SUNScholar - Browsing by Author "Moller, Marlo"

Browsing by Author "Moller, Marlo"

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Analysis of eight genes modulating interferon gamma and human genetic susceptibility to tuberculosis : a case-control association study
(BioMed Central, 2010-06) Moller, Marlo; Nebel, Almut; Van Helden, Paul D.; Schreiber, Stefan; Hoal, Eileen G.
Background: Interferon gamma is a major macrophage-activating cytokine during infection with Mycobacterium tuberculosis, the causative pathogen of tuberculosis, and its role has been well established in animal models and in humans. This cytokine is produced by activated T helper 1 cells, which can best deal with intracellular pathogens such as M. tuberculosis. Based on the hypothesis that genes which regulate interferon gamma may influence tuberculosis susceptibility, we investigated polymorphisms in eight candidate genes. Methods: Fifty-four polymorphisms in eight candidate genes were genotyped in over 800 tuberculosis cases and healthy controls in a population-based case-control association study in a South African population. Genotyping methods used included the SNPlex Genotyping System™, capillary electrophoresis of fluorescently labelled PCR products, TaqMan® SNP genotyping assays or the amplification mutation refraction system. Single polymorphisms as well as haplotypes of the variants were tested for association with TB using statistical analyses. Results: A haplotype in interleukin 12B was nominally associated with tuberculosis (p = 0.02), but after permutation testing, done to assess the significance for the entire analysis, this was not globally significant. In addition a novel allele was found for the interleukin 12B D5S2941 microsatellite. Conclusions: This study highlights the importance of using larger sample sizes when attempting validation of previously reported genetic associations. Initial studies may be false positives or may propose a stronger genetic effect than subsequently found to be the case.
The complete genome sequence of the African buffalo (Syncerus caffer)
(BioMed Central, 2016-12-07) Glanzmann, Brigitte; Moller, Marlo; Le Roex, Nikki; Tromp, Gerard; Hoal, Eileen G.; Van Helden, Paul D.
Background: The African buffalo (Syncerus caffer) is an important role player in the savannah ecosystem. It has become a species of relevance because of its role as a wildlife maintenance host for an array of infectious and zoonotic diseases some of which include corridor disease, foot-and-mouth disease and bovine tuberculosis. To date, no complete genome sequence for S. caffer had been available for study and the genomes of other species such as the domestic cow (Bos taurus) had been used as a proxy for any genetics analysis conducted on this species. Here, the high coverage genome sequence of the African buffalo (S. caffer) is presented. Results: A total of 19,765 genes were predicted and 19,296 genes could be successfully annotated to S. caffer while 469 genes remained unannotated. Moreover, in order to extend a detailed annotation of S. caffer, gene clusters were constructed using twelve additional mammalian genomes. The S. caffer genome contains 10,988 gene clusters, of which 62 are shared exclusively between B. taurus and S. caffer. Conclusions: This study provides a unique genomic perspective for the S. caffer, allowing for the identification of novel variants that may play a role in the natural history and physiological adaptations.
Evaluating the accuracy of imputation methods in a five-way admixed population
(Frontiers Media, 2019) Schurz, Haiko; Muller, Stephanie J.; Van Helden, Paul David; Tromp, Gerard; Hoal, Eileen G.; Kinnear, Craig J.; Moller, Marlo
Genotype imputation is a powerful tool for increasing statistical power in an association analysis. Meta-analysis of multiple study datasets also requires a substantial overlap of SNPs for a successful association analysis, which can be achieved by imputation. Quality of imputed datasets is largely dependent on the software used, as well as the reference populations chosen. The accuracy of imputation of available reference populations has not been tested for the five-way admixed South African Colored (SAC) population. In this study, imputation results obtained using three freely-accessible methods were evaluated for accuracy and quality. We show that the African Genome Resource is the best reference panel for imputation of missing genotypes in samples from the SAC population, implemented via the freely accessible Sanger Imputation Server.
