Browsing by Author "Van der Merwe, Lize"
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- ItemAfrican HIV/AIDS trials are more likely to report adequate allocation concealment and random generation than North American trials(Public Library of Science (PLOS), 2008-10) Siegfried, Nandi; Clarke, Michael; Volmink, Jimmy; Van der Merwe, LizeBackground: Adherence to good methodological quality is necessary to minimise bias in randomised conrolled trials (RCTs). Specific trial characteristics are associated with better trial quality, but no studies to date are specific to HIV/AIDS or African trials. We postulated that location may negatively impact on trial quality in regions where resources are scarce. Methods: 1) To compare the methodological quality of all HIV/AIDS RCTs conducted in Africa with a random sample of similar trials conducted in North America; 2) To assess whether location is predictive of trial quality. We searched MEDLINE, EMBASE, CENTRAL and LILACS. Eligible trials were 1) randomized, 2) evaluations of preventive or treatment interventions for HIV/AIDS, 3) reported before 2004, and 4) conducted wholly or partly (if multi-centred) in Africa or North America. We assessed adequacy of random generation, allocation concealment and masking of assessors. Using univariate and multivariate logistic regression analyses we evaluated the association between location (Africa versus North America) and these domains. Findings: The African search yielded 12,815 records, from which 80 trials were identified. The North American search yielded 13,158 records from which 785 trials were identified and a random sample of 114 selected for analysis. African trials were three times more likely than North American trials to report adequate allocation concealment (OR = 3.24; 95%CI: 1.59 to 6.59; p<0.01) and twice as likely to report adequate generation of the sequence (OR = 2.36; 95%CI: 1.20 to 4.67; p = 0.01), after adjusting for other confounding factors. Additional significant factors positively associated with quality were an a priori sample size power calculation, restricted randomization and inclusion of a flow diagram detailing attrition. We did not detect an association between location and outcome assessor masking. Conclusions: The higher quality of reporting of methodology in African trials is noteworthy. Most African trials are externally funded, and it is possible that stricter agency requirements when leading trials in other countries and greater experience and training of principal investigators of an international stature, may account for this difference. © 2008 Siegfried et al.
- ItemAltered mitochondrial respiration and other features of mitochondrial function in parkin-mutant fibroblasts from parkinson’s disease patients(Hindawi Publishing Corporation, 2016) Haylett, William; Swart, Chrisna; Van der Westhuizen, Francois; Van Dyk, Hayley; Van der Merwe, Lize; Van der Merwe, Celia; Loos, Ben; Carr, Jonathan; Kinnear, Craig; Bardien, SorayaMutations in the parkin gene are the most common cause of early-onset Parkinson’s disease (PD). Parkin, an E3 ubiquitin ligase, is involved in respiratory chain function, mitophagy, and mitochondrial dynamics. Human cellular models with parkin null mutations are particularly valuable for investigating the mitochondrial functions of parkin. However, published results reporting on patient-derived parkin-mutant fibroblasts have been inconsistent. This study aimed to functionally compare parkin-mutant fibroblasts from PD patients with wild-type control fibroblasts using a variety of assays to gain a better understanding of the role of mitochondrial dysfunction in PD. To this end, dermal fibroblasts were obtained from three PD patients with homozygous whole exon deletions in parkin and three unaffected controls. Assays of mitochondrial respiration, mitochondrial network integrity, mitochondrial membrane potential, and cell growth were performed as informative markers of mitochondrial function. Surprisingly, it was found that mitochondrial respiratory rates were markedly higher in the parkin-mutant fibroblasts compared to control fibroblasts (p = 0.0093), while exhibiting more fragmented mitochondrial networks (). Moreover, cell growth of the parkin-mutant fibroblasts was significantly higher than that of controls (). These unanticipated findings are suggestive of a compensatory mechanism to preserve mitochondrial function and quality control in the absence of parkin in fibroblasts, which warrants further investigation.
