Jacobs, Clifford Winston
Philosophiae Doctor - PhD Solute carrier transporters belonging to the major facilitator family of membrane transporter are increasingly being recognized as a possible mechanism to explain inter-individual variation in drug efficacy and response. Genetic factors are estimated to be responsible for approximately 15-30% of inter-individual variation in drug disposition and response. The aims of this study were to determine the minor allele frequencies of 78 previously identified single nucleotide polymorphisms in the pharmacogenetically relevant SLC22A1-3 and SLC47A1 genes in the indigenous African population of South Africa. Secondly, to determine whether allele and genotype frequencies for these SNP were different from that reported for other African, Caucasian, and Asian populations. Thirdly, to infer haplotypes from the genetic information which can potentially be used in future to design and interpret results of pharmacogenetics association studies involving these genes and their substrate drugs. Finally, to determine whether the Xhosa population harbour novel SNPs in the SLC22A2 gene, that encodes the kidney-specific hOCT2. SNaPshot™ multiplex single base minisequencing systems were developed and optimized for each of SLC22A1, SLC22A2, SLC22A3, and SLC47A1 covering the previously identified 78 SNPs. These systems were then used to genotype the alleles of 148 healthy Xhosa subjects residing in Cape Town, South Africa. In addition, the proximal promoter region and all 11 exons and flanking regions of the SLC22A2 gene of 96 of the participants were screened for novel SNPs by direct sequencing. The Xhosa subjects investigated lacked heterozygosity and were monomorphic for 91% of the SNPs screened. None of the SLC22A3 and SLC47A1 SNPs investigated was observed in this study. Sequencing of the SLC22A2 gene revealed 28 SNPs, including seven novel polymorphic sites, in the 96 Xhosa subjects that were screened. The minor allele frequencies of the seven previously identified variant SNPs observed in this study were different compared to that observed for American and European Caucasian, and Asian populations. Moreover, the allele frequencies for these SNPs differed amongst African populations themselves. Eight and seven haplotypes were inferred for SLC22A1 and SLC22A2, respectively, for the Xhosa population from the information gathered with SNaPshot™ genotyping. This study highlights the fact that African populations do not have the same allele frequencies for SNPs in pharmacogenetically relevant genes. Furthermore, the Xhosa and other African populations do not share all reduced function variants of the SLC22A1-3 and SLC47A1 genes with Caucasian and Asian populations. Moreover, this study has demonstrated that the Xhosa population harbours novel and rare genetic polymorphisms in the key pharmacogene SLC22A2. This study lays the foundation for the design and interpretation of future pharmacogenetic association studies between the variant alleles of the SLC22A1-3 and SLC47A1 genes in the Xhosa population and drug disposition and efficacy.
Drug mutation patterns and risk factors associated with patients failing first-line antiretroviral therapy regimen in Oshikoto and Oshana regions, NamibiaShiningavamwe, Andreas Ndafudifwa 2015 (has links)
Magister Public Health - MPH HIV/AIDS is a major health problem in Namibia with HIV prevalence estimated at 18.2% among pregnant women. Antiretroviral therapy (ART) was introduced in the public sector in 2003 and ART roll out was expanded throughout the country in the subsequent years. There are 221 ART sites in Namibia which include 34 district hospitals and 187 outreach service points. Currently there are 127,486 patients registered on ART in Namibia. However, there have been cases of patients experiencing treatment failure. The treatment failure can give rise to the emergence of HIV drug resistance. Genotyping information from patients with treatment failure can be valuable for tracking the dominant mutations conferring HIV drug resistance. However, HIV genotyping is not routinely available in Namibia due to cost. It is essential to determine the risk factors associated with development of HIV drug resistance so that these factors can be addressed. The aim of the current study was to describe HIV drug resistance mutations and the risk factors associated with HIV drug resistance among patients failing first- line ART regimen in Oshikoto and Oshana regions in Namibia. The case-control study design was used to collect data from cases who were being suspected of treatment failure to the first–line regimen in Oshikoto and Oshana regions in Namibia. The demographic, clinical and genotype information was collected from patient records. Out of 168 cases, 97 cases were eligible for this study and were matched with 105 controls. The mean age was 44.8 (±13.2) years for controls and 43.3 (±13.3) years for cases. Cases from Oshana and Oshikoto regions harboured 63% and 71% respectively for nucleoside reverse transcriptase inhibitors mutations with the dominant mutation being M184V/I. Sixty-eight percent (68%) and 76% respectively harboured mutations for non-nucleoside reverse transcriptase inhibitors with dominant mutation being K103N. Missed appointments, initiating inappropriate first-line regimen and adverse events or side effects were identified as risk factors for virological failure with odd ratios (OR) of 21.58 (95% CI 6.50 -71.59); 11.70 (95% CI 1.69 - 80.99) and 7.17 (95% CI 1.89 -27.22) respectively. Patients failing the first-line regimen need to be genotyped to assess the development of HIV drug resistance. The patients initiating ART should be educated on impacts of missing clinical appointments and adverse events of the drugs in order to prevent the emergence of drug resistance.
