The administration of the questionnaire was done by the researcher and a research assistant. Socio- demographic characteristics of the participants were obtained, anthropometric measurements were height and weight of each participant with subsequent determination of the BMI. Dietary intake was assessed using questions from a modified food frequency questionnaire of 16 food groups that reflect the commonest food items available. Results: The results showed that 86% (43/50) of the participants were females and 14% (7/50) were males with a female: male ratio of 6:1. The majority (72%) were above age 50 years and with regards to educational status, 62% had primary school education as the highest level attained. Four percent (4%) had no formal education. Fifty percent (50%) of the participants were unemployed. The mean weight of the participants was 84.22 ± 13.51 kg and the mean height was 157.76 ± 6.10 cm. The mean BMI was 33.97 ± 4.99 kg/m². Seventy-eight percent (38/50) of the participants were obese, and 14% (7/50) of the participants who were females, were morbidly obese with BMIs ≥ 40kg/m². The prevalence of obesity when stratified by gender showed that 57% (4/7) of male participants and 81% (35/43) of female participants were obese. According to the dietary assessments, food groups with the highest reported consumption per unit per month were; maize meals, breakfast-cereals and bread respectively. Conclusion: The study showed a predominantly female and elderly population of type 2 diabetics at Scott Hospital, Morija, Lesotho. The prevalence of obesity was high (78%) among the participants and this further supports the view that obesity is a major risk factor for type 2 diabetes. Reported dietary intake showed a higher consumption of carbohydrates and a very low intake of dietary fibre as represented by legumes. Keywords: Type 2 diabetes mellitus, dietary habits and obesity.

There is substantial evidence of the elevated risk of cancer among individuals with type 2 diabetes. Very little is known, however, about the role that antidiabetic therapies play in this relationship. The objective of this program of research was to examine whether there is a therapeutic risk associated with antidiabetic therapies that increase circulating insulin levels, such as sulfonylureas and exogenous insulin, or a therapeutic benefit associated with antidiabetic therapies that reduce insulin resistance, such as metformin and the glitazones. This objective was achieved through four related population-based cohort studies using the administrative databases from Saskatchewan Health. The first study looked at the effect of the older antidiabetic therapies metformin and sulfonylureas on cancer mortality. The focus of the second study was to explore more closely the effect of metformin and sulfonylurea by using a time-varying Cox regression to define drug exposures. The third study looked more closely at the effect of exogenous insulin therapy and cancer mortality, and the last study focused on the more recently available antidiabetic therapy the glitazones and cancer mortality. We found that individuals with type 2 diabetes exposed to sulfonylurea monotherapy had a significantly increased risk of cancer-related mortality, compared to patients exposed to metformin. We also observed a dose-response gradient with exogenous insulin therapy and cancer mortality, whereby individuals exposed to higher levels of insulin had a higher risk of cancer mortality. In the last study, we found that the newer class of antidiabetic therapies, the glitazones, were associated with a decreased risk of cancer mortality. These finding add further support that antidiabetic therapies may play a moderating role in the relationship between type 2 diabetes and cancer outcomes. However, it is unclear whether the increased risk of cancer mortality we observed was related to a toxic effect of sulfonylureas and exogenous insulin or a protective effect of metformin and glitazones, or due to some unmeasured effect related to both choice of drug therapy and cancer risk. Future research should incorporate a non-diabetes control cohort for comparison and examine the more proximal outcome measure cancer incidence. / Epidemiology

Adiposity has been shown to secrete bioactive cytokines and growth factor known as adipocytokines, they can contribute to obesity, diabetes and complications of diabetes. Visfatin is a novel adipocytokine, and it was shown to exert insulin-mimetic effects in stimulating glucose transport and induced triglyceride accumulation in preadipocytes and triglyceride synthesis from gluvose. Visfatin plasma levels are increased in morbid obesity and type 2 diabetes mellitus. These finding indicate that visfatin may play a role in the association between visceral obesity and increased metabolic risk, visfatin gene suggested that genetic variation in the visfatin gene may, indeed, have a minor effect on visceral and subcutaneous visfatin messenger RNA expression profiles and parameters of glucose and insulin metabolism. In this study, we explored the relationships between the plasma level of visfatin and genetic single nucleotide polymorphisms (SNPs) of visfatin gene in type 2 diabetes mellitus (T2DM) with and without macrovascular disease. Plasma visfatin was found to be elevated significantly in T2DM with macrovascular disease patients. Moreover, waist to hip ratio was independently associated with plasma visfatin level. There were statistically significant differences in visfatin -948 G/T genetic variants distribution between T2DM with macrovascular disease and the T2DM control group. The visfatin -948 G/T heterozygotes showed higher mean high-density lipoprotein cholesterol than the carriers of the G allele. The results of the current study indicated that plasma visfatin levels were associated with macrovascular complications in type 2 diabetes. However, the definite roles of visfatin in the pathogenesis of insulin resistance, glucose and lipid metabolism are unclear. The observation of changes in the plasma concentrations of visfatin seen in T2DM and T2DM with macrovascular diseases may exert beneficial effects in understanding roles of visfatin in physiologic activity and metabolic disorder. Further studies are needed to elucidate the mechanisms behind visfatin overexpression in humans.

