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Journal ArticleDOI

Identification of a haplotype block in the 5q31 cytokine gene cluster associated with the susceptibility to severe malaria

TL;DR: A haplotype block in which a primary polymorphism associated with severe malaria is likely to be encoded was identified in Thai malaria patients.
Abstract: It has been previously demonstrated that a single nucleotide polymorphism (SNP) in the IL13 promoter region, IL13 -1055T>C (rs1800925), was associated with susceptibility to severe malaria in Thais. In the present study, fine association mapping for a cytokine gene cluster including IL4, IL5, and IL13 on chromosome 5q31 was conducted using the same malaria subjects to refine the region containing a primary variant or a haplotype susceptible to severe malaria. A total of 82 SNPs spanning 522 kb of the 5q31 region were analysed in 368 patients with Plasmodium falciparum malaria (203 mild malaria and 165 severe malaria patients). Only rs1881457 located in the promoter region of IL13, which is in linkage disequilibrium with rs1800925 (r2 = 0.73), showed a significant association with severe malaria after adjusting for multiple testing (P = 0.046 by permutation test). This SNP was in a haplotype block spanning 97 kb (from rs2069812 to rs2240032). The detected haplotype block contained the RAD50 gene and the promoter of IL13, but not the other genes. A haplotype block in which a primary polymorphism associated with severe malaria is likely to be encoded was identified in Thai malaria patients.

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TL;DR: The findings from the past and present studies on murine models of hepatic and erythrocytic stages of malaria are reviewed and how the current mouse models benefit from the recent development in CRISPR/Cas9 gene editing technology is speculated on.
Abstract: Malaria remains a deadly parasitic disease caused by Plasmodium, claiming almost half a million lives every year. While parasite genetics and biology are often the major targets in many studies, it is becoming more evident that host genetics plays a crucial role in the outcome of the infection. Similarly, Plasmodium infections in mice also rely heavily on the genetic background of the mice, and often correlate with observations in human studies, due to their high genetic homology with humans. As such, murine models of malaria are a useful tool for understanding host responses during Plasmodium infections, as well as dissecting host-parasite interactions through various genetic manipulation techniques. Reverse genetic approach such as quantitative trait loci studies and random mutagenesis screens have been employed to discover novel host genes that affect malaria susceptibility in mouse models, while other targeted studies utilize mouse models to validate observation from human studies. Herein, we review the findings from the past and present studies on murine models of hepatic and erythrocytic stages of malaria and speculate on how the current mouse models benefit from the recent development in CRISPR/Cas9 gene editing technology.

15 citations


Cites background from "Identification of a haplotype block..."

  • ...These effectors have been repeatedly implicated in many linkage studies influencing parasitemia in human populations (Milet et al. 2010; Naka et al. 2009; Rihet et al. 1998)....

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Journal ArticleDOI
TL;DR: The most convincing results obtained through genetic epidemiology studies concerning the genetic control of malaria in human caused by Plasmodium falciparum infection are reviewed.

15 citations

Journal ArticleDOI
TL;DR: The landscape of vtRNA expression cancer-wide is presented, identifying co-regulated gene networks and ontological pathways associated with the different vtRNAs that may account for their diverse roles in cancer.
Abstract: Background: The vault RNAs (vtRNAs) are a class of 84-141-nt eukaryotic non-coding RNAs transcribed by RNA polymerase III, associated to the ribonucleoprotein complex known as vault particle. Of the four human vtRNA genes, vtRNA1-1, vtRNA1-2 and vtRNA1-3, clustered at locus 1, are integral components of the vault particle, while vtRNA2-1 is a more divergent homologue located in a second locus. Gene expression studies of vtRNAs in large cohorts have been hindered by their unsuccessful sequencing using conventional transcriptomic approaches. Methods: VtRNA expression in The Cancer Genome Atlas (TCGA) Pan-Cancer cohort was estimated using the genome-wide DNA methylation and chromatin accessibility data (ATAC-seq) of their genes as surrogate variables. The association between vtRNA expression and patient clinical outcome, immune subtypes and transcriptionally co-regulated gene programs was analyzed in the dataset. Results: VtRNAs promoters are enriched in transcription factors related to viral infection. VtRNA2-1 is likely the most independently regulated homologue. VtRNA1-1 has the most accessible chromatin, followed by vtRNA1-2, vtRNA2-1 and vtRNA1-3. VtRNA1-1 and vtRNA1-3 chromatin status does not significantly change in cancer tissues. Meanwhile, vtRNA2-1 and vtRNA1-2 expression is widely deregulated in neoplastic tissues and its alteration is compatible with a broad oncogenic role for vtRNA1-2, and both tumor suppressor and oncogenic functions for vtRNA2-1. Yet, vtRNA1-1, vtRNA1-2 and vtRNA2-1 promoter DNA methylation predicts a shorter patient overall survival cancer-wide. In addition, gene ontology analyses of vtRNAs co-regulated genes identify a chromosome regulatory domain, epithelial differentiation, immune and thyroid cancer gene sets for specific vtRNAs. Furthermore, vtRNA expression patterns are associated with cancer immune subtypes and vtRNA1-2 expression is positively associated with cell proliferation and wound healing. Conclusions: Our study presents the landscape of vtRNA chromatin status cancer-wide, identifying co-regulated gene networks and ontological pathways associated with the different vtRNA genes that may account for their diverse roles in cancer.