Single nucleotide polymorphism association studies of ABCA13 and ABHD11 genes and the bioinformatics analysis of the autism candidate genes localized on chromosome 7Davids, Muneera 2016 (has links)
Magister Scientiae - MSc Autism, Aspergers Syndrome and Pervasive Developmental Delay-Not Otherwise Specified (PDD-NOS), among others, fall under an umbrella of disorders known as Autism Spectrum Disorder. Twin studies show that autism is a highly heritable disorder. More than 100 genes have been implicated in the aetiology of autism, each of which is involved in numerous biological processes and a variety of molecular interactions. William-Beuren syndrome is a multisystem developmental disorder caused by the deletion of contiguous genes at the 7q11.23 position. The aims of this study were (i) to genotype three SNPs (rs10279013, rs2293484 and rs17060) in the ABHD11 and ABCA13 genes, respectively, using Taqman® SNP Genotyping assays to detect association with autism in three distinct South African (SA) ethnic groups (Black, Caucasian and Mixed), and (ii) to ascertain common pathways or regulating transcription factors for genes on chromosome 7 that may attribute to it being an “autism hotspot”. Chapter 3 objectives were to identify potential candidate genes using STRING analysis and the Gene Cards database. The Taqman® study indicated significant association for SNP rs2293484 in the South African Caucasian group, as well as for the G allele in the South African Mixed group, where p<0.001. STRING analysis yielded 2 new candidate genes, FZD1 and FZD9. It was also found that the Wnt pathway in mammals plays a significant role in both ASDs and cancer, and there is a definite link between genes regulating cancer, and genes implicated in autism. The study provides evidence for not only the association of the investigated SNP in a South African population, but also provides evidence for the co-morbidity of several neurological and psychological disorders such as depression and bipolar disorder with autism.
Berryman, Lindsay, Cameron, Caitlin
Class of 2007 Abstract Objectives: The objective of this study was to determine the cost-effectiveness of using the Invader® UGT1A1 Molecular Assay to identify patients at risk of experiencing neutropenia from irinotecan monotherapy and FOLFIRI. Methods: Publicly available search engines were used to search for literature reporting the rate, treatment, and cost of adverse events and the population rate of genotypes. Drug acquisition costs were determined using average wholesale prices. Additional costs were determined using the Physicians’ Fee and Coding Guide. Monte Carlo Simulations were performed to reveal average cost, average effectiveness, and 95% confidence intervals. Tornado diagrams were derived to identify variables most likely to affect the outcomes and sensitivity analyses. Results: Monte Carlo simulations of monotherapy revealed a mean cost of treatment with genotype assay information of $6,620 (SD: $3,235; 95% CI: $5,408 to $15, 258) and an effectiveness ratio of 0.877 (SD: 0.328; 95% CI: 0 to 1). Without the genotype assay information the mean cost of treatment was $7,358 (SD: $4,183; 95% CI: $5,083 to $14,883) and the effectiveness ratio was 0.764 (SD: 0.425; 95% CI: 0 to 1). Monte Carlo simulations of FOLFIRI data showed a mean cost of treatment with genotype assay information of $6,105 (SD: $3,438; 95% CI: $4,706 to $14,556) and an effectiveness ratio of 0.858 (SD: 0.349; 95% CI: 0 to 1). When genotype information was unknown, the mean cost of FOLFIRI was $6,833 (SD: $4,288; 95% CI: $4,331 to $14,181) and the effectiveness ratio was 0.746 (SD: 0.435; 95% CI: 0 to 1). Conclusions: Genotyping patients exposed to irinotecan monotherapy or FOLFIRI may be a cost-effective means of identifying at risk patients but the results from this study while favorable are not statistically significant.
Prevalence and molecular characterization of Cryptosporidium spp. in dairy cattle in South Bohemia, the Czech Republic Prevalence and molecular characterization of Cryptosporidium spp. in dairy cattle in South Bohemia, the Czech RepublicONDRÁČKOVÁ, Zuzana 2009 (has links)
The prevalence and molecular characterization of Cryptosporidium spp. in slaughtered cattle 6 months and older was performed. Three species of Cryptosporidium were identified. A subtype of C. parvum was obtained.