Exome sequencing identifies a novel MAP3K14 mutation in recessive atypical combined immunodeficiency
(Frontiers, 2017-11) Schlechter, Nikola; Glanzmann, Brigitte; Hoal, Eileen Garner; Schoeman, Mardelle; Petersen, Britt-Sabina; Franke, Andre; Lau, Yu-Lung; Urban, Michael; Van Helden, Paul David; Esser, Maria Esser; Moller, Marlo; Kinnear, Craig
ENGLISH ABSTRACT: Primary immunodeficiency disorders (PIDs) render patients vulnerable to infection with a wide range of microorganisms and thus provide good in vivo models for the assessment of immune responses during infectious challenges. Priming of the immune system, especially in infancy, depends on different environmental exposures and medical practices. This may determine the timing and phenotype of clinical appearance of immune deficits as exemplified with early exposure to Bacillus Calmette-Guérin (BCG) vaccination and dissemination in combined immunodeficiencies. Varied phenotype expression poses a challenge to identification of the putative immune deficit. Without the availability of genomic diagnosis and data analysis resources and with limited capacity for functional definition of immune pathways, it is difficult to establish a definitive diagnosis and to decide on appropriate treatment.
Exome sequencing identifies a novel TTC37 mutation in the first reported case of Trichohepatoenteric syndrome (THE-S) in South Africa
(BioMed Central, 2017-03-14) Kinnear, Craig; Glanzmann, Brigitte; Banda, Eric; Schlechter, Nikola; Durrheim, Glenda; Neethling, Annika; Nel, Etienne; Schoeman, Mardelle; Johnson, Glynis; Van Helden, Paul D.; Hoal, Eileen G; Esser, Monika; Urban, Michael; Moller, Marlo
Background Trichohepatoenteric syndrome (THE-S) or phenotypic diarrhoea of infancy is a rare autosomal recessive disorder characterised by severe infantile diarrhoea, facial dysmorphism, immunodeficiency and woolly hair. It was first described in 1982 in two infants with intractable diarrhoea, liver cirrhosis and abnormal hair structure on microscopy. We report on two siblings from a consanguineous family of Somali descent who, despite extensive clinical investigation, remained undiagnosed until their demise. The index patient died of fulminant cytomegalovirus pneumonitis at 3 months of age. Methods Whole exome sequencing (WES) was performed on a premortem DNA sample from the index case. Variants in a homozygous recessive state or compound heterozygous state were prioritized as potential candidate variants using TAPER™. Sanger sequencing was done to genotype the parents, unaffected sibling and a deceased sibling for the variant of interest. Results Exome sequencing identified a novel homozygous mutation (c.4507C > T, rs200067423) in TTC37 which was confirmed by Sanger sequencing in the index case. The identification of this mutation led to the diagnosis of THE-S in the proband and the same homozygous variant was confirmed in a male sibling who died 4 years earlier with severe chronic diarrhoea of infancy. The unaffected parents and sister were heterozygous for the identified variant. Conclusions WES permitted definitive genetic diagnosis despite an atypical presentation in the index case and suggests that severe infection, likely secondary to immunodeficiency, may be a presenting feature. In addition definitive molecular diagnosis allows for genetic counseling and future prenatal diagnosis, and demonstrates the value of WES for post-mortem diagnosis of disorders with a non-specific clinical presentation in which a Mendelian cause is suspected.
Genetic resistance to Mycobacterium Tuberculosis infection and disease
(Frontiers Media, 2018-09) Moller, Marlo; Kinnear, Craig J.; Orlova, Marianna; Kroon, Elouise E.; van Helden, Paul D.; Schurr, Erwin; Hoal, Eileen G.; Biomedical Sciences: Molecular Biology and Human Genetics
Natural history studies of tuberculosis (TB) have revealed a spectrum of clinical outcomes after exposure to Mycobacterium tuberculosis, the cause of TB. Not all individuals exposed to the bacteriumwill become diseased and depending on the infection pressure, many will remain infection-free. Intriguingly, complete resistance to infection is observed in some individuals (termed resisters) after intense, continuing M. tuberculosis exposure. After successful infection, the majority of individuals will develop latent TB infection (LTBI). This infection state is currently (and perhaps imperfectly) defined by the presence of a positive tuberculin skin test (TST) and/or interferon gamma release assay (IGRA), but no detectable clinical disease symptoms. The majority of healthy individuals with LTBI are resistant to clinical TB, indicating that infection is remarkably well-contained in these non-progressors. The remaining 5–15% of LTBI positive individuals will progress to active TB. Epidemiological investigations have indicated that the host genetic component contributes to these infection and disease phenotypes, influencing both susceptibility and resistance. Elucidating these genetic correlates is therefore a priority as it may translate to new interventions to prevent, diagnose or treat TB. The most successful approaches in resistance/susceptibility investigation have focused on specific infection and disease phenotypes and the resister phenotype may hold the key to the discovery of actionable genetic variants in TB infection and disease. This review will not only discuss lessons from epidemiological studies, but will also focus on the contribution of epidemiology and functional genetics to human genetic resistance to M. tuberculosis infection and disease.
