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Title: A functional SNP associated with atopic dermatitis controls cell type-specific methylation of the VSTM1 gene locus
Authors: Kumar D.
Puan K.J.
Andiappan A.K.
Lee B.
Westerlaken G.H.A.
Haase D.
Melchiotti R.
Li Z.
Yusof N.
Lum J.
Koh G.
Foo S.
Yeong J.
Alves A.C.
Pekkanen J.
Sun L.D.
Irwanto A.
Fairfax B.P.
Naranbhai V.
Common J.E.A.
Tang M.
Chuang C.K. 
Jarvelin M.-R.
Knight J.C.
Zhang X.
Chew F.T. 
Prabhakar S.
Jianjun L.
Wang D.Y. 
Zolezzi F.
Poidinger M. 
Lane E.B. 
Meyaard L.
Rötzschke O.
Keywords: bisulfite
regulator protein
signal inhibitory receptor on leukocyte 1
transcription factor PU 1
transcription factor YY1
unclassified drug
immunoglobulin receptor
SIRL1 protein, human
atopic dermatitis
binding affinity
binding site
chromatin immunoprecipitation
cohort analysis
controlled study
CpG island
disease activity
disease association
DNA methylation
flow cytometry
gel mobility shift assay
gene expression
gene frequency
gene function
gene identification
genetic association
human cell
molecular docking
molecular pathology
promoter region
protein determination
protein DNA binding
protein expression
protein function
sequence analysis
single nucleotide polymorphism
VSTM1 gene
Asian continental ancestry group
atopic dermatitis
gene expression regulation
young adult
Asian Continental Ancestry Group
Dermatitis, Atopic
DNA Methylation
Gene Expression Regulation
Polymorphism, Single Nucleotide
Promoter Regions, Genetic
Receptors, Immunologic
Young Adult
Issue Date: 2017
Citation: Kumar D., Puan K.J., Andiappan A.K., Lee B., Westerlaken G.H.A., Haase D., Melchiotti R., Li Z., Yusof N., Lum J., Koh G., Foo S., Yeong J., Alves A.C., Pekkanen J., Sun L.D., Irwanto A., Fairfax B.P., Naranbhai V., Common J.E.A., Tang M., Chuang C.K., Jarvelin M.-R., Knight J.C., Zhang X., Chew F.T., Prabhakar S., Jianjun L., Wang D.Y., Zolezzi F., Poidinger M., Lane E.B., Meyaard L., Rötzschke O. (2017). A functional SNP associated with atopic dermatitis controls cell type-specific methylation of the VSTM1 gene locus. Genome Medicine 9 (1) : 18. ScholarBank@NUS Repository.
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. © 2017 The Author(s).
Source Title: Genome Medicine
ISSN: 1756994X
DOI: 10.1186/s13073-017-0404-6
Appears in Collections:Staff Publications

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