candidate-gene-testing-clinical-cohort-studies-with-multiplexed

Candidate Gene Testing in Clinical Cohort Studies with Multiplexed Genotyping and Mass Spectrometry

Complex diseases are often underpinned by multiple common genetic variants that contribute to disease susceptibility. Here, we describe a cost-effective ...

Murdoch Childrens Research Institute

University of Melbourne

University of Western Australia

The profile of allergic disease worldwide continues to change as the number of severe IgE-mediated allergies increases. This phenomenon is thought to reflect the outcome of combined genetic/environmental/developmental/stochastic effects on immune development, but understanding this remains a challenge. Epigenetic disruption at key immune genes during development has been proposed as a potential explanation for how environmental exposures may alter immune cell development and function. This represents an emerging area of research with the potential to yield new understanding of how disease risk is modified. Here, we examine recent developments in this field that are defining new epigenetic paradigms of allergic disease.

Progress in understanding the epigenetic basis for immune development, immune function, and the rising incidence of allergic disease.

The endothelial compartment, comprising arterial, venous and lymphatic cell types, is established prenatally in association with rapid phenotypic and functional changes. The molecular mechanisms underpinning this process in utero have yet to be fully elucidated. The aim of this study was to investigate the potential for DNA methylation to act as a driver of the specific gene expression profiles of arterial and venous endothelial cells.

Variable promoter methylation contributes to differential expression of key genes in human placenta-derived venous and arterial endothelial cells.

It is well-established that vitamin D impacts gene regulation via vitamin D response elements (VDREs) across the genome. Recent evidence, primarily at a locus-specific level, suggests that alterations to DNA methylation may also be a relevant mechanism through which vitamin D regulates gene expression. Given the intense interest in vitamin D, particularly as an immune modifier, we sought to examine the impact of vitamin D exposure on the immune cell methylome in vitro. We exposed primary human blood mononuclear cells with up to 100nM calcitriol for up to 120h, and measured genome-scale DNA methylation response using the Illumina Infinium HumanMethylation450 beadchip array. We observed that, while the expression of known vitamin D responsive genes was clearly altered by calcitriol exposure, substantial genome-scale changes to DNA methylation were not induced. Our data suggests that, over the exposure period measured, changes to DNA methylation may not be a predominant mechanism through which vitamin D impacts gene expression in human immune cells. 

In vitro exposure of human blood mononuclear cells to active vitamin D does not induce substantial change to DNA methylation on a genome-scale.

Epigenetic mechanisms such as DNA methylation, histone modification, and micro RNA signaling regulate the activity of the genome. Virtually all aspects of immunity involve some level of epigenetic regulation, whether it be host defense or in mediating tolerance. These processes are critically important in mediating dynamic responses to the environment over the life course of the individual, yet we are only just beginning to understand how dysregulation in these pathways may play a role in immune disease. Here, we give a brief chronological overview of epigenetic processes during immune development in health and disease.

Epigenetics in immune development and in allergic and autoimmune diseases.

The rates of IgE-mediated food allergy have increased globally, particularly in developed countries. The rising incidence is occurring more rapidly than changes to the genome sequence would allow, suggesting that environmental exposures that alter the immune response play an important role. Genetic factors may also be used to predict an increased predisposition to these environmental risk factors, giving rise to the concept of gene-environment interactions, whereby differential risk of environmental exposures is mediated through the genome. Increasing evidence also suggests a role for epigenetic mechanisms, which are sensitive to environmental exposures, in the development of food allergy. This paper discusses the current state of knowledge regarding the environmental and genetic risk factors for food allergy and how environmental exposures may interact with immune genes to modify disease risk or outcome. 

The role of gene-environment interactions in the development of food allergy.

Regulatory T cells (Tregs) are critical for development of oral tolerance, and studies suggest that dysfunction of Tregs may lead to food allergy. However, to date, no study has investigated Treg responses following in vivo exposure to peanut or egg allergens in humans.

Food-allergic infants have impaired regulatory T-cell responses following in vivo allergen exposure.

The rise in IgE-mediated food allergy in recent times is the likely result of gene-environment interactions mediated via epigenetic pathways. As epigenetic modifications, including DNA methylation, are at the interface between the environment and the genome, they may be ideal biomarkers of modifiable disease pathways. High-throughput methylation profiling of immune cell subtypes or whole blood from patients allows the identification of disease specific epigenetic variants. If faithfully tracking with disease parameters, these 'signatures' may have clinical applications as biomarkers of disease or therapeutic response. Development of such tools will depend on a number of factors, including determining the most appropriate experimental approach, analysis methodology, patient groups, and informative target cells/tissues. Here we discuss these potential applications and their implications for food allergy practise.

Epigenetic modifications: mechanisms of disease and biomarkers of food allergy.

Food allergy naturally resolves in a proportion of food-allergic children without intervention; however the underlying mechanisms governing the persistence or resolution of food allergy in childhood are not understood.

Article	Year
Progress in understanding the epigenetic basis for immune development, immune function, and the rising incidence of allergic disease. Current allergy and asthma reports\| PubMed ID: 23054626	2013
Variable promoter methylation contributes to differential expression of key genes in human placenta-derived venous and arterial endothelial cells. BMC genomics\| PubMed ID: 23855827	2013
In vitro exposure of human blood mononuclear cells to active vitamin D does not induce substantial change to DNA methylation on a genome-scale. The Journal of steroid biochemistry and molecular biology\| PubMed ID: 24525112	2014
Epigenetics in immune development and in allergic and autoimmune diseases. Journal of reproductive immunology\| PubMed ID: 25034262	2014
The role of gene-environment interactions in the development of food allergy. Expert review of gastroenterology & hepatology\| PubMed ID: 26357960	2015
Food-allergic infants have impaired regulatory T-cell responses following in vivo allergen exposure. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology\| PubMed ID: 26456457	2016
Epigenetic modifications: mechanisms of disease and biomarkers of food allergy. Current opinion in immunology\| PubMed ID: 27218660	2016
Early life innate immune signatures of persistent food allergy. The Journal of allergy and clinical immunology\| PubMed ID: 29154959	2017

David J. Martino

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