Genetic susceptibility to infectious diseases: big is beautiful, but will bigger be even better?
Ontology highlight
ABSTRACT:
SUBMITTER: Burgner D
PROVIDER: S-EPMC2330096 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Although genetic variation among humans in their susceptibility to infectious diseases has long been appreciated, little focus has been devoted to identifying patterns in levels of variation in susceptibility to different diseases. Levels of genetic variation in susceptibility associated with 40 human infectious diseases were assessed by a survey of studies on both pedigree-based quantitative variation, as well as studies on different classes of marker alleles. These estimates were correlated with pathogen traits, epidemiological characteristics, and effectiveness of the human immune response. The strongest predictors of levels of genetic variation in susceptibility were disease characteristics negatively associated with immune effectiveness. High levels of genetic variation were associated with diseases with long infectious periods and for which vaccine development attempts have been unsuccessful. These findings are consistent with predictions based on theoretical models incorporating fitness costs associated with the different types of resistance mechanisms. An appreciation of these observed patterns will be a valuable tool in directing future research given that genetic variation in disease susceptibility has large implications for vaccine development and epidemiology.
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Project description:BACKGROUND:The interleukin-2-mediated immune response is critical for host defense against infectious pathogens. Cytokine-inducible SRC homology 2 (SH2) domain protein (CISH), a suppressor of cytokine signaling, controls interleukin-2 signaling. METHODS:Using a case-control design, we tested for an association between CISH polymorphisms and susceptibility to major infectious diseases (bacteremia, tuberculosis, and severe malaria) in blood samples from 8402 persons in Gambia, Hong Kong, Kenya, Malawi, and Vietnam. We had previously tested 20 other immune-related genes in one or more of these sample collections. RESULTS:We observed associations between variant alleles of multiple CISH polymorphisms and increased susceptibility to each infectious disease in each of the study populations. When all five single-nucleotide polymorphisms (SNPs) (at positions -639, -292, -163, +1320, and +3415 [all relative to CISH]) within the CISH-associated locus were considered together in a multiple-SNP score, we found an association between CISH genetic variants and susceptibility to bacteremia, malaria, and tuberculosis (P=3.8x10(-11) for all comparisons), with -292 accounting for most of the association signal (P=4.58x10(-7)). Peripheral-blood mononuclear cells obtained from adult subjects carrying the -292 variant, as compared with wild-type cells, showed a muted response to the stimulation of interleukin-2 production--that is, 25 to 40% less CISH expression. CONCLUSIONS:Variants of CISH are associated with susceptibility to diseases caused by diverse infectious pathogens, suggesting that negative regulators of cytokine signaling have a role in immunity against various infectious diseases. The overall risk of one of these infectious diseases was increased by at least 18% among persons carrying the variant CISH alleles.
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Project description:Transposable elements (TEs) are ubiquitous in both prokaryotes and eukaryotes, and the dynamic character of their interaction with host genomes brings about numerous evolutionary innovations and shapes genome structure and function in a multitude of ways. In traditional classification systems, TEs are often being depicted in simplistic ways, based primarily on the key enzymes required for transposition, such as transposases/recombinases and reverse transcriptases. Recent progress in whole-genome sequencing and long-read assembly, combined with expansion of the familiar range of model organisms, resulted in identification of unprecedentedly long transposable units spanning dozens or even hundreds of kilobases, initially in prokaryotic and more recently in eukaryotic systems. Here, we focus on such oversized eukaryotic TEs, including retrotransposons and DNA transposons, outline their complex and often combinatorial nature and closely intertwined relationship with viruses, and discuss their potential for participating in transfer of long stretches of DNA in eukaryotes.
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Project description:Genome-wide association studies (GWASs) have been widely applied to identify genetic factors that affect complex diseases or traits. Presently, the GWAS Catalog includes >2800 human studies. Of these, only a minority have investigated the susceptibility to infectious diseases or the response to therapies for the treatment or prevention of infections. Despite their limited application in the field, GWASs have provided valuable insights by pinpointing associations to both innate and adaptive immune response loci, as well as novel unexpected risk factors for infection susceptibility. Herein, we discuss some issues and caveats of GWASs for infectious diseases, we review the most recent findings ensuing from these studies, and we provide a brief summary of selected GWASs for infections in non-human mammals. We conclude that, although the general trend in the field of complex traits is to shift from GWAS to next-generation sequencing, important knowledge on infectious disease-related traits can be still gained by GWASs, especially for those conditions that have never been investigated using this approach. We suggest that future studies will benefit from the leveraging of information from the host's and pathogen's genomes, as well as from the exploration of models that incorporate heterogeneity across populations and phenotypes. Interactions within HLA genes or among HLA variants and polymorphisms located outside the major histocompatibility complex may also play an important role in shaping the susceptibility and response to invading pathogens.