The Molecular Epidemiology of Tuberculosis in South Carolina, 2005-2011: Estimates of Recent Transmission and Risk Factors for Genotype ClusteringRoach, Amy Kathleen 1 January 2017 (has links)
Because tuberculosis (TB) is a public health threat that continues to elude elimination in the United States, there is a need to identify contributing factors that may have implications for targeted control measures. Molecular studies of genetic clustering are crucial for pinpointing these contributing factors. It is for this reason this study was conducted. This was a non-experimental, cross-sectional population-based molecular epidemiological study of TB in SC from 2005 to 2011. Its purpose was to estimate the proportion of TB that may be due to recently acquired infection and to determine the risk factors associated with the genetic clustering of identical M. tuberculosis isolates from TB patients in South Carolina from 2005-2011. The analysis sample included 627 confirmed pulmonary and/or pleural cases of TB, for which complete data on all covariates and a valid genotype were available. The results strongly suggested that about 50% of TB in South Carolina is recently transmitted. The study also revealed that being born in the United States and Black race were independently and significantly associated with being part of a TB genotype cluster. The key messages of this study were as follows: a substantial portion of TB in South Carolina is due to recent transmission, not reactivation or importation, and transmission of TB in South Carolina occurs in groups often defined by American birth and Black race. These important findings indicate that most TB in South Carolina is preventable and that enhanced TB control efforts should be explored. The implication for positive social change is that employing targeted contact investigation informed by these findings could lead to decreased disease transmission. Future studies should explore pilot programs that investigate alternatives to the traditional TB contact investigation.
APPLICATIONS OF THE HARDY-WEINBERG PRINCIPLE TO DETECTION OF LINKAGE DISEQUILIBRIUM AND GENOTYPING ERRORS IN THE CONTEXT OF ASSOCIATION STUDIESLondono-Vasquez, Douglas 8 June 2007 (has links)
No description available.
Genetic Study of Compositional and Physical Kernel Quality Traits in Diverse Maize (Zea mays L.) GermplasmRyu, Si Hwan 2010 (has links)
No description available.
Bowler, Frank Ray
Single nucleotide polymorphisms (SNPs) and insertions/deletions (indels) constitute important sources of genetic variation which provide insight into disease aetiology and idiosyncratic differences in drug response. The analysis of such genetic variation relies upon the generation of allele-specific products, typically by enzymatic extension or the hybridization of allele-specific DNA probes. Herein, a distinct enzyme-free, dynamic chemistry-based method of producing allele-specific products for genotyping was developed. The approach was initially demonstrated in model systems using synthetic DNA, which was used as a template in a base-filling reductive amination reaction on a PNA backbone. The templated dynamic reaction between a free secondary amine at a ‘blank’ position on the PNA strand and four aldehyde-modified nucleobases drove selective formation of the ‘correct’ iminium intermediate according to Watson-Crick base-pairing rules. In a blind trial, the method was extended to genotype twelve cystic fibrosis patients for two mutations (one SNP and one indel) linked to this disease. Enzyme-free dynamic chemistry thus permitted successful genotyping in both singleplex and duplex formats, demonstrating the application of dynamic chemistry as a distinct method of allelediscrimination with certain advantages over those reported previously. The application of this method as a tool for the discovery of non-natural nucleobases with improved properties for antisense and genotyping applications was also investigated. Furthermore, progress was made towards the use of dynamic chemistry as a means of full nucleic acid sequence analysis, through the templated sequence-selective extension of PNA probes by reductive amination.
The Influence of Host Genetics on JCV and EBV Antibody Levels in Multiple Sclerosis Patients and ControlsStrid, Elin 2012 (has links)
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), characterized by lesions formed due to demyelination. MS is a complex disease thought to be triggered by environmental factors in genetically predisposed individuals. The strongest associated susceptibility allele is HLA-DRB1*1501. Environmental factors include smoking, latitude and previous infection of Epstein-Barr virus (EBV), a common herpes virus. There is no cure for MS, but several inhibitor and symptomatic drugs. Tysabri® (natalizumab) is the most effective drug, but it may lead to progressive multifocal leukoencephalopathy (PML), a rare but often fatal disease caused by reactivation of JC virus. The aim of this thesis was to replicate previous findings from a genome-wide association study and to find host genetic factors influencing JCV seropositivity and EBNA1 IgG titers in Swedish MS patients and healthy controls. Samples from the EIMS and IMSE studies were genotyped by TaqMan® OpenArray™ PCR, an end-point SNP genotyping analysis. 1143 cases and 556 healthy controls were genotyped. Due to poor call rates, genotype data from an Immunochip study was added. A total of 3408 samples (1664 cases and 1744 controls) were analyzed. EBNA1 IgG antibodies were previously measured as a detection of EBV infection and increased MS risk, and JCV IgG antibodies were measured to find patients potentially at risk for PML. One significant result was found, gene 105 (p = 0.01674, OR 0.68, CI 95% 0.49-0.93), with a protective effect in MS. More significant results might have been found with better loading of the plate, or with a different genotyping method.
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