3. Electronic Theses and Dissertations (ETDs) - All submissions
Permanent URI for this communityhttps://wiredspace.wits.ac.za/handle/10539/45
Browse
4 results
Search Results
Item Characterization of genes conferring v factor independence in haemophilus parainfluenzae and haemophilus ducreyi(1994-12-18) Windsor, Helen. MarieHaemophilus influenzae and Haemophilus parainfluenzae are obligate human parasites that form part of the flora of the mucous membranes. They are normally present in the mouth and upper respiratory tract of healthy individuals. H. influenzae is known as a major pathogen in children while H. parainfluenzae is an opportunistic pathogen which is also found in the urogenital tract. H. ducreyi, however, has only been isolated from genital ulcers in patients suffering from chancroid. The various species of the genus Haemophilus are characterised by their requirements for two growth factors, X factor or haemin and V factor or nicotinamide adenine dinucleotide (NAD).Item Variants in four genes associated with lipid levels: a study in African populations(2018) Hayat, MahtaabNon-communicable diseases, including cardiovascular disease (CVD), are on the rise in African populations. High serum LDL cholesterol (LDL-C) levels is a risk factor for CVD, but the contribution of high LDL-C levels to CVD in African populations remains poorly understood. Genetic variation in the LDLR, APOB, PCSK9 and LDLRAP1 genes is known to be associated with alteration in LDL-C levels in many populations. This study aims to examine whether genetic variants in these four genes are associated with differing LDL-C levels in African populations, considering LDL-C as a polygenic trait. Publicly available African whole genome sequence data were interrogated, and variants were selected for genotyping using functional predictive bioinformatics tools. Participants (n=1000) from the AWI-Gen study were selected using a case-control study design based on clinical cut-offs of LDL-C levels (500 with LDL-C>3.5 mmol/l, 500 with LDL-C<1.1 mmol/l). Genotyping was carried out on 19 selected SNPs chosen from across the four genes. Logistic regression analysis revealed that, after adjusting for sex, fasting glucose levels, BMI and geographic region, the minor alleles at two SNPs remained significantly associated (p<0.05) with low LDL-C levels - LDLRAP1 rs12071264, c.533-22A>G (OR 0.5866, p<0.01) and APOB rs6752026, c.433G>A (OR 0.6898, p=0.04). The minor alleles G and A, were associated with lower LDL-C levels, suggesting gain of function effects. The variant alleles at both loci are extremely rare in European populations (MAF<0.001) and this may explain why they have not previously been reported in LDL-C association studies. Since African populations, in general, have reduced LDL-C levels these variants could be African-specific LDL-C associated variants and may suggest a unique gene-environment interaction. Using a limited number of potentially functional variants in African populations and after extensive adjustment for potential covariates, significant associations were detected with variants in two of the four genes studied.Item Exploring the role of genetic variation at the leptin and leptin receptor genes (LEP and LEPR) in obesity and hypertension in a black South African cohort(2014-04-04) Ngcungcu, ThandiswaObesity and hypertension often occur together and are risk factors for cardio-metabolic disorders. Single nucleotide polymorphisms (SNPs) in the leptin (LEP) and leptin receptor (LEPR) genes have been shown to be associated with obesity and hypertension, but have not been well explored in African populations. The aims of this study were to determine the heritability estimates of anthropometric and blood pressure (BP) measures and leptin levels; to identify additional informative SNPs in and around the LEP and LEPR genes; and to examine the potential relationships between these SNPs and measures of obesity, hypertension and leptin levels in a black South African cohort. Participants from the African Programme on Genes in Hypertension (APOGH) with various anthropometric and BP measurements were genotyped for LEP and LEPR SNPs using the BeadXpress platform. Heritability estimates were determined using Statistical Analysis for Genetic Epidemiology (S.A.G.E.) software and relationships between LEP or LEPR SNPs and obesity, leptin levels and hypertension were assessed using SAS 9.3 and gPLINK vs2.050, taking into account family relationships, various confounders and correcting for multiple testing. The Bonferroni method was used to correct for multiple testing and P≤0.00076 was considered as statistically significant for SNP association tests. Seven-hundred-and-thirteen individuals were successfully genotyped and there were more women (66%) than men. The prevalence of obesity (42%) and hypertension (46%) were high in the sample. Significant heritability (h2 %, P<0.05) was noted for body weight (38%), body mass index (26%), waist (35%) and hip circumference (42%), waist-to-hip ratio (46%), skinfold thickness (44%), systolic (34%), diastolic (27%) and central systolic (33%) BP; but leptin levels were not significantly heritable (h2 %=15%, P=0.228). LEP rs17151914 (P=0.0002) and LEPR rs6690661 (P=0.0007) were significantly associated with leptin levels and diastolic BP, respectively, in women. The LEP rs17151913T-rs6956510G haplotype was associated with an increase in central systolic BP in women (P=0.012 with Bonferroni correction) whereas the LEPR rs2154381C-rs1171261T haplotype was associated with lower systolic BP in men (P=0.0359 with Bonferroni correction). LEP gene variants were significantly correlated with effects on leptin levels in women and the LEPR gene variants were significantly correlated with effects on diastolic BP also in women. These results indicate that further exploration of the role of genetic variation in the LEP and LEPR genes in obesity and hypertension in individuals of African ancestry is warranted.Item Genetic factors influencing bone health in the black South African population(2012) May, AndrewMaintaining suitable bone health is emerging as a serious point of concern worldwide, as the prevalence of skeletal disorders threatens to reach unmanageable proportions. Despite unfavourable environmental factors, black South Africans demonstrate elevated bone mass, especially at the femoral neck, when compared to whites. Genetic factors are thought to mediate this effect, which may have clinical or therapeutic value. Using a candidate gene approach, this study investigated associations of six candidate genes (ESR1, TNFRSF11A, TNFRSF11B, TNFSF11, SOST and SPP1) with bone mineral content amongst pre-pubertal black South African children that formed part of the longitudinal Birth to Twenty cohort. The GoldenGate genotyping assay with VeraCode microbeads was used to genotype 151 black children at 366 polymorphic loci, including 112 previously associated and 254 tagging SNPs. A linear regression approach was implemented to highlight significant associations whilst adjusting for height, weight, sex and bone area. Twenty seven markers (8 previously associated and 19 tag SNPs; P <0.05) were found to link to either femoral neck (18) or lumbar spine (9) BMC. These signals derived from three genes, namely ESR1 (17), TNFRSF11B (9) and SPP1 (1). One marker (rs2485209) maintained its association with the femoral neck after correction for multiple testing (P = 0.038). These results fully support the existence of a strong genetic effect acting at the femoral neck in African ancestry individuals. Tagging SNP signals suggest the presence of a number of population specific variants that require further investigation. Combined, these markers may help to account for increased bone mass amongst black South Africans, when adjusted for covariates.