Genetic resistance to mycobacterium tuberculosis infection and disease
(Frontiers Media, 2017) Moller, Marlo; Kinnear, Craig J.; Orlova, Marianna; Kroon, Elouise E.; Van Helden, Paul D.; Schurr, Erwin; Hoal, Eileen G.
Natural history studies of tuberculosis (TB) have revealed a spectrum of clinical outcomes after exposure to Mycobacterium tuberculosis, the cause of TB. Not all individuals exposed to the bacterium will become diseased and depending on the infection pressure, many will remain infection-free. Intriguingly, complete resistance to infection is observed in some individuals (termed resisters) after intense, continuing M. tuberculosis exposure. After successful infection, the majority of individuals will develop latent TB infection (LTBI). This infection state is currently (and perhaps imperfectly) defined by the presence of a positive tuberculin skin test (TST) and/or interferon gamma release assay (IGRA), but no detectable clinical disease symptoms. The majority of healthy individuals with LTBI are resistant to clinical TB, indicating that infection is remarkably well-contained in these non-progressors. The remaining 5–15% of LTBI positive individuals will progress to active TB. Epidemiological investigations have indicated that the host genetic component contributes to these infection and disease phenotypes, influencing both susceptibility and resistance. Elucidating these genetic correlates is therefore a priority as it may translate to new interventions to prevent, diagnose or treat TB. The most successful approaches in resistance/susceptibility investigation have focused on specific infection and disease phenotypes and the resister phenotype may hold the key to the discovery of actionable genetic variants in TB infection and disease. This review will not only discuss lessons from epidemiological studies, but will also focus on the contribution of epidemiology and functional genetics to human genetic resistance to M. tuberculosis infection and disease.
High diversity, inbreeding and a dynamic Pleistocene demographic history revealed by African buffalo genomes
(Nature Research (part of Springer Nature), 2021) De Jager, Deon; Glanzmann, Brigitte; Moller, Marlo; Hoal, Eileen; Van Helden, Paul; Harper, Cindy; Bloomer, Paulette
Genomes retain records of demographic changes and evolutionary forces that shape species and populations. Remnant populations of African buffalo (Syncerus caffer) in South Africa, with varied histories, provide an opportunity to investigate signatures left in their genomes by past events, both recent and ancient. Here, we produce 40 low coverage (7.14×) genome sequences of Cape buffalo (S. c. caffer) from four protected areas in South Africa. Genome-wide heterozygosity was the highest for any mammal for which these data are available, while differences in individual inbreeding coefficients reflected the severity of historical bottlenecks and current census sizes in each population. PSMC analysis revealed multiple changes in Ne between approximately one million and 20 thousand years ago, corresponding to paleoclimatic changes and Cape buffalo colonisation of southern Africa. The results of this study have implications for buffalo management and conservation, particularly in the context of the predicted increase in aridity and temperature in southern Africa over the next century as a result of climate change.
Human genetic susceptibility to tuberculosis : the investigation of candidate genes influencing interferon gamma levels and other candidate genes affecting immunological pathways
(Stellenbosch : University of Stellenbosch, 2007-12) Moller, Marlo; Hoal, Eileen; Van Helden, Paul; University of Stellenbosch. Faculty of Health Sciences. Dept. of Biomedical Sciences. Molecular Biology and Human Genetics.
