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      A functional SNP associated with atopic dermatitis controls cell type-specific methylation of the VSTM1 gene locus

      research-article
      1 , 1 , 1 , 1 , 2 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 16 , 3 , 4 , 5 , 6 , 7 , 8 , 7 , 8 , 9 , 12 , 17 , 18 , 3 , 13 , 14 , 15 , 7 , 5 , 19 , 6 , 6 , 10 , 11 , 1 , 1 , 9 , 2 , , 1 ,
      Genome Medicine
      BioMed Central
      VSTM1, Signal inhibitory receptor on leukocytes-1 (SIRL-1), Expression quantitative trait loci (eQTL), Atopic dermatitis, Monocytes, Reactive oxygen species (ROS), Neutrophils

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          Abstract

          Background

          Expression quantitative trait loci (eQTL) databases represent a valuable resource to link disease-associated SNPs to specific candidate genes whose gene expression is significantly modulated by the SNP under investigation. We previously identified signal inhibitory receptor on leukocytes-1 (SIRL-1) as a powerful regulator of human innate immune cell function. While it is constitutively high expressed on neutrophils, on monocytes the SIRL-1 surface expression varies strongly between individuals. The underlying mechanism of regulation, its genetic control as well as potential clinical implications had not been explored yet.

          Methods

          Whole blood eQTL data of a Chinese cohort was used to identify SNPs regulating the expression of VSTM1, the gene encoding SIRL-1. The genotype effect was validated by flow cytometry (cell surface expression), correlated with electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP) and bisulfite sequencing (C-methylation) and its functional impact studied the inhibition of reactive oxygen species (ROS).

          Results

          We found a significant association of a single CpG-SNP, rs612529T/C, located in the promoter of VSTM1. Through flow cytometry analysis we confirmed that primarily in the monocytes the protein level of SIRL-1 is strongly associated with genotype of this SNP. In monocytes, the T allele of this SNP facilitates binding of the transcription factors YY1 and PU.1, of which the latter has been recently shown to act as docking site for modifiers of DNA methylation. In line with this notion rs612529T associates with a complete demethylation of the VSTM1 promoter correlating with the allele-specific upregulation of SIRL-1 expression. In monocytes, this upregulation strongly impacts the IgA-induced production of ROS by these cells. Through targeted association analysis we found a significant Meta P value of 1.14 × 10 –6 for rs612529 for association to atopic dermatitis (AD).

          Conclusion

          Low expression of SIRL-1 on monocytes is associated with an increased risk for the manifestation of an inflammatory skin disease. It thus underlines the role of both the cell subset and this inhibitory immune receptor in maintaining immune homeostasis in the skin. Notably, the genetic regulation is achieved by a single CpG-SNP, which controls the overall methylation state of the promoter gene segment.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s13073-017-0404-6) contains supplementary material, which is available to authorized users.

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          Most cited references24

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          Combining probability from independent tests: the weighted Z-method is superior to Fisher's approach.

          The most commonly used method in evolutionary biology for combining information across multiple tests of the same null hypothesis is Fisher's combined probability test. This note shows that an alternative method called the weighted Z-test has more power and more precision than does Fisher's test. Furthermore, in contrast to some statements in the literature, the weighted Z-method is superior to the unweighted Z-transform approach. The results in this note show that, when combining P-values from multiple tests of the same hypothesis, the weighted Z-method should be preferred.
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            Immune inhibitory receptors.

            With the detailed description and analysis of several inhibitory receptor systems on lymphoid and myeloid cells, a central paradigm has emerged in which the pairing of activation and inhibition is necessary to initiate, amplify, and then terminate immune responses. In some cases, the activating and inhibitory receptors recognize similar ligands, and the net outcome is determined by the relative strength of these opposing signals. The importance of this modulation is demonstrated by the sometimes fatal autoimmune disorders observed in mice with targeted disruption of inhibitory receptors. The significance of these receptors is further evidenced by the conservation of immunoreceptor tyrosine-based inhibitory motifs during their evolution.
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              Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages.

              The transcription factor PU.1 is a hematopoietic-specific member of the ets family. Mice carrying a mutation in the PU.1 locus were generated by gene targeting. Homozygous mutant embryos died at a late gestational stage. Mutant embryos produced normal numbers of megakaryocytes and erythroid progenitors, but some showed an impairment of erythroblast maturation. An invariant consequence of the mutation was a multilineage defect in the generation of progenitors for B and T lymphocytes, monocytes, and granulocytes. Thus, the developmental programs of lymphoid and myeloid lineages require a common genetic function likely acting at the level of a multipotential progenitor.
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                Author and article information

