205 research outputs found
IL23R (Interleukin 23 Receptor) variants protective against inflammatory bowel diseases (IBD) display loss of functiondue to impaired protein stability and intracellular trafficking
Genome-wide association studies as well as murine models
have shown that the interleukin 23 receptor (IL23R) pathway
plays a pivotal role in chronic inflammatory diseases such as
Crohn disease (CD), ulcerative colitis, psoriasis, and type 1 diabetes. Genome-wide association studies and targeted re-sequencing studies have revealed the presence of multiple potentially causal variants of the IL23R. Specifically the G149R,
V362I, and R381Q IL23R chain variants are linked to protection against the development of Crohn disease and ulcerative
colitis in humans. Moreover, the exact mechanism of action of
these receptor variants has not been elucidated. We show that
all three of these IL23R variants cause a reduction in IL23
receptor activation-mediated phosphorylation of the signaltransducing activator of transcription 3 (STAT3) and phosphorylation of signal transducing activator of transcription 4
(STAT4). The reduction in signaling is due to lower levels of cell
surface receptor expression. For G149R, the receptor retention
in the endoplasmic reticulum is due to an impairment of receptor maturation, whereas the R381Q and V362I variants have
reduced protein stability. Finally, we demonstrate that the
endogenous expression of IL23R protein from V362I and
R381Q variants in human lymphoblastoid cell lines exhibited
lower expression levels relative to susceptibility alleles. Our
results suggest a convergent cause of IL23R variant protection
against chronic inflammatory disease
A transcriptome-based approach to identify functional modules within and across primary human immune cells
Genome-wide transcriptomic analyses have provided valuable insight into fundamental biology and disease pathophysiology. Many studies have taken advantage of the correlation in
the expression patterns of the transcriptome to infer a potential biologic function of uncharacterized genes, and multiple groups have examined the relationship between co-expression,
co-regulation, and gene function on a broader scale. Given the unique characteristics of
immune cells circulating in the blood, we were interested in determining whether it was possible to identify functional co-expression modules in human immune cells. Specifically, we
sequenced the transcriptome of nine immune cell types from peripheral blood cells of healthy
donors and, using a combination of global and targeted analyses of genes within co-expression modules, we were able to determine functions for these modules that were cell lineagespecific or shared among multiple cell lineages. In addition, our analyses identified transcription factors likely important for immune cell lineage commitment and/or maintenance
Phenotypes associated with genetic determinants of type I interferon regulation in the UK Biobank:a protocol
BACKGROUND: Type I interferons are cytokines involved in innate immunity against viruses. Genetic disorders of type I interferon regulation are associated with a range of autoimmune and cerebrovascular phenotypes. Carriers of pathogenic variants involved in genetic disorders of type I interferons are generally considered asymptomatic. Preliminary data suggests, however, that genetically determined dysregulation of type I interferon responses is associated with autoimmunity, and may also be relevant to sporadic cerebrovascular disease and dementia. We aim to determine whether functional variants in genes involved in type I interferon regulation and signalling are associated with the risk of autoimmunity, stroke, and dementia in a population cohort.METHODS: We will perform a hypothesis-driven candidate pathway association study of type I interferon-related genes using rare variants in the UK Biobank (UKB). We will manually curate type I interferon regulation and signalling genes from a literature review and Gene Ontology, followed by clinical and functional filtering. Variants of interest will be included based on pre-defined clinical relevance and functional annotations (using LOFTEE, M-CAP and a minor allele frequency <0.1%). The association of variants with 15 clinical and three neuroradiological phenotypes will be assessed with a rare variant genetic risk score and gene-level tests, using a Bonferroni-corrected p-value threshold from the number of genetic units and phenotypes tested. We will explore the association of significant genetic units with 196 additional health-related outcomes to help interpret their relevance and explore the clinical spectrum of genetic perturbations of type I interferon.ETHICS AND DISSEMINATION: The UKB has received ethical approval from the North West Multicentre Research Ethics Committee, and all participants provided written informed consent at recruitment. This research will be conducted using the UKB Resource under application number 93160. We expect to disseminate our results in a peer-reviewed journal and at an international cardiovascular conference.</p
Building a Field: The Future of Astronomy with Gravitational Waves
Harnessing the sheer discovery potential of GW Astronomy will require bold, deliberate,and sustained efforts to train and develop the requisite workforce. The next decaderequires a strategic plan to build - from the ground up - a robust, open, andwell-connected GW Astronomy community with deep participation from traditionalastronomers, physicists, data scientists, and instrumentalists. This basic infrastructure issorely needed as an enabling foundation for research. We outline a set ofrecommendations for funding agencies, universities, and professional societies to helpbuild a thriving, diverse, and inclusive new field
Leucine-rich repeat kinase-2 (LRRK2) modulates paraquat-induced inflammatory sickness and stress phenotype
Background: Leucine-rich repeat kinase 2 (LRRK2) is a common gene implicated in Parkinson's disease (PD) and is also thought to be fundamentally involved in numerous immune functions. Thus, we assessed the role of LRRK2 in the context of the effects of the environmental toxicant, paraquat, that has been implicated in PD and is known to affect inflammatory processes. Methods: Male LRRK2 knockout (KO) and transgenic mice bearing the G2019S LRRK2 mutation (aged 6-8 months) or their littermate controls were exposed to paraquat (two times per week for 3 weeks), and sickness measures, motivational scores, and total home-cage activity levels were assessed. Following sacrifice, western blot and ELISA assays were performed to
Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.
Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis
Identifying high-impact variants and genes in exomes of Ashkenazi Jewish inflammatory bowel disease patients
Inflammatory bowel disease (IBD) is a group of chronic digestive tract inflammatory conditions whose genetic etiology is still poorly understood. The incidence of IBD is particularly high among Ashkenazi Jews. Here, we identify 8 novel and plausible IBD-causing genes from the exomes of 4453 genetically identified Ashkenazi Jewish IBD cases (1734) and controls (2719). Various biological pathway analyses are performed, along with bulk and single-cell RNA sequencing, to demonstrate the likely physiological relatedness of the novel genes to IBD. Importantly, we demonstrate that the rare and high impact genetic architecture of Ashkenazi Jewish adult IBD displays significant overlap with very early onset-IBD genetics. Moreover, by performing biobank phenome-wide analyses, we find that IBD genes have pleiotropic effects that involve other immune responses. Finally, we show that polygenic risk score analyses based on genome-wide high impact variants have high power to predict IBD susceptibility
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