Context-specific regulation of monocyte surface IL7R expression and soluble receptor secretion by a common autoimmune risk allele

Al-Mossawi, Hussein; Yager, Nicole; Taylor, Chelsea; Lau, Evelyn; Danielli, Sara; Wit, Jelle de; Makino, Seiko; Gilchrist, James J.; Nassiri, Isar; Mahé, Elise A.; Rizvi, Laila; Cheeseman, Jane; Neville, Matt J.; Knight, Julian C.; Bowness, Paul; Fairfax, Benjamin P.

doi:10.1101/262410

Cited by 3 publications

(3 citation statements)

References 34 publications

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“…Another example of opposite associations can be seen at IL7RA between autoimmune disease and allergic disease, and relevant phenotypes such as eosinophil count, is illustrated in UK Biobank using the GWAS results from https://biobankengine.stanford.edu versus its association with a number of autoimmune diseases, including MS 37 : the minor C allele of rs6897932 predisposes to autoimmunity and protects from allergic disease.…”

Section: Pleiotropy: Genetic Variation Can Affect Multiple Diseasesmentioning

confidence: 99%

Approaches and advances in the genetic causes of autoimmune disease and their implications

et al. 2018

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Genome-wide association studies are transformative in revealing the polygenetic basis of common diseases, with autoimmune diseases leading the charge. Although the field is just over 10 years old, advances in understanding the underlying mechanistic pathways of these conditions, which result from a dense multifactorial blend of genetic, developmental and environmental factors, have already been informative, including insights into therapeutic possibilities. Nevertheless, the challenge of identifying the actual causal genes and pathways and their biological effects on altering disease risk remains for many identified susceptibility regions. It is this fundamental knowledge that will underpin the revolution in patient stratification, the discovery of therapeutic targets and clinical trial design in the next 20 years. Here we outline recent advances in analytical and phenotyping approaches and the emergence of large cohorts with standardized gene-expression data and other phenotypic data that are fueling a bounty of discovery and improved understanding of human physiology.

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Section: Pleiotropy: Genetic Variation Can Affect Multiple Diseasesmentioning

confidence: 99%

Approaches and advances in the genetic causes of autoimmune disease and their implications

et al. 2018

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“…The variant affects splicing of the IL7R transcript, with the minor C allele, the risk allele for multiple sclerosis (MS), favouring secreted over surface isoform of the protein. Elevated levels of secreted isoform exacerbate symptoms of MS in animal model[157,158]. In common with opposite effects seen in AD compared to autoimmune diseases, the minor allele is protective in eczema[150].…”

Section: Resultsmentioning

confidence: 99%

Triangulating molecular evidence to prioritise candidate causal genes at established atopic dermatitis loci

Sobczyk

Richardson

Zuber

et al. 2020

Preprint

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Background: Genome-wide association studies for atopic dermatitis (AD, eczema) have identified 25 reproducible loci associated in populations of European descent. We attempt to prioritise candidate causal genes at these loci using a multifaceted bioinformatic approach and extensive molecular resources compiled into a novel pipeline: ADGAPP (Atopic Dermatitis GWAS Annotation & Prioritisation Pipeline). Methods: We identified a comprehensive list of 103 accessible molecular resources for AD aetiology, including expression, protein and DNA methylation QTL datasets in skin or immune-relevant tissues. These were used to test for overlap with GWAS signals (including colocalisation testing where possible). This was combined with functional annotation based on regulatory variant prediction, and independent genomic features such as chromatin accessibility, promoter-enhancer interactions, splicing sites, non-coding RNA regions, differential expression studies involving eczema patients and fine-mapping of causal variants. For each gene at each locus, we condensed the evidence into a prioritisation score. Results: Across the 25 AD loci investigated, we detected significant enrichment of genes with adaptive immune regulatory function and epidermal barrier formation among the top prioritised genes. At 8 loci, we were able to prioritise a single candidate gene (IL6R, ADO, PRR5L, IL7R, ETS1, INPP5D, MDM1, TRAF3). At a further 2 loci, 2 candidate genes emerge (IL18R1/IL18RAP, LRRC32/EMSY). For the majority of these, the prioritised gene has been previously proposed as a plausible candidate, but the evidence we combine here, strengthens the case for many of these. In addition, at 6 of the 25 loci, our ADGAPP analysis prioritises novel alternative candidates (SLC22A5, IL2RA, MDM1, DEXI, ADO, STMN3), highlighting the importance of this comprehensive approach. Conclusions: Our ADGAPP analysis provides additional support for previously implicated genes at several AD GWAS loci, as well as evidence for plausible novel candidates at others. We highlight several genes with good/converging evidence of involvement in AD that represent potential new targets for drug discovery.

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“…Their study showed that monocytes upregulate IL7R expression and soluble IL7R secretion after LPS treatment in a functional, genotype- and TNFα-dependant manner. These data draw attention to an unappreciated key myeloid role for AS risk variants at IL7R (62).…”

Section: Transcription Factors Associated With Asmentioning

confidence: 94%

RUNX3 and T-Bet in Immunopathogenesis of Ankylosing Spondylitis—Novel Targets for Therapy?

et al. 2019

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Susceptibility to ankylosing spondylitis (AS) is polygenic with more than 100 genes identified to date. These include HLA-B27 and the aminopeptidases (ERAP1, ERAP2, and LNPEPS), which are involved in antigen processing and presentation to T-cells, and several genes (IL23R, IL6R, STAT3, JAK2, IL1R1/2, IL12B, and IL7R) involved in IL23 driven pathways of inflammation. AS is also strongly associated with polymorphisms in two transcription factors, RUNX3 and T-bet (encoded by TBX21), which are important in T-cell development and function. The influence of these genes on the pathogenesis of AS and their potential for identifying drug targets is discussed here.

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Context-specific regulation of monocyte surface IL7R expression and soluble receptor secretion by a common autoimmune risk allele

Cited by 3 publications

References 34 publications

Approaches and advances in the genetic causes of autoimmune disease and their implications

Approaches and advances in the genetic causes of autoimmune disease and their implications

Triangulating molecular evidence to prioritise candidate causal genes at established atopic dermatitis loci

RUNX3 and T-Bet in Immunopathogenesis of Ankylosing Spondylitis—Novel Targets for Therapy?

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