                Contributors
                L.Meyaard@umcutrecht.nl
                Olaf_Rotzschke@immunol.a-star.edu.sg
                Journal
                Genome Med
                Genome Med
                Genome Medicine
                BioMed Central (London )
                1756-994X
                20 February 2017
                20 February 2017
                2017
                : 9
                : 18
                Affiliations
                [1 ]ISNI 0000 0004 0387 2429, GRID grid.430276.4, , Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), ; 8A Biomedical Grove #04-06, Singapore, 138648 Republic of Singapore
                [2 ]ISNI 0000000090126352, GRID grid.7692.a, Laboratory of Translational Immunology, Department of Immunology, , University Medical Center Utrecht, ; P.O. box 85090, Utrecht, 3508 AB The Netherlands
                [3 ]ISNI 0000 0001 2113 8111, GRID grid.7445.2, Department of Epidemiology and Biostatistics, , School of Public Health, Imperial College London, ; London, UK
                [4 ]ISNI 0000 0001 1013 0499, GRID grid.14758.3f, Department of Environmental Health, , National Institute for Health and Welfare, ; Kuopio, Finland
                [5 ]ISNI 0000 0000 9490 772X, GRID grid.186775.a, Institute of Dermatology and Department of Dermatology at No.1 Hospital, , Anhui Medical University, ; Hefei, Anhui China
                [6 ]ISNI 0000 0004 0637 0221, GRID grid.185448.4, Genome Institute of Singapore (GIS), , Agency for Science, Technology and Research of Singapore (A*STAR), ; Singapore, Republic of Singapore
                [7 ]ISNI 0000 0004 1936 8948, GRID grid.4991.5, , Wellcome Trust Centre for Human Genetics, ; Oxford, UK
                [8 ]ISNI 0000 0004 0488 9484, GRID grid.415719.f, Department of Oncology, , Cancer and Haematology Centre, Churchill Hospital, ; Oxford, UK
                [9 ]ISNI 0000 0004 0637 0221, GRID grid.185448.4, Institute of Medical Biology (IMB), , A*STAR (Agency for Science, Technology and Research), ; Singapore, Republic of Singapore
                [10 ]ISNI 0000 0001 2180 6431, GRID grid.4280.e, Department of Otolaryngology, , National University of Singapore, ; Singapore, Republic of Singapore
                [11 ]ISNI 0000 0001 2180 6431, GRID grid.4280.e, Biological Sciences, , National University of Singapore, ; Singapore, Republic of Singapore
                [12 ]ISNI 0000 0004 0640 6896, GRID grid.410763.7, , National Skin Center, ; Singapore, Republic of Singapore
                [13 ]ISNI 0000 0001 0941 4873, GRID grid.10858.34, Center for Life Course Epidemiology, , Faculty of Medicine, University of Oulu, ; P.O. Box 5000, 90014 Oulu, Finland
                [14 ]ISNI 0000 0001 0941 4873, GRID grid.10858.34, Biocenter Oulu, , University of Oulu, ; P.O. Box 5000, Aapistie 5A, 90014 Oulu, Finland
                [15 ]ISNI 0000 0004 4685 4917, GRID grid.412326.0, , Unit of Primary Care, Oulu University Hospital, ; Kajaanintie 50, 90029 OYS, P.O. Box 20, 90220 Oulu, Finland
                [16 ]ISNI 0000 0000 9486 5048, GRID grid.163555.1, Department of Pathology, , Singapore General Hospital, ; Singapore, Republic of Singapore
                [17 ]ISNI 0000 0004 0637 0221, GRID grid.185448.4, Institute of Molecular & Cellular Biology (IMCB), Agency for Science, , Technology and Research (A*STAR), ; Singapore, 138648 Republic of Singapore
                [18 ]ISNI 0000 0001 2180 6431, GRID grid.4280.e, Department of Physiology, , NUS Yong Loo Lin School of Medicine, National University of Singapore, ; Singapore, Republic of Singapore
                [19 ]ISNI 0000 0001 2180 6431, GRID grid.4280.e, Department of Biological Sciences, , National University of Singapore, ; Singapore, Republic of Singapore
                Article
                404
                10.1186/s13073-017-0404-6
                5319034
                28219444
                c18d6e61-3fe6-4221-aee6-391fa5bfb5e6
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 10 August 2016
                : 11 January 2017
                Funding
                Funded by: Biomedical Research Council
                Funded by: FundRef http://dx.doi.org/10.13039/501100001349, National Medical Research Council;
                Funded by: FundRef http://dx.doi.org/10.13039/501100001348, Agency for Science, Technology and Research;
                Categories
                Research
                Custom metadata
                © The Author(s) 2017

                Molecular medicine
                vstm1,signal inhibitory receptor on leukocytes-1 (sirl-1),expression quantitative trait loci (eqtl),atopic dermatitis,monocytes,reactive oxygen species (ros),neutrophils

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