A functional SNP associated with atopic dermatitis controls cell type-specific methylation of the VSTM1 gene locus
|Author:||Kumar, Dilip1; Puan, Kia Joo1; Andiappan, Anand Kumar1;|
1Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research)
2Laboratory of Translational Immunology, Department of Immunology, University Medical Center Utrecht
3Department of Pathology, Singapore General Hospital
4Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London
5Department of Environmental Health, National Institute for Health and Welfare
6Institute of Dermatology and Department of Dermatology at No.1 Hospital, Anhui Medical University
7Genome Institute of Singapore (GIS), Agency for Science, Technology and Research of Singapore (A*STAR)
8Wellcome Trust Centre for Human Genetics
9Department of Oncology, Cancer and Haematology Centre, Churchill Hospital
10Institute of Medical Biology (IMB), A*STAR (Agency for Science, Technology and Research)
11National Skin Center
12Institute of Molecular & Cellular Biology (IMCB), Agency for Science, Technology and Research (A*STAR)
13Department of Physiology, NUS Yong Loo Lin School of Medicine, National University of Singapore
14Center for Life Course Epidemiology, Faculty of Medicine, University of Oulu
15Biocenter Oulu, University of Oulu
16Unit of Primary Care, Oulu University Hospital
17 Institute of Dermatology and Department of Dermatology at No.1 Hospital, Anhui Medical University
18Department of Biological Sciences, National University of Singapore
19Department of Otolaryngology, National University of Singapore
20Biological Sciences, National University of Singapore
|Online Access:||PDF Full Text (PDF, 6.6 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe201704256254
|Publish Date:|| 2017-04-25
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.
|Pages:||1 - 16|
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
The study was supported by the Singapore Ministry of Education Academic Research Fund (R-154-000-404-112, R-154-000-553-112, R-154-000-565-112, R-154-000-630-112), National Medical Research Council (NMRC; Singapore, NMRC/1150/2008), and Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR) Singapore (SIgN-06-006, SIgN-08-020, and SIgN-10-029).
For the data relevant for the Caucasian eQTL study, the gene expression data are already available at www.ebi.ac.uk (E-MTAB-945), while the genotyping data are accessible at European Genome-Phenome Archive (EGA; EGAS00000000109) and available on request.
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