- ItemAssociation between serotonin transporter gene polymorphisms and increased suicidal risk among HIV positive patients in Uganda(BioMed Central, 2017-07-25) Kalungi, Allan; Seedat, Soraya; Hemmings, Sian M. J.; Van der Merwe, Lize; Joloba, Moses L.; Nanteza, Ann; Nakassujja, Noeline; Birabwa, Harriet; Serwanga, Jennifer; Kaleebu, Pontiano; Kinyanda, EugeneBackground: Persons living with HIV/AIDS (PLWHA) are at an increased risk of suicide. Increased suicidal risk is a predictor of future attempted and completed suicides and has been associated with poor quality of life and poor adherence with antiretroviral therapy. Clinical risk factors have low predictive value for suicide, hence the interest in potential neurobiological correlates and specific heritable markers of suicide vulnerability. The serotonin transporter gene has previously been implicated in the aetiology of increased suicidal risk in non-HIV infected study populations and its variations may provide a platform for identifying genetic risk for suicidality among PLWHA. The present cross-sectional study aimed at identifying two common genetic variants of the serotonin transporter gene and their association with increased suicidal risk among human immunodeficiency virus (HIV)-positive adults in Uganda. Results: The prevalence of increased suicidal risk (defined as moderate to high risk suicidality on the suicidality module of the Mini Neuropsychiatric Interview (M.I.N.I) was 3.3% (95% CI, 2.0–5.3). The 5-HTTLPR was found to be associated with increased suicidal risk before Bonferroni correction (p-value = 0.0174). A protective effect on increased suicidal risk was found for the 5-HTTLPR/rs25531 S A allele (p-value = 0.0046)- which directs reduced expression of the serotonin transporter gene (5-HTT). Conclusion: The S A allele at the 5-HTTLPR/rs25531 locus is associated with increased suicidal risk among Ugandan PLWHA. Further studies are needed to validate this finding in Ugandan and other sub-Saharan samples.
- ItemCYP2D6 genotyping and use of antidepressants in breast cancer patients : test development for clinical application(Springer Verlag, 2012-05) Van der Merwe, Nicole; Bouwens, Christianne S. H.; Pienaar, Rika; Van der Merwe, Lize; Yako, Yandiswa Y.; Geiger, Dieter H.; Kotze, Maritha J.Approximately 25 % of clinically important drugs and numerous environmental carcinogens are metabolised by CYP2D6. Variation in the CYP2D6 gene and concomitant use of tamoxifen (TAM) with certain antidepressants may increase recurrence risk in breast cancer patients due to reduced enzyme activity. In this study we determined the appropriateness of adding CYP2D6 genotyping to the breast cancer genetic testing options already available in South Africa, which include BRCA mutation screening and transcriptional profiling to assess estrogen receptor (ER) status. A total of 114 South African breast cancer patients, including 52 Caucasian and 62 Coloured (Mixed ancestry), and 63 Caucasian control individuals were genotyped for the most common inactivating allele (CYP2D6*4, rs3892097) previously identified in the CYP2D6 gene. In the initial validation data set consisting of 25 Caucasian and 62 Coloured patients, the CYP2D6*4 allele frequency was significantly higher in Caucasian compared to Coloured patients (24 % vs. 3 %, p≤0.001), similar to previous findings in the general South African population. Extended CYP2D6 genotyping was subsequently performed in an implementation data set of 27 Caucasian breast cancer patients, to determine the prevalence of depression and use of antidepressants in a clinical setting. A medical history of depression and/or use of antidepressants was reported in 37 % (10/27) of these breast cancer patients genotyped for CYP2D6*4. This translational research study has led to increased awareness among clinicians of the potential benefits of CYP2D6 genotyping to facilitate prevention of cumulative risk in a high-risk genetic subgroup of breast cancer patients considered for concomitant treatment of TAM and antidepressants that may reduce enzyme function. © Springer Science+Business Media, LLC 2012.
