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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
A functional SNP associated with atopic dermatitis controls cell type-specific methylation of the VSTM1 gene locus
Genome Medicine, Volume 9, No. 1, Article 18, Year 2017
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Description
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. © 2017 The Author(s).
Authors & Co-Authors
Kumar, Dilip
Singapore, Singapore City
Agency for Science, Technology and Research, Singapore
Andiappan, Anand Kumar
Singapore, Singapore City
Agency for Science, Technology and Research, Singapore
Lee, Bernett Teck Kwong
Singapore, Singapore City
Agency for Science, Technology and Research, Singapore
Lum, Josephine
Singapore, Singapore City
Agency for Science, Technology and Research, Singapore
Foo, Shihui
Singapore, Singapore City
Agency for Science, Technology and Research, Singapore
Couto-Alves, Alexessander Silva
United Kingdom, London
Imperial College London
Pekkanen, Juha R.
Finland, Helsinki
Terveyden ja Hyvinvoinnin Laitos
Fairfax, Benjamin Peter
United Kingdom, Oxford
The Wellcome Centre for Human Genetics
United Kingdom, Oxford
Churchill Hospital
Naranbhai, Vivek
United Kingdom, Oxford
The Wellcome Centre for Human Genetics
United Kingdom, Oxford
Churchill Hospital
Common, John E.A.
Singapore, Singapore City
Agency for Science, Technology and Research, Singapore
J̈arvelin, Märjo Riitta R.
United Kingdom, London
Imperial College London
Finland, Oulu
Oulun Yliopisto
Finland, Oulu
Oulu University Hospital
Knight, Julian C.
United Kingdom, Oxford
The Wellcome Centre for Human Genetics
Prabhakar, Shyam
Singapore, Singapore City
Agency for Science, Technology and Research, Singapore
Wang, De Yun
Singapore, Singapore City
National University of Singapore
Zolezzi, Francesca
Singapore, Singapore City
Agency for Science, Technology and Research, Singapore
Poidinger, Michael
Singapore, Singapore City
Agency for Science, Technology and Research, Singapore
Lane, Ellen Birgitte
Singapore, Singapore City
Agency for Science, Technology and Research, Singapore
Rötzschke, Olaf
Singapore, Singapore City
Agency for Science, Technology and Research, Singapore
Statistics
Citations: 25
Authors: 18
Affiliations: 12
Identifiers
Doi:
10.1186/s13073-017-0404-6
ISSN:
1756994X
Research Areas
Genetics And Genomics
Study Design
Cohort Study
Study Approach
Quantitative