Genetic susceptibility to infectious diseases: big is beautiful, but will bigger be even better?

Burgner, David; Jamieson, Sarra E.; Blackwell, Jenefer M.

doi:10.1016/s1473-3099(06)70601-6

Cited by 199 publications

(178 citation statements)

References 166 publications

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“…The association between Slc11a1 with leishmaniasis was corroborated in a Sudanese population study, where two new polymorphisms, one located in exon 3 (274C/T) and another one located in intron 4 (469 + 14G/C) were found [2,17]. Beyond the Slc11a1 polymorphism interactions with multiple other genes and candidate regions, such as MHC, IL-4, IFNGR or loci 22q12 and 2q23-24 have been implicated [4,9]. Studies with canine and murine disease models are necessary to further advance our knowledge of the molecular basis of Leishmania infection and disease predisposition or resistance.…”

Section: Introductionmentioning

confidence: 73%

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Slc11a1 (formerly Nramp1) and susceptibility to canine visceral leishmaniasis

et al. 2008

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-Visceral leishmaniasis is the most important zoonosis in Europe and it is caused by Leishmania infantum, a protozoan intracellular parasite. Canine visceral leishmaniasis (CVL) is endemic in the Mediterranean basin, Middle East, and South America, and is emerging within non endemic areas such as the United Kingdom and North America. We have analyzed 24 polymorphisms in the canine Slc11a1 (formerly NRAMP1) gene: 19 new polymorphisms characterized by direct sequencing from 40 dogs of different breeds and five polymorphisms previously described. Data analysis in a case-control study including 164 dogs of 19 different breeds revealed that two of the 24 polymorphisms were associated with increased risk for CVL: one intronic single nucleotide polymorphism (SNP) (A4549G in intron 6: odds ratio (OR) = 6.78, P = 0.001) and one silent SNP in exon 8 (C4859T: OR = 13.44, P = 0.004). In silico analysis of the significant SNP revealed that SNP in the promoter region affect putative transcription binding sites and SNP C4859T in exon 8 disrupts a putative exonic splicing enhancer (ESE). These results corroborate that Slc11a1 polymorphisms are associated with increased risk for CVL. leishmaniasis / Slc11a1 / polymorphism / dog / susceptibility

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Section: Introductionmentioning

confidence: 73%

“…Infections with HIV, Mycobacteria, Malaria, and Leishmania have been most commonly studied [4]. Leishmania is a protozoan intracellular parasite and transmitted by sandflies.…”

Section: Introductionmentioning

confidence: 99%

Slc11a1 (formerly Nramp1) and susceptibility to canine visceral leishmaniasis

et al. 2008

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“…Associations between human genetic variation and infectious disease incidence subsequently have been shown by linkage analysis (for reviews, see refs. 5,6), and by genome-wide association studies (GWASs) using haplotype maps of the human genome (7), highdensity microarray analysis (8,9), and DNA sequencing methods (7,(10)(11)(12)(13). However, GWAS normally requires examination of a very large cohort to generate statistically significant associations (14), and inherently lacks the ability to demonstrate causality between a variant and the disease phenotype.…”

mentioning

confidence: 99%

Human genetic variation altering anthrax toxin sensitivity

Martchenko¹,

Candille²,

Tang³

et al. 2012

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

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The outcome of exposure to infectious microbes or their toxins is influenced by both microbial and host genes. Some host genes encode defense mechanisms, whereas others assist pathogen functions. Genomic analyses have associated host gene mutations with altered infectious disease susceptibility, but evidence for causality is limited. Here we demonstrate that human genetic variation affecting capillary morphogenesis gene 2 ( CMG2 ), which encodes a host membrane protein exploited by anthrax toxin as a principal receptor, dramatically alters toxin sensitivity. Lymphoblastoid cells derived from a HapMap Project cohort of 234 persons of African, European, or Asian ancestry differed in sensitivity mediated by the protective antigen (PA) moiety of anthrax toxin by more than four orders of magnitude, with 99% of the cohort showing a 250-fold range of sensitivity. We find that relative sensitivity is an inherited trait that correlates strongly with CMG2 mRNA abundance in cells of each ethnic/geographical group and in the combined population pool ( P = 4 × 10 −11 ). The extent of CMG2 expression in transfected murine macrophages and human lymphoblastoid cells affected anthrax toxin binding, internalization, and sensitivity. A CMG2 single-nucleotide polymorphism (SNP) occurring frequently in African and European populations independently altered toxin uptake, but was not statistically associated with altered sensitivity in HapMap cell populations. Our results reveal extensive human diversity in cell lethality dependent on PA-mediated toxin binding and uptake, and identify individual differences in CMG2 expression level as a determinant of this diversity. Testing of genomically characterized human cell populations may offer a broadly useful strategy for elucidating effects of genetic variation on infectious disease susceptibility.

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“…Norwalk virus [55]. However, the role of genetic variation in determining resistance to infection by zoonotic pathogens remains unclear, although evidence from genetic epidemiological studies has demonstrated that immunity to disease usually arises from a complex interaction of environmental, pathogen and host genetic factors [56]. Genetically controlled host defence factors can affect the susceptibility of individuals to zoonotic challenge, e.g.…”

Section: Acquired Immunity and Environmental Exposurementioning

confidence: 99%

Subclinical infection and asymptomatic carriage of gastrointestinal zoonoses: occupational exposure, environmental pathways, and the anonymous spread of disease

et al. 2013

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SUMMARYAsymptomatic carriage of gastrointestinal zoonoses is more common in people whose profession involves them working directly with domesticated animals. Subclinical infections (defined as an infection in which symptoms are either asymptomatic or sufficiently mild to escape diagnosis) are important within a community as unknowing (asymptomatic) carriers of pathogens do not change their behaviour to prevent the spread of disease; therefore the public health significance of asymptomatic human excretion of zoonoses should not be underestimated. However, optimal strategies for managing diseases where asymptomatic carriage instigates further infection remain unresolved, and the impact on disease management is unclear. In this review we consider the environmental pathways associated with prolonged antigenic exposure and critically assess the significance of asymptomatic carriage in disease outbreaks. Although screening high-risk groups for occupationally acquired diseases would be logistically problematical, there may be an economic case for identifying and treating asymptomatic carriage if the costs of screening and treatment are less than the costs of identifying and treating those individuals infected by asymptomatic hosts.

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Genetic susceptibility to infectious diseases: big is beautiful, but will bigger be even better?

Cited by 199 publications

References 166 publications

Slc11a1 (formerly Nramp1) and susceptibility to canine visceral leishmaniasis

Slc11a1 (formerly Nramp1) and susceptibility to canine visceral leishmaniasis

Human genetic variation altering anthrax toxin sensitivity

Subclinical infection and asymptomatic carriage of gastrointestinal zoonoses: occupational exposure, environmental pathways, and the anonymous spread of disease

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