- ItemErrors in the completion of the death notification form(Health and Medical Publishing Group (HMPG), 2007-11) Burger, Elsie Helena; Van der Merwe, Lize; Volmink, JimmyObjectives. To determine the frequency of errors in the cause of death sequence and to assess the completeness of information recorded on death notification forms (DNFs). Design. A population-based descriptive study. Setting. All residents of two residential areas in the Cape Town metropole who died during the period 1 June 2003 to 31 May 2004. Methods. We examined DNFs for pre-specified major and minor errors, assessed potential predictors of major errors using multivariate analysis, and assessed the DNFs for completeness in terms of particulars of the deceased, the informant and the health professional certifying death. Results. 844 DNFs were evaluated. Errors were found in 91.7% (95% CI 89.7 - 93.4%) of DNFs, and 43.4% (95% CI 40.1 - 46.7%) had at least one major error, most commonly an illogical cause of death sequence. Factors that seemed to affect the frequency of major errors were the number of lines of the cause of death sequence that had been completed, the age, gender and area of residence of the deceased, and the type of facility where the DNF had been completed. Varying levels of completeness were found for different items of information with some questions such as the education, occupation, usual business and smoking history of deceased being largely ignored by health professionals. Conclusion. An unacceptably high proportion of DNFs in the greater Cape Town area contain errors sufficiently serious to affect the accuracy of cause of death coding. This has far-reaching implications for the reliability of mortality data in South Africa. Educational, managerial and administrative interventions are urgently needed to improve the standard of DNF completion.
- ItemFat mass and obesity-associated (FTO) gene polymorphisms are associated with physical activity, food intake, eating behaviors, psychological health, and modeled change in body mass index in overweight/obese caucasian adults(MDPI, 2014-08-06) Harbron, Janetta; Van der Merwe, Lize; Zaahl, Monique G.; Kotze, Maritha J.; Senekal, MarjanneThe fat mass and obesity-associated (FTO) gene is currently recognized as the most robust predictor of polygenic obesity. We investigated associations between the FTO rs1421085 and rs17817449 polymorphisms and the FTO rs1421085–rs17817449 haplotype and dietary intake, eating behavior, physical activity, and psychological health, as well as the effect of these associations on BMI. N = 133 treatment seeking overweight/obese Caucasian adults participated in this study. Genotyping was performed from whole blood samples. Weight and height was measured and a non-quantified food frequency questionnaire was completed to assess food group intake. Validated questionnaires were completed to assess physical activity (Baecke questionnaire),psychological health (General Health questionnaire, Rosenburg self-esteem scale and Beck Depression Inventory), and eating behavior (Three Factor Eating questionnaire). The risk alleles of the FTO polymorphisms were associated with poorer eating behaviors (higher hunger, internal locus for hunger, and emotional disinhibition scores), a higher intake of high fat foods and refined starches and more depressive symptoms. The modeled results indicate that interactions between the FTO polymorphisms or haplotypes and eating behavior, psychological health, and physical activity levels may be associated with BMI. The clinical significance of these results for implementation as part of weight management interventions needs further investigation.
- ItemIdentification of a novel functional deletion variant in the 5'-UTR of the DJ-1 gene(BioMed Central, 2009-10) Keyser, Rowena J.; Van der Merwe, Lize; Venter, Mauritz; Kinnear, Craig; Warnich, Louise; Carr, Jonathan; Bardien, SorayaBackground: DJ-1 forms part of the neuronal cellular defence mechanism against oxidative insults, due to its ability to undergo self-oxidation. Oxidative stress has been implicated in the pathogenesis of central nervous system damage in different neurodegenerative disorders including Alzheimer's disease and Parkinson's disease (PD). Various mutations in the DJ-1 (PARK7) gene have been shown to cause the autosomal recessive form of PD. In the present study South African PD patients were screened for mutations in DJ-1 and we aimed to investigate the functional significance of a novel 16 bp deletion variant identified in one patient. Methods: The possible effect of the deletion on promoter activity was investigated using a Dual- Luciferase Reporter assay. The DJ-1 5'-UTR region containing the sequence flanking the 16 bp deletion was cloned into a pGL4.10-Basic luciferase-reporter vector and transfected into HEK293 and BE(2)-M17 neuroblastoma cells. Promoter activity under hydrogen peroxide-induced oxidative stress conditions was also investigated. Computational (in silico) cis-regulatory analysis of DJ-1 promoter sequence was performed using the transcription factor-binding site database, TRANSFAC via the PATCH™ and rVISTA platforms. Results: A novel 16 bp deletion variant (g.-6_+10del) was identified in DJ-1 which spans the transcription start site and is situated 93 bp 3' from a Sp1 site. The deletion caused a reduction in luciferase activity of approximately 47% in HEK293 cells and 60% in BE(2)-M17 cells compared to the wild-type (P < 0.0001), indicating the importance of the 16 bp sequence in transcription regulation. The activity of both constructs was up-regulated during oxidative stress. Bioinformatic analysis revealed putative binding sites for three transcription factors AhR, ARNT, HIF-1 within the 16 bp sequence. The frequency of the g.-6_+10del variant was determined to be 0.7% in South African PD patients (2 heterozygotes in 148 individuals). Conclusion: This is the first report of a functional DJ-1 promoter variant, which has the potential to influence transcript stability or translation efficiency. Further work is necessary to determine the extent to which the g.-6_+10del variant affects the normal function of the DJ-1 promoter and whether this variant confers a risk for PD.