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The goal of this study was to compare different anthropometric measures in terms of their ability to predict T2DM and to determine whether predictive ability was modified by ethnicity. Anthropometrics were measured at baseline on 1073 non-Hispanic Whites (nHW), African Americans (AA) and Hispanics (HA), of which 146 developed T2DM after 5.2 years. Logistic regression models were used with areas under the receiver operator characteristic curve (AROC) comparing the prediction of models. Overall, there was no clear distinction between measures of overall and central obesity in terms of T2DM prediction. Waist-height ratio (AROC=0.678) was the most predictive measure, followed by BMI (AROC=0.674). Results were similar in nHW and HA, although, in AA, central adiposity measures best predicted T2DM. Measures of central and overall adiposity predicted T2DM to a similar degree, except in AA where central measures were most predictive.

The goal of this study was to compare different anthropometric measures in terms of their ability to predict T2DM and to determine whether predictive ability was modified by ethnicity. Anthropometrics were measured at baseline on 1073 non-Hispanic Whites (nHW), African Americans (AA) and Hispanics (HA), of which 146 developed T2DM after 5.2 years. Logistic regression models were used with areas under the receiver operator characteristic curve (AROC) comparing the prediction of models. Overall, there was no clear distinction between measures of overall and central obesity in terms of T2DM prediction. Waist-height ratio (AROC=0.678) was the most predictive measure, followed by BMI (AROC=0.674). Results were similar in nHW and HA, although, in AA, central adiposity measures best predicted T2DM. Measures of central and overall adiposity predicted T2DM to a similar degree, except in AA where central measures were most predictive.

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. / Revisión por pares / INTRODUCCIÓN: Los pacientes con diabetes mellitus tipo 2 son más propensos a una baja calidad de vida, discapacidad e incluso muerte. También, tienen una mayor predisposición a la depresión en comparación con los pacientes no diabéticos; así como una evolución favorable producto de la evaluación e intervención de su salud mental. OBJETIVOS: El objetivo de este estudio fue explorar la presencia de síntomas depresivos en una población ambulatoria con diagnóstico de diabetes mellitus tipo 2 y filiación militar. También examinar los factores asociados a la presencia de síntomas depresivos. MÉTODOS: Realizamos un estudio transversal en 108 personas con diabetes mellitus tipo 2, durante enero de 2012 en una muestra ambulatoria de un hospital de las fuerzas armadas. Los síntomas depresivos se evaluaron con el test autoaplicado de Zung. Usamos la prueba de Chi-cuadrado para examinar las asociaciones entre síntomas depresivos y los factores asociados de interés. Usamos modelos lineales generalizados crudos y ajustados para estimar las Razones de Prevalencia (RP) de la asociación entre las características clínicas y sociodemográficas con la presencia de síntomas depresivos. RESULTADOS: La prevalencia de sintomatología depresiva fue de 56,5% (intervalo de confianza 95%: 46,6-66,0%). El análisis bivariado mostró como significativa la asociación entre la presencia de síntomas depresivos con las variables: sexo, edad y complicaciones clínicas de la diabetes. En los análisis ajustados, la retinopatía diabética [RP: 1,3; intervalo de confianza 95%: 1,1-1,7], y la neuropatía diabética [RP: 1,4; intervalo de confianza 95%: 1,1-1,7] se asociaron a una mayor presencia de síntomas depresivos luego de considerar el sexo de los participantes. CONCLUSIONES: Observamos una elevada presencia de síntomas depresivos en la población de estudio, especialmente en los pacientes geriátricos o del sexo femenino. También en aquellos con complicaciones tardías de la diabetes mellitus tipo 2, y que probablemente representen la repercusión de la enfermedad en la calidad de vida del paciente. Un abordaje multidisciplinario, con enfoque físico y mental, debe ser considerado ya que podría beneficiar a la evolución de los pacientes con esta concomitancia en Perú.