The infectious disease tuberculosis (TB) is one of the leading causes of death worldwide. The idea that infectious diseases are the most important driving force in natural selection and that they sustain frequent polymorphisms in the human genome was formally suggested by Haldane in 1949. This hypothesis implicated the human genetic component in the response to infectious disease. Today the involvement of host genetics in TB has been proven unequivocally and, together with environmental factors (e.g. nutrition and crowding) and the causative bacterium, Mycobacterium tuberculosis (M.tuberculosis), may influence the outcome of disease. As is evident, TB is a complex disease and the implication for studying genetic susceptibility is that a number of genes will be involved. Interferon gamma (IFN-7) is the major macrophage-activating cytokine during infection with M.tuberculosis and its role has been well established in animal models and in humans. This cytokine is produced by activated T helper 1 (Th1) cells. These Th1 responses can best deal with intracellular pathogens such as M.tuberculosis. We selected twelve candidate genes based on the hypothesis that genes which regulate the production of IFN-7 may influence TB susceptibility. We also selected polymorphisms from 27 other candidate genes, which may affect immunological pathways involved in TB, to investigate as susceptibility factors based on the following hypotheses: 1) granulomatous diseases can share susceptibility genes; 2) gene expression studies done by DNA-array analysis experiments may reveal TB susceptibility genes; 3) genomewide linkage studies in TB can determine susceptibility loci and genes in this region are possibly susceptibility factors; and 4) functional susceptibility polymorphisms in genes involved in immune-mediated diseases other than TB may contribute to susceptibility to TB. This research tested the association of 136 genetic polymorphisms in 39 potentially important genes with TB in the South African Coloured population. Well-designed case-control association studies were used and we attempted to replicate these findings in an independent sample set using family-based case-control designs (transmission disequilibrium tests (TDTs)). In addition, haplotypes and linkage disequilibrium (LD) in the candidate genes were also investigated. During the case-control analyses we found significant associations for 6 single nucleotide polymorphisms (SNPs) in the following genes: SH2 domain protein 1A, tolllike receptor 2, class II major histocompatibility complex transactivator, interleukin 1 receptor antagonist, runt-related transcription factor 1 and tumour necrosis factor superfamily, member 1B. Discrepant results were obtained during the TDT analyses. The number of families available was small and for this reason we cannot conclude that the case-control results were spurious. We also tested the association of haplotypes with TB. Haplotypes in the interleukin 12, beta (IL12B) and toll-like receptor 4 genes were nominally associated with TB in both the case-control and TDT analyses. We observed strong LD for the genes in the South African Coloured population. In total 17 novel SNPs were identified and one novel allele was found for a microsatellite in IL12B. This research contributes to the increasing amount of information available on genes involved in TB susceptibility, which in the future may help to predict high risk individuals.
Human whole genome sequencing in South Africa
(Nature, 2021-01) Glanzmann, Brigitte; Jooste, Tracey; Ghoor, Samira; Gordon, Richard; Mia, Rizwana; Mao, Jun; Li, Hao; Charls, Patrick; Douman, Craig; Kotze, Maritha J.; Peeters, Armand V.; Loots, Glaudina; Esser, Monika; Tiemessen, Caroline T.; Wilkinson, Robert J.; Louw, Johan; Gray, Glenda; Warren, Robin M.; Moller, Marlo; Kinnear, Craig
The advent and evolution of next generation sequencing has considerably impacted genomic research. Until recently, South African researchers were unable to access affordable platforms capable of human whole genome sequencing locally and DNA samples had to be exported. Here we report the whole genome sequences of the first six human DNA samples sequenced and analysed at the South African Medical Research Council’s Genomics Centre. We demonstrate that the data obtained is of high quality, with an average sequencing depth of 36.41, and that the output is comparable to data generated internationally on a similar platform. The Genomics Centre creates an environment where African researchers are able to access world class facilities, increasing local capacity to sequence whole genomes as well as store and analyse the data.
Investigating 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.
Neutrophils : innate effectors of TB resistance?
(Frontiers Media, 2018) Kroon, Elouise E.; Coussens, Anna K.; Kinnear, Craig; Orlova, Marianna; Moller, Marlo; Seeger, Allison; Wilkinson, Robert J.; Hoal, Eileen G.; Schurr, Erwin
ENGLISH ABSTRACT: Certain individuals are able to resist Mycobacterium tuberculosis infection despite persistent and intense exposure. These persons do not exhibit adaptive immune priming as measured by tuberculin skin test (TST) and interferon-γ (IFN-γ) release assay (IGRA) responses, nor do they develop active tuberculosis (TB). Genetic investigation of individuals who are able to resist M. tuberculosis infection shows there are likely a combination of genetic variants that contribute to the phenotype. The contribution of the innate immune system and the exact cells involved in this phenotype remain incompletely elucidated. Neutrophils are prominent candidates for possible involvement as primers for microbial clearance. Significant variability is observed in neutrophil gene expression and DNA methylation. Furthermore, inter-individual variability is seen between the mycobactericidal capacities of donor neutrophils. Clearance of M. tuberculosis infection is favored by the mycobactericidal activity of neutrophils, apoptosis, effective clearance of cells by macrophages, and resolution of inflammation. In this review we will discuss the different mechanisms neutrophils utilize to clear M. tuberculosis infection. We discuss the duality between neutrophils' ability to clear infection and how increasing numbers of neutrophils contribute to active TB severity and mortality. Further investigation into the potential role of neutrophils in innate immune-mediated M. tuberculosis infection resistance is warranted since it may reveal clinically important activities for prevention as well as vaccine and treatment development.
