Genome-Wide Linkage Analysis of Malaria Infection Intensity and Mild Disease

Timmann, Christian; Evans, Jennifer; König, Inke R.; Kleensang, André; Rüschendorf, Franz; Lenzen, Julia; Sievertsen, Jürgen; Becker, Christian; Enuameh, Yeetey; Kwakye, Kingsley Osei; Opoku, Ernest; Browne, Edmund; Ziegler, Andreas; Nürnberg, Peter; Horstmann, Rolf D.

doi:10.1371/journal.pgen.0030048

Cited by 59 publications

(56 citation statements)

References 54 publications

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“…Other factors such as population structure and chance, as well as the experimental design or the phenotype(s) of malaria diagnosed in a given study, may impact the conclusions. Efforts to use genomics approaches and genome-wide association analysis have been initiated (Ayodo et al, 2007;Timmann et al, 2007;The Malaria Genomic Epidemiology Network, 2008;Jallow et al, 2009;Eid et al, 2010) and some new regions of potential malaria resistance have been identified.…”

Section: Resistance Mutantsmentioning

confidence: 99%

Population genetics of malaria resistance in humans

2011

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Section: Resistance Mutantsmentioning

confidence: 99%

Population genetics of malaria resistance in humans

2011

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“…39 The associations of malaria infection with the human sickle-cell trait and certain genotypes of G6PD were demonstrated to be a function of balancing selection. [40][41][42] As shown by Zhou's study, the percentage of a(+) thalassemia carriers in the Li population is very high (56.7%) to counteract the malaria epidemic. 43 Furthermore, an SNP located in the TNF promoter region is associated with cerebral malaria, with high levels of circulating TNF.…”

Section: Discussionmentioning

confidence: 93%

Nucleotide polymorphism of the TNF gene cluster in six Chinese populations

Zhang

Lin

et al. 2010

J Hum Genet

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DNA variants in a 31-kb region of the human major histocompatibility complex, encompassing the tumor necrosis factor (TNF) gene cluster, were surveyed by direct sequencing of 283 unrelated individuals from six Chinese populations. A total of 273 polymorphic sites were identified, with nearly half of them novel. We observed an excess of rare variants and negative values of selection tests of the region, implying either that these populations experienced a historical expansion or that the surveyed region was subjected to natural selection. Different characteristics of the sequence variation in the six populations outline the genetic differentiation between Northern and Southern Chinese populations. The distributions of recombination rates are similar among all the populations, with variation in the magnitude and/or in the fine location of hot spots. Tag single-nucleotide polymorphisms (SNPs) selected from HapMap (Phase II) CHB data accounted for an average of 64% of common SNPs from the six Chinese populations. We also observed a limited transferability of tag SNPs between Chinese populations on the 31-kb region with an excess of untaggable SNPs and ragged linkage disequilibrium blocks. It suggested that the design and interpretation of future association studies should be more cautious, and that a resequencing approach may refine tag SNP selection on Chinese-specific disease mapping.

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“…The major histocompatibility complex as well as a cytokine-gene cluster on chromosome 5q31-q33 were also shown to associate with susceptibility/resistance to malaria (96,97). Recently, with the advance in genome-wide scanning and association, analysis a genome-wide linkage analysis was performed on 241 malaria susceptible siblings from 68 selected families from Ghana, West Africa, who were exposed to hyperendemic malaria transmission and were homozygous wild type for the established malaria resistance factors of Hb (Hb)S, HbC, alpha ϩ thalassemia, and glucose-6-phosphate-dehydrogenase deficiency (98). Several regions showed significant linkage to certain parasitological and clinical phenotypes such as a linkage of a region on chromosome 10p15 with malaria fever episodes.…”

Section: Predisposition To Herpes Simplex Encephalitis (Hse)mentioning

confidence: 99%

Recent Advances in Primary Immunodeficiencies: Identification of Novel Genetic Defects and Unanticipated Phenotypes

2009

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Primary immunodeficiencies (PIDs) have traditionally been defined according to their immunologic phenotype. Far from being concluded, the search for human genes that, when mutated, cause PID is actively being pursued. During the last year, four novel genetic defects that cause severe combined immunodeficiency and severe congenital neutropenia have been identified. At the same time, the immunologic definition of primary immunodeficiencies has been expanded by the recognition that genetic defects affecting innate immunity may result in selective predisposition to certain infections, such as mycobacterial disease, herpes simplex encephalitis, and invasive pneumococcal infections. Studies of genetically determined susceptibility to infections have recently shown that immunologic defects may also account for novel infectious phenotypes, such as malaria or leprosy. Finally, a growing body of evidence indicates that primary immunodeficiencies may present with a noninfectious clinical phenotype that may be restricted to single organs, as in the case of atypical hemolytic uremic syndrome or pulmonary alveolar proteinosis. Overall, these achievements highlight the importance of human models, which often differ from the corresponding animal models. (Pediatr Res 65: 3R-12R, 2009) F or many years, "classical primary immunodeficiencies," in which broad susceptibility to infections is due to mutations of a single gene, have represented a unique model to identify gene products that play a key role in initiating, maintaining, or regulating immune function. The study of diseases such as severe combined immunodeficiency (SCID), X-linked agammaglobulinemia (XLA), chronic granulomatous disease (CGD), and many more has led to better understanding of the mechanisms that are involved in development and function of T and B lymphocytes and of phagocytic cells. Since 1952, when unique susceptibility to recurrent infections was linked to lack of serum gammaglobulins (1), and for more than 30 y, primary immunodeficiencies (PID) were mainly defined in terms of clinical and immunologic phenotype. The careful analysis of the pattern of inheritance of PIDs, and the availability of more potent immunologic tools, such as MAb and sophisticated assays to explore the phenotype and function of immune cells, have helped identify an unexpected heterogeneity within clinically homogeneous forms of PID. For example, both X-linked and autosomal recessive forms of SCID have been identified; furthermore, it became clear that-while retaining similar clinical features and the consistent lack of circulating T cells-infants with SCID may or may not present deficiencies also of B and/or NK lymphocytes (2). Similarly, X-linked and autosomal recessive forms of congenital agammaglobulinemia and of CGD were disclosed.The heterogeneity of PIDs was further illustrated when advances in molecular genetics and the development of the Human Genome Project made cloning of PID-causing genes feasible. Yet, many forms of PID are still "orphan" as to the genetic defect...

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Genome-Wide Linkage Analysis of Malaria Infection Intensity and Mild Disease

Cited by 59 publications

References 54 publications

Population genetics of malaria resistance in humans

Population genetics of malaria resistance in humans

Nucleotide polymorphism of the TNF gene cluster in six Chinese populations

Recent Advances in Primary Immunodeficiencies: Identification of Novel Genetic Defects and Unanticipated Phenotypes

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