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Molokhia, Mariam; McKeigue, Paul

doi:10.1186/ar76

Cited by 61 publications

(23 citation statements)

References 55 publications

(65 reference statements)

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“…Given that lupus affects predominantly young females and is a cause of significant morbidity and mortality, the protective effect of the Fc␥RIIb T232 polymorphism in malarial infection could be offset by a predisposition to autoimmunity. However, the prevalence and severity of autoimmune diseases, particularly lupus, in endemic African populations is low (42,43) in contrast to Africans living in Western societies (14). The apparent difference may be because of a reporting bias, but a number of lines of evidence suggest that the development of autoimmune diseases in genetically susceptible individuals can be significantly altered by exposure to pathogens.…”

Section: Discussionmentioning

confidence: 99%

“…The frequency of the different Fc␥RIIb 232 genotypes worldwide demonstrates significant geographical variation: Fc␥RIIb T/T232 is found in 0.7-1% of populations of European origin but is up to 10 times more prevalent in south and east Asian populations (8,12). Interestingly, the severity and prevalence of SLE is also much higher in these racial groups (14). Given that malarial infection, particularly due to Plasmodium falciparum, is or has been a major cause of death in these geographic areas (15) and that the Fc␥RIIb T/T232 genotype encodes a nonfunctioning receptor (12, 13), we wished to examine whether Fc␥RIIb deficiency might protect against malaria.…”

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confidence: 99%

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Systemic lupus erythematosus-associated defects in the inhibitory receptor FcγRIIb reduce susceptibility to malaria

Clatworthy

Willcocks

Urban

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

163

164

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Polygenic autoimmune diseases, such as systemic lupus erythematosus (SLE), are a significant cause of morbidity and mortality worldwide. In recent years, functionally important genetic polymorphisms conferring susceptibility to SLE have been identified, but the evolutionary pressures driving their retention in the gene pool remain elusive. A defunctioning, SLE-associated polymorphism of the inhibitory receptor Fc␥RIIb is found at an increased frequency in African and Asian populations, broadly corresponding to areas where malaria is endemic. Here, we show that Fc␥RIIb-deficient mice have increased clearance of malarial parasites (Plasmodium chabaudi chabaudi) and develop less severe disease. In vitro, the human lupus associated Fc␥RIIb polymorphism enhances phagocytosis of Plasmodium falciparum-infected erythrocytes. These results demonstrate that Fc␥RIIb is important in controlling the immune response to malarial parasites and suggests that the higher frequency of human Fc␥RIIb polymorphisms predisposing to SLE in Asians and Africans may be maintained because these variants reduce susceptibility to malaria. autoimmunity ͉ evolution ͉ Fc␥ receptors

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Systemic lupus erythematosus-associated defects in the inhibitory receptor FcγRIIb reduce susceptibility to malaria

Clatworthy

Willcocks

Urban

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

163

164

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“…More recently, in mixed population groups such as in the United States, ancestry informative markers (AIMs) or sufficient numbers of unselected independent markers (low intermarker LD) have been used to examine ancestry relationships between and within continents as well as admixture and autoimmune disease. Evidence for increased frequency of SLE has been associated with both West African ancestry and Native American ancestry [103-105]. Several studies of SLE have used this approach to examine whether endophenotypes of this disease are more likely to be associated with particular ancestry [106-109].…”

Section: Ancestry Makes a Differencementioning

confidence: 99%

The genetics of human autoimmune disease: A perspective on progress in the field and future directions

Seldin

2015

Journal of Autoimmunity

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Progress in defining the genetics of autoimmune disease has been dramatically enhanced by large scale genetic studies. Genome-wide approaches examining hundreds or for some diseases thousands of cases and controls have been implemented using high throughput genotyping and appropriate algorithms to provide a wealth of data over the last decade. These studies have identified hundreds of non-HLA loci as well as further defining HLA region variations that predispose to different autoimmune diseases. These studies to identify genetic risk loci are also complemented by progress in gene expression studies including definition of expression quantitative trait loci (eQTL), various alterations in chromatin structure including histone marks, DNase I sensitivity, repressed chromatin regions as well as transcript factor binding sites. Integration of this information can partially explain why particular variations can alter proclivity to autoimmune phenotypes. Despite our incomplete knowledge base with only partial definition of hereditary factors and possible functional connections, this progress has and will continue to facilitate a better understanding of critical pathways and critical changes in immunoregulation. Advances in defining and understanding functional variants potentially can lead to both novel therapeutics and personalized medicine in which therapeutic approaches are chosen based on particular molecular phenotypes and genomic alterations.

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“…Variation in individual admixture introduces population stratification, which in turn can inflate the number of significant associations that are observed [53,55,56] and is a potential confounder in association studies [29,57-59]. Various statistical approaches have been developed to detect and control for stratification within a population sample [14,15,17,42,60-62].…”

Section: Admixture Studies and Their Use In Disease Gene Mappingmentioning

confidence: 99%

Measuring and using admixture to study the genetics of complex diseases

Halder

Shriver

2003

Hum Genomics

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Admixture is an important evolutionary force that can and should be used in efforts to apply genomic data and technology to the study of complex disease genetics. Admixture linkage disequilibrium (ALD) is created by the process of admixture and, in recently admixed populations, extends for substantial distances (of the order of 10 to 20 cM). The amount of ALD generated depends on the level of admixture, ancestry information content of markers and the admixture dynamics of the population, and thus influences admixture mapping (AM). The authors discuss different models of admixture and how these can have an impact on the success of AM studies. Selection of markers is important, since markers informative for parental population ancestry are required and these are uncommon. Rarely does the process of admixture result in a population that is uniform for individual admixture levels, but instead there is substantial population stratification. This stratification can be understood as variation in individual admixtures and can be both a source of statistical power for ancestry-phenotype correlation studies as well as a confounder in causing false-positives in gene association studies. Methods to detect and control for stratification in case/control and AM studies are reviewed, along with recent studies showing individual ancestry-phenotype correlations. Using skin pigmentation as a model phenotype, implications of AM in complex disease gene mapping studies are discussed. Finally, the article discusses some limitations of this approach that should be considered when designing an effective AM study.

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Cited by 61 publications

References 55 publications

Systemic lupus erythematosus-associated defects in the inhibitory receptor FcγRIIb reduce susceptibility to malaria

Systemic lupus erythematosus-associated defects in the inhibitory receptor FcγRIIb reduce susceptibility to malaria

The genetics of human autoimmune disease: A perspective on progress in the field and future directions

Measuring and using admixture to study the genetics of complex diseases

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