6 citations

Journal ArticleDOI
TL;DR: A better understanding of this type of inflammatory response and its implication in malaria disease and how it impacts Plasmodium parasite development may provide additional tools to alleviate or to cure this deadly disease.
Abstract: One of the effector arms of the pathogenesis of severe forms of malaria disease is the development of uncontrolled or excessive inflammatory response. A characteristic inflammatory response may arise from the propensity of some individuals to produce IgE antibodies against environmental antigens or against parasite components. We believe that an allergic inflammatory response which develops concomitantly with a malaria episode may drive the disease course towards severe forms. The role of IgE-FceRI complex in malaria severity in Plasmodium falciparum-hosting patients is unknown. Subsequently, except a very limited number of reports, study of effector cells that express this complex such as mast cells and basophils and that may contribute to malaria pathogenesis have been particularly neglected. A better understanding of this type of inflammatory response and its implication in malaria disease and how it impacts Plasmodium parasite development may provide additional tools to alleviate or to cure this deadly disease.

5 citations


Cites background from "Identification of a haplotype block..."

  • ...In a more recent study, this SNP was found to be included in a haplotype block on chromosome 5q31 encompassing the whole RAD50 gene and the promoter of the IL-13 gene (Naka et al., 2009)....

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Journal ArticleDOI
TL;DR: The chromosomal regions linked to IgG3 and IgG4 levels are of special interest and may provide new insights in understanding both the genetic control of IgG production and malaria resistance.
Abstract: A genome-wide scan was conducted for the levels of total immunoglobulin G (IgG) and IgG subclasses directed against Plasmodium falciparum antigens in an urban population living in Burkina Faso. Non-parametric multipoint linkage analysis provided three chromosomal regions with genome-wide significant evidence (logarithm of the odds (LOD) score >3.6), and five chromosomal regions with genome-wide suggestive evidence (LOD score >2.2). IgG3 levels were significantly linked to chromosomes 8p22-p21 and 20q13, whereas IgG4 levels were significantly linked to chromosome 9q34. In addition, we detected suggestive linkage of IgG1 levels to chromosomes 18p11-q12 and 18q12-q21, IgG4 levels to chromosomes 1p31 and 12q24 and IgG levels to chromosome 6p24-p21. Moreover, we genotyped genetic markers located within the regions of interest in a rural population living in Burkina Faso. We detected genome-wide significant and suggestive linkage results when combining the two study populations for chromosomes 1p31, 6p24-p21, 8p22-p21, 9q34, 12q24 and 20q13. Because high anti-parasite IgG3 and low anti-parasite IgG4 levels were associated with malaria resistance, the chromosomal regions linked to IgG3 and IgG4 levels are of special interest. Although the results should be confirmed in an independent population, they may provide new insights in understanding both the genetic control of IgG production and malaria resistance.

5 citations

References
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Journal ArticleDOI
TL;DR: Haploview is a software package that provides computation of linkage disequilibrium statistics and population haplotype patterns from primary genotype data in a visually appealing and interactive interface.
Abstract: Summary: Research over the last few years has revealed significant haplotype structure in the human genome. The characterization of these patterns, particularly in the context of medical genetic association studies, is becoming a routine research activity. Haploview is a software package that provides computation of linkage disequilibrium statistics and population haplotype patterns from primary genotype data in a visually appealing and interactive interface. Availability: http://www.broad.mit.edu/mpg/haploview/ Contact: jcbarret@broad.mit.edu

13,862 citations

Journal ArticleDOI
TL;DR: The quantitative and qualitative changes of all three databases and connected programs are described.
Abstract: TRANSFAC, TRRD (Transcription Regulatory Region Database) and COMPEL are databases which store information about transcriptional regulation in eukaryotic cells. The three databases provide distinct views on the components involved in transcription: transcription factors and their binding sites and binding profiles (TRANSFAC), the regulatory hierarchy of whole genes (TRRD), and the structural and functional properties of composite elements (COMPEL). The quantitative and qualitative changes of all three databases and connected programs are described. The databases are accessible via WWW:http://transfac.gbf.de/TRANSFAC orhttp://www.bionet.nsc.ru/TRRD

1,515 citations

Journal ArticleDOI
TL;DR: The Mre 11 complex is a multisubunit nuclease that is composed of Mre11, Rad50 and Nbs1/Xrs2 and its functions in checkpoint signalling and DNA replication are uncovered.
Abstract: The Mre11 complex is a multisubunit nuclease that is composed of Mre11, Rad50 and Nbs1/Xrs2. Mutations in the genes that encode components of this complex result in DNA- damage sensitivity, genomic instability, telomere shortening and aberrant meiosis. The molecular defect that underlies these phenotypes has long been thought to be related to a DNA repair deficiency. However, recent studies have uncovered functions for the Mre11 complex in checkpoint signalling and DNA replication.

899 citations


"Identification of a haplotype block..." refers background in this paper

  • ...Together with MRE11 and NBS1, RAD50 forms a conserved multiprotein complex, MRE11-RAD50-NBS1 (MRN), which plays an important role in double-strand break repair, cell cycle checkpoint control, meiotic recombination, and telomere maintenance [11-13]....

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Journal ArticleDOI
TL;DR: It is concluded that increased TNF production is a normal host response to P falciparum infection, but that excessive levels of production may predispose to cerebral malaria and a fatal outcome.

861 citations


"Identification of a haplotype block..." refers background in this paper

  • ...It has been reported that increased concentrations of TNF and IL1β in serum are observed in severe malaria patients [16]....

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Journal ArticleDOI
TL;DR: This work discusses the possible role of the Mre11 complex as a primary damage sensor and the complex relationship between DNA damage sensors, transducers and mediators and proposed criteria for defining sensor proteins.

347 citations

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