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Project description:Exponential growth bias is the phenomenon whereby humans underestimate exponential growth. In the context of infectious diseases, this bias may lead to a failure to understand the magnitude of the benefit of non-pharmaceutical interventions. Communicating the same scenario in different ways (framing) has been found to have a large impact on people's evaluations and behavior in the contexts of social behavior, risk taking and health care. We find that framing matters for people's assessment of the benefits of non-pharmaceutical interventions. In two commonly used frames, most subjects in our experiment drastically underestimate the number of cases avoided by adopting non-pharmaceutical interventions. Framing growth in terms of doubling times rather than growth rates reduces the bias. When the scenario is framed in terms of time gained rather than cases avoided, the median subject assesses the benefit of non-pharmaceutical interventions correctly. These findings suggest changes that could be adopted to better communicate the exponential spread of infectious diseases.
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Project description:We enjoy the illusion that visual resolution is high across the entire field of vision. However, this illusion can be easily dispelled by trying to identify objects in a cluttered environment out of the corner of your eye. This reflects, in part, the well-known decline in visual resolution in peripheral vision; however, the main bottleneck for reading or object recognition in peripheral vision is crowding. Objects that can be easily identified in isolation seem indistinct and jumbled in clutter. Crowding is thought to reflect inappropriate integration of the target and flankers in peripheral vision [1, 2]. Here, we uncover and explain a paradox in peripheral crowding: under certain conditions, increasing the size or number of flanking rings results in a paradoxical decrease in the magnitude of crowding-i.e., the bigger or more numerous the flanks, the smaller the crowding. These surprising results are predicted by a model in which crowding is determined by the centroids of approximately 4-8 independent features within approximately 0.5x the target eccentricity. These features are then integrated into a texture beyond the stage of feature analysis. We speculate that this process may contribute to the illusion of high resolution across the field of vision.
| S-EPMC3045113 | biostudies-literature
Project description:The main functions of the kidney are to excrete metabolic waste products and actively reabsorb essential molecules such as amino acids, ions, glucose and water. In humans, a wide range of genetic disorders exist characterized by wasting of metabolically important compounds. At the cellular level, more than 20 highly specialized renal epithelial cell types located in different segments of the nephron contribute to the reabsorption process. In particular, proximal tubular cells play a crucial role and are uniquely adapted to maximize reabsorption efficiency. They accommodate high numbers of transporters and channels by increasing the apical surface area in contact with the primary filtrate by forming a brush border as well as undergoing hypertrophy and hyperplasia. This adaptation is evolutionarily conserved and is detected in the primitive pronephric kidney of fish and amphibians as well as the metanephric kidney of higher vertebrates. Surprisingly, signaling pathways regulating these three processes have remained largely unknown. Here we summarize recent studies that highlight the early phases of kidney development as a critical juncture in establishing proximal tubule size.
| S-EPMC3944135 | biostudies-literature
Project description:ObjectivesTo quantify and analyse the quality of evidence that is presented in national guidelines.SettingLevels of evidence used in all the current valid recommendations in the Scottish Intercollegiate Guideline Network (SIGN) guidelines were reviewed and statistically analysed.Outcome measuresThe proportion of level D evidence used in each guideline and a statistical analysis.MethodData were collected from published guidelines available online to the public. SIGN methodology entails a professional group selected by a national organisation to develop each of these guidelines. Statistical analysis of the relationship between the number of guideline recommendations and the quality of evidence used in its recommendations was performed.ResultThe proportion of level D evidence increases with the number of recommendations made. This correlation is significant with Kendall's τ=0.22 (approximate 95% CI 0.008 to 0.45), p = 0.04; and Spearman ρ=0.22 (approximate 95% CI 0.02 to 0.57), p=0.04.ConclusionsPractice guidelines should be brief and based on scientific evidence. Paradoxically the longest guidelines have the highest proportion of recommendations based on the lowest level of evidence. Guideline developers should be more aware of the need for brevity and a stricter application of evidence-based principles could achieve this. The findings support calls for a review of how evidence is used and presented in guidelines.
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