- ItemInvestigating the role of gene-gene interactions in TB susceptibility(Public Library of Science, 2015-04) Daya, Michelle; Van der Merwe, Lize; Van Helden, Paul D.; Moller, Marlo; Hoal, Eileen G.Tuberculosis (TB) is the second leading cause of mortality from infectious disease worldwide. One of the factors involved in developing disease is the genetics of the host, yet the field of TB susceptibility genetics has not yielded the answers that were expected. A commonly posited explanation for the missing heritability of complex disease is gene-gene interactions, also referred to as epistasis. In this study we investigate the role of gene-gene interactions in genetic susceptibility to TB using a cohort recruited from a high TB incidence community from Cape Town, South Africa. Our discovery data set incorporates genotypes from a large a number of candidate gene studies as well as genome-wide data. After limiting our search space to pairs of putative TB susceptibility genes, as well as pairs of genes that have been curated in online databases as potential interactors, we use statistical modelling to identify pairs of interacting SNPs. We attempt to validate the top models identified in our discovery data set using an independent genome-wide TB case-control data set from The Gambia. A number of models were successfully validated, indicating that interplay between the NRG1 - NRG3, GRIK1 - GRIK3 and IL23R - ATG4C gene pairs may modify susceptibility to TB. Gene pairs involved in the NF-κB pathway were also identified in the discovery data set (SFTPD - NOD2, ISG15 - TLR8 and NLRC5 - IL12RB1), but could not be tested in the Gambian study group due to lack of overlapping data.
- ItemLong-term follow-up of R403W MYH7 and R92W TNNT2 HCM families : mutations determine left ventricular dimensions but not wall thickness during disease progression(Clinics Cardiv Publishing, 2007-06) Revera, Miriam; Van der Merwe, Lize; Heradien, Marshall; Goosen, Althea; Corfield, Valerie A.; Brink, Paul A.; Moolman-Smook, Johanna C.The clinical profile and prognosis of patients with hypertrophic cardiomyopathy, a primary cardiac muscle disease caused mostly by mutations in sarcomeric protein-encoding genes, have been linked to particular disease-causing mutations in the past. However, such associations are often based on cross-sectional observations, as longitudinal studies of the progression of the disease in genotypically defined patients are sparse. Most importantly, the relative contribution of age, gender and genetic cause to disease profile and progression has not yet been reported, and the question remains whether one or more of these factors could mask the effect of the other(s). Methods: We previously described cross-sectional family studies of two hypertrophic cardiomyopathy (HCM)-causing mutations, R92WTNNT2 and R403WMYH7, both associated with minimal hypertrophy, but with widely different life expectancies. We re-investigated 22 and 26 R92WTNNT2 and R403WMYH7 mutation carriers in these and additional South African R92WTNNT2 families after a mean 11.08 ± 2.79 years, and compared the influence of the two mutations, in the context of age and gender, on disease progression. Results: We demonstrated a positive correlation between age and interventricular septal thickness for both mutations, with more than a third of all mutation carriers developing clinically recognised hypertrophy only after the age of 35 years. This period of hypertrophically silent HCM also coincided with the years in which most sudden cardiac deaths occurred, particularly in male R92WTNNT2 carriers. Statistical analyses indicated that the particular mutation was the strongest determinant of left ventricular remodelling; particularly, LVESD increased and EF reduction was noted in the majority of R403WMYH7 carriers, which may require clinical follow-up over the longer term. Conclusions: Statistical modelling of follow-up data suggests that an interplay between unidentified, possibly genderassociated factors, and the causal mutation are the determinants of eventual cardiac function and survival, but not of the extent of hypertrophy, and emphasises the need for long-term follow-up even in individuals with apparently mild disease.