A new tool for prioritization of sequence variants from whole exome sequencing data
(BioMed Central, 2016-07) Glanzmann, Brigitte; Herbst, Hendri; Kinnear, Craig J.; Moller, Marlo; Gamieldien, Junaid; Bardien, Soraya
Background: Whole exome sequencing (WES) has provided a means for researchers to gain access to a highly enriched subset of the human genome in which to search for variants that are likely to be pathogenic and possibly provide important insights into disease mechanisms. In developing countries, bioinformatics capacity and expertise is severely limited and wet bench scientists are required to take on the challenging task of understanding and implementing the barrage of bioinformatics tools that are available to them. Results: We designed a novel method for the filtration of WES data called TAPER™ (Tool for Automated selection and Prioritization for Efficient Retrieval of sequence variants). Conclusions: TAPER™ implements a set of logical steps by which to prioritize candidate variants that could be associated with disease and this is aimed for implementation in biomedical laboratories with limited bioinformatics capacity. TAPER™ is free, can be setup on a Windows operating system (from Windows 7 and above) and does not require any programming knowledge. In summary, we have developed a freely available tool that simplifies variant prioritization from WES data in order to facilitate discovery of disease-causing genes.
A post-GWAS analysis of predicted regulatory variants and tuberculosis susceptibility
(Public Library of Science, 2017) Uren, Caitlin; Henn, Brenna M.; Franke, Andre; Wittig, Michael; Van Helden, Paul D.; Hoal, Eileen G.; Moller, Marlo
Utilizing data from published tuberculosis (TB) genome-wide association studies (GWAS), we use a bioinformatics pipeline to detect all polymorphisms in linkage disequilibrium (LD) with variants previously implicated in TB disease susceptibility. The probability that these variants had a predicted regulatory function was estimated using RegulomeDB and Ensembl's Variant Effect Predictor. Subsequent genotyping of these 133 predicted regulatory polymorphisms was performed in 400 admixed South African TB cases and 366 healthy controls in a population-based case-control association study to fine-map the causal variant. We detected associations between tuberculosis susceptibility and six intronic polymorphisms located in MARCO, IFNGR2, ASHAS2, ACACA, NISCH and TLR10. Our post- GWAS approach demonstrates the feasibility of combining multiple TB GWAS datasets with linkage information to identify regulatory variants associated with this infectious disease.
Putting RFMix and ADMIXTURE to the test in a complex admixed population
(BMC (part of Springer Nature), 2020) Uren, Caitlin; Hoal, Eileen G.; Moller, Marlo
Background: Global and local ancestry inference in admixed human populations can be performed using computational tools implementing distinct algorithms. The development and resulting accuracy of these tools has been tested largely on populations with relatively straightforward admixture histories but little is known about how well they perform in more complex admixture scenarios. Results: Using simulations, we show that RFMix outperforms ADMIXTURE in determining global ancestry proportions even in a complex 5-way admixed population, in addition to assigning local ancestry with an accuracy of 89%. The ability of RFMix to determine global and local ancestry to a high degree of accuracy, particularly in admixed populations provides the opportunity for more accurate association analyses. Conclusion: This study highlights the utility of the extension of computational tools to become more compatible to genetically structured populations, as well as the need to expand the sampling of diverse world-wide populations. This is particularly noteworthy as modern-day societies are becoming increasingly genetically complex and some genetic tools and commonly used ancestral populations are less appropriate. Based on these caveats and the results presented here, we suggest that RFMix be used for both global and local ancestry estimation in worldwide complex admixture scenarios particularly when including these estimates in association studies.
