Interferon Gamma Allelic Variants

Kantarci, Orhun H.; Hebrink, David D.; Schaefer-Klein, Janet; Sun, Yulong; Achenbach, Sara J.; Atkinson, Elizabeth J.; Heggarty, Shirley; Cotleur, Anne C.; Andrade, Mariza de; Vandenbroeck, Koen; Pelfrey, Clara M.; Weinshenker, Brian G.

doi:10.1001/archneurol.2007.66

Cited by 33 publications

(10 citation statements)

References 56 publications

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“…Multiple studies have documented gender-specific association of allelic variants at IFNG regulatory elements or IFNG protein levels with human disease. For example, IFNG variants are associated with multiple sclerosis (Kantarci et al, 2008) and asthma (Loisel et al, 2011) in males but not females, but the mechanisms are not known. NeST (also known as IFNG-AS1 or TMEVPG1 ) is located proximal to IFNG and encodes a long noncoding RNA that is required to program active chromatin state and promote expression of IFNG .…”

Section: Resultsmentioning

confidence: 99%

Individuality and Variation of Personal Regulomes in Primary Human T Cells

et al. 2015

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Here we survey variation and dynamics of active regulatory elements genome-wide using longitudinal samples from human individuals. We applied Assay of Transposase Accessible Chromatin with sequencing (ATAC-seq) to map chromatin accessibility in primary CD4+ T cells isolated from standard blood draws of 12 healthy volunteers over time, from cancer patients, and during T cell activation. Over 4,000 predicted regulatory elements (7.2%) showed reproducible variation in accessibility between individuals. Gender was the most significant attributable source of variation. ATAC-seq revealed previously undescribed elements that escape X chromosome inactivation and predicted gender-specific gene regulatory networks across autosomes, which coordinately affect genes with immune function. Noisy regulatory elements with personal variation in accessibility are significantly enriched for autoimmune disease loci. Over one third of regulome variation lacked genetic variation in cis, suggesting contributions from environmental or epigenetic factors. These results refine concepts of human individuality and provide a foundational reference for comparing disease-associated regulomes.

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Section: Resultsmentioning

confidence: 99%

Individuality and Variation of Personal Regulomes in Primary Human T Cells

et al. 2015

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“…ASGE is also present in several tissues [21], indicating that this is a common mechanism of genomic regulation for many pathways and cell types. Indeed, ASGE is also implicated in a variety of disease states [23].…”

Section: Discussionmentioning

confidence: 99%

Allele-Specific Gene Expression Is Widespread Across the Genome and Biological Processes

et al. 2009

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Allelic specific gene expression (ASGE) appears to be an important factor in human phenotypic variability and as a consequence, for the development of complex traits and diseases. In order to study ASGE across the human genome, we have performed a study in which genotyping was coupled with an analysis of ASGE by screening 11,500 SNPs using the Mapping 10 K Array to identify differential allelic expression. We found that from the 5,133 SNPs that were suitable for analysis (heterozygous in our sample and expressed in peripheral blood mononuclear cells), 2,934 (57%) SNPs had differential allelic expression. Such SNPs were equally distributed along human chromosomes and biological processes. We validated the presence or absence of ASGE in 18 out 20 SNPs (90%) randomly selected by real time PCR in 48 human subjects. In addition, we observed that SNPs close to -but not included in- segmental duplications had increased levels of ASGE. Finally, we found that transcripts of unknown function or non-coding RNAs, also display ASGE: from a total of 2,308 intronic SNPs, 1510 (65%) SNPs underwent differential allelic expression. In summary, ASGE is a widespread mechanism in the human genome whose regulation seems to be far more complex than expected.

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“…Responses in females to various immune challenges are stronger than in males 16 . This is also true when comparing autoantigen specific responses in women versus men with MS 17–19 .…”

Section: Gender Differences In Msmentioning

confidence: 95%

Sex-related factors in multiple sclerosis susceptibility and progression

2012

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The pathogenesis of multiple sclerosis (MS) involves complex interactions between genetic susceptibility and environmental triggers. Clinical observations suggest that the study of sex differences may provide important insight into mechanisms of MS pathogenesis and progression. One clinical observation is that MS occurs more frequently in women than in men, indicating an impact of sex-related factors on susceptibility to MS. These factors include hormonal, genetic, and environmental influences, as well as gene x environment interactions and epigenetic mechanisms. Despite a higher incidence and more robust immune responses, females do not have a poorer prognosis, suggesting a biological mechanism of resilience. A second clinical observation is the pregnancy strongly affects disease activity, leading to a reduction in relapse rates in the last trimester but an increase post partum. However, pregnancy has little effects on long-term disability. Unraveling mechanisms underlying these clinical observations at the laboratory bench, with subsequent translation back to the bedside is a unique and potentially fruitful strategy in MS. In this paper, we review the current knowledge in the field and discuss novel therapeutic approaches currently in development that were derived from the study of sex-related factors.

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Interferon Gamma Allelic Variants

Cited by 33 publications

References 56 publications

Individuality and Variation of Personal Regulomes in Primary Human T Cells

Individuality and Variation of Personal Regulomes in Primary Human T Cells

Allele-Specific Gene Expression Is Widespread Across the Genome and Biological Processes

Sex-related factors in multiple sclerosis susceptibility and progression

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