- ItemA panel of ancestry informative markers for the complex five-way admixed South African Coloured population(PLoS, 2013-12) Daya, Michelle; Van der Merwe, Lize; Ushma Galal; Möller, Marlo; Salie, Muneeb; Chimusa, Emile R.; Galanter, Joshua M.; Van Helden, Paul D.; Henn, Brenna M.; Gignoux, Chris R.; Hoal, EileenAdmixture is a well known confounder in genetic association studies. If genome-wide data is not available, as would be the case for candidate gene studies, ancestry informative markers (AIMs) are required in order to adjust for admixture. The predominant population group in the Western Cape, South Africa, is the admixed group known as the South African Coloured (SAC). A small set of AIMs that is optimized to distinguish between the five source populations of this population (African San, African non-San, European, South Asian, and East Asian) will enable researchers to cost-effectively reduce falsepositive findings resulting from ignoring admixture in genetic association studies of the population. Using genome-wide data to find SNPs with large allele frequency differences between the source populations of the SAC, as quantified by Rosenberg et. al’s In-statistic, we developed a panel of AIMs by experimenting with various selection strategies. Subsets of different sizes were evaluated by measuring the correlation between ancestry proportions estimated by each AIM subset with ancestry proportions estimated using genome-wide data. We show that a panel of 96 AIMs can be used to assess ancestry proportions and to adjust for the confounding effect of the complex five-way admixture that occurred in the South African Coloured population.
- ItemA rapid method for detection of five known mutations associated with aminoglycoside-induced deafness(BioMed Central, 2009-01) Bardien, Soraya; Human, Hannique; Harris, Tashneem; Hefke, Gwynneth; Veikondis, Rene; Schaaf, H. Simon; Van der Merwe, Lize; Greinwald, John H.; Fagan, Johan; De Jong, GreetjeBackground: South Africa has one of the highest incidences of multidrug-resistant tuberculosis (MDR-TB) in the world. Concomitantly, aminoglycosides are commonly used in this country as a treatment against MDR-TB. To date, at least five mutations are known to confer susceptibility to aminoglycoside-induced hearing loss. The aim of the present study was to develop a rapid screening method to determine whether these mutations are present in the South African population. Methods: A multiplex method using the SNaPshot technique was used to screen for five mutations in the MT-RNR1 gene: A1555G, C1494T, T1095C, 961delT+C(n) and A827G. A total of 204 South African control samples, comprising 98 Mixed ancestry and 106 Black individuals were screened for the presence of the five mutations. Results: A robust, cost-effective method was developed that detected the presence of all five sequence variants simultaneously. In this pilot study, the A1555G mutation was identified at a frequency of 0.9% in the Black control samples. The 961delT+C(n) variant was present in 6.6% of the Black controls and 2% of the Mixed ancestry controls. The T1095C, C1494T and A827G variants were not identified in any of the study participants. Conclusion: The frequency of 0.9% for the A1555G mutation in the Black population in South Africa is of concern given the high incidence of MDR-TB in this particular ethnic group. Future larger studies are warranted to determine the true frequencies of the aminoglycoside deafness mutations in the general South African population. The high frequencies of the 961delT+C(n) variant observed in the controls suggest that this change is a common non-pathogenic polymorphism. This genetic method facilitates the identification of individuals at high risk of developing hearing loss prior to the start of aminoglycoside therapy. This is important in a low-resource country like South Africa where, despite their adverse side-effects, aminoglycosides will continue to be used routinely and are accompanied with very limited or no audiological monitoring.