A sex-stratified genome-wide association study of tuberculosis using a multi-ethnic genotyping array
(Frontiers Media, 2019) Schurz, Haiko; Kinnear, Craig J.; Gignoux, Chris; Wojcik, Genevieve; Van Helden, Paul D.; Tromp, Gerard; Henn, Brenna; Hoal, Eileen G.; Moller, Marlo
Tuberculosis (TB), caused by Mycobacterium tuberculosis, is a complex disease with a known human genetic component. Males seem to be more affected than females and in most countries the TB notification rate is twice as high in males than in females. While socio-economic status, behavior and sex hormones influence the male bias they do not fully account for it. Males have only one copy of the X chromosome, while diploid females are subject to X chromosome inactivation. In addition, the X chromosome codes for many immune-related genes, supporting the hypothesis that X-linked genes could contribute to TB susceptibility in a sex-biased manner. We report the first TB susceptibility genome-wide association study (GWAS) with a specific focus on sex-stratified autosomal analysis and the X chromosome. A total of 810 individuals (410 cases and 405 controls) from an admixed South African population were genotyped using the Illumina Multi Ethnic Genotyping Array, specifically designed as a suitable platform for diverse and admixed populations. Association testing was done on the autosome (8,27,386 variants) and X chromosome (20,939 variants) in a sex stratified and combined manner. SNP association testing was not statistically significant using a stringent cut-off for significance but revealed likely candidate genes that warrant further investigation. A genome wide interaction analysis detected 16 significant interactions. Finally, the results highlight the importance of sex-stratified analysis as strong sex-specific effects were identified on both the autosome and X chromosome.
TLR1, 2, 4, 6 and 9 variants associated with tuberculosis susceptibility: a systematic review and meta-analysis
(PLoS ONE, 2015) Schurz, Haiko; Daya, Michelle; Moller, Marlo; Hoal, Eileen G.; Salie, Muneeb
Background: Studies investigating the influence of toll-like receptor (TLR) polymorphisms and tuberculosis susceptibility have yielded varying and often contradictory results in different ethnic groups. A meta-analysis was conducted to investigate the relationship between TLR variants and susceptibility to tuberculosis, both across and within specific ethnic groups. Methods: An extensive database search was performed for studies investigating the relationship between TLR and tuberculosis (TB) susceptibility. Data was subsequently extracted from included studies and statistically analysed. Results: 32 articles involving 18907 individuals were included in this meta-analysis, and data was extracted for 14 TLR polymorphisms. Various genetic models were employed. An increased risk of TB was found for individuals with the TLR2 rs3804100 CC and the TLR9 rs352139 GA and GG genotypes, while decreased risk was identified for those with the AG genotype of TLR1 rs4833095. The T allele of TLR6 rs5743810 conferred protection across all ethnic groups. TLR2 rs5743708 subgroup analysis identified the A allele to increase susceptibility to TB in the Asian ethnic group, while conferring protection in the Hispanic group. The T allele of TLR4 rs4986791 was also found to increase the risk of TB in the Asian subgroup. All other TLR gene variants investigated were not found to be associated with TB in this meta-analysis. Discussion: Although general associations were identified, most TLR variants showed no significant association with TB, indicating that additional studies investigating a wider range of pattern recognition receptors is required to gain a better understanding of this complex disease
Using 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.
The X chromosome and sex-specific effects in infectious disease susceptibility
(BMC (part of Springer Nature), 2019-01-08) Schurz, Haiko; Salie, Muneeb; Tromp, Gerard; Hoal, Eileen G.; Kinnear, Craig J.; Moller, Marlo
ENGLISH ABSTRACT: The X chromosome and X-linked variants have largely been ignored in genome-wide and candidate association studies of infectious diseases due to the complexity of statistical analysis of the X chromosome. This exclusion is significant, since the X chromosome contains a high density of immune-related genes and regulatory elements that are extensively involved in both the innate and adaptive immune responses. Many diseases present with a clear sex bias, and apart from the influence of sex hormones and socioeconomic and behavioural factors, the X chromosome, X-linked genes and X chromosome inactivation mechanisms contribute to this difference. Females are functional mosaics for X-linked genes due to X chromosome inactivation and this, combined with other X chromosome inactivation mechanisms such as genes that escape silencing and skewed inactivation, could contribute to an immunological advantage for females in many infections. In this review, we discuss the involvement of the X chromosome and X inactivation in immunity and address its role in sexual dimorphism of infectious diseases using tuberculosis susceptibility as an example, in which male sex bias is clear, yet not fully explored.

Browsing by Author "Moller, Marlo"

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