- ItemReduced DNA methylation at the PEG3 DMR and KvDMR1 loci in children exposed to alcohol in utero : a South African Fetal Alcohol Syndrome cohort study(Frontiers, 2015-03-10) Masemola, Matshane L.; Van der Merwe, Lize; Lombard, Zane; Viljoen, Denis; Ramsay, MicheleFetal alcohol syndrome (FAS) is a devastating developmental disorder resulting from alcohol exposure during fetal development. It is a considerable public health problem worldwide and is characterized by central nervous system abnormalities, dysmorphic facial features, and growth retardation. Imprinted genes are known to play an important role in growth and development and therefore four imprinting control regions (ICRs), H19 ICR, IG-DMR, KvDMR1 and PEG3 DMR were examined. It is proposed that DNA methylation changes may contribute to developmental abnormalities seen in FAS and which persist into adulthood. The participants included FAS children and controls from the Western and Northern Cape Provinces. DNA samples extracted from blood and buccal cells were bisulfite modified, the ICRs were amplified by PCR and pyrosequencing was used to derive a quantitative estimate of methylation at selected CpG dinucleotides: H19 ICR (six CpG sites; 50 controls and 73 cases); KvDMR1 (7, 55, and 86); IG-DMR (10, 56, and 84); and PEG3 DMR (7, 50, and 79). The most profound effects of alcohol exposure are on neuronal development. In this study we report on epigenetic effects observed in blood which may not directly reflect tissue-specific alterations in the developing brain. After adjusting for age and sex (known confounders for DNA methylation), there was a significant difference at KvDMR1 and PEG3 DMR, but not the H19 ICR, with only a small effect (0.84% lower in cases; p D 0.035) at IG-DMR. The two maternally imprinted loci, KvDMR1 and PEG3 DMR, showed lower average locus-wide methylation in the FAS cases (1.49%; p < 0.001 and 7.09%; p < 0.001, respectively). The largest effect was at the PEG3 DMR though the functional impact is uncertain. This study supports the role of epigenetic modulation as a mechanism for the teratogenic effects of alcohol by altering the methylation profiles of imprinted loci in a locus-specific manner.
- ItemDie rol en persoon van die fasiliteerder van 'n christelike tienergespreksgroep(Stellenbosch : Stellenbosch University, 2001) Van der Merwe, Elizabeth; Van der Merwe, Lize; Ackermann, C. J.; Stellenbosch University. Faculty of Education. Dept. of Educational Psychology.ENGLISH ABSTRACT: This study addresses the role and person of the facilitator of a Christian teen discussion group. From the literature study it is evident that there are specific requirements concerning the role and person of the facilitator of a teen discussion group. These requirements and definitions should only serve as guidelines for the success of a teen discussion group The empirical study investigated the role and person of the facilitator of a teen discussion group. According to the results it seems that the most important characteristics of a facilitator, according to the teen discussion groups, are that of warmth as a person, caring and insight and that he must be a role model. The study also showed that the role and person of a facilitator of a teen discussion group to a great extent contributes to the success of these groups.
- ItemUsing multi-way admixture mapping to elucidate TB susceptibility in the South African Coloured population(BioMed Central, 2014-11) Daya, Michelle; Van der Merwe, Lize; Gignoux, Christopher R.; Van Helden, Paul D.; Moller, Marlo; Hoal, Eileen G.Background: The admixed South African Coloured population is ideally suited to the discovery of tuberculosis susceptibility genetic variants and their probable ethnic origins, but previous attempts at finding such variants using genome-wide admixture mapping were hampered by the inaccuracy of local ancestry inference. In this study, we infer local ancestry using the novel algorithm implemented in RFMix, with the emphasis on identifying regions of excess San or Bantu ancestry, which we hypothesize may harbour TB susceptibility genes. Results Using simulated data, we demonstrate reasonable accuracy of local ancestry inference by RFMix, with a tendency towards miss-calling San ancestry as Bantu. Regions with either excess San ancestry or excess African (San or Bantu) ancestry are less likely to be affected by this bias, and we therefore proceeded to identify such regions, found in cases but not in controls (642 cases and 91 controls). A number of promising regions were found (overall p-values of 7.19×10-5 for San ancestry and <2.00×10-16 for African ancestry), including chromosomes 15q15 and 17q22, which are close to genomic regions previously implicated in TB. Promising immune-related susceptibility genes such as the GADD45A, OSM and B7-H5 genes are also harboured in the identified regions. Conclusion Admixture mapping is feasible in the South African Coloured population and a number of novel TB susceptibility genomic regions were uncovered.