TY - JOUR
T1 - A functional SNP associated with atopic dermatitis controls cell type-specific methylation of the VSTM1 gene locus
AU - Kumar, Dilip
AU - Puan, Kia Joo
AU - Andiappan, Anand Kumar
AU - Lee, Bernett
AU - Westerlaken, Geertje H.A.
AU - Haase, Doreen
AU - Melchiotti, Rossella
AU - Li, Zhuang
AU - Yusof, Nurhashikin
AU - Lum, Josephine
AU - Koh, Geraldine
AU - Foo, Shihui
AU - Yeong, Joe
AU - Alves, Alexessander Da Silva Couto
AU - Pekkanen, Juha
AU - Sun, Liang Dan
AU - Irwanto, Astrid
AU - Fairfax, Benjamin P.
AU - Naranbhai, Vivek
AU - Common, John E.A.
AU - Tang, Mark B Y
AU - Chuang, Chin Keh
AU - Jarvelin, Marjo-Riitta
AU - Knight, Julian C.
AU - Zhang, Xuejun
AU - Chew, Fook Tim
AU - Prabhakar, Shyam
AU - Jianjun, Liu
AU - Wang, De Yun
AU - Zolezzi, Francesca
AU - Poidinger, Michael
AU - Lane, E. Birgitte
AU - Meyaard, Linde
AU - Rötzschke, Olaf
N1 - Funding Information:
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).
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/2/20
Y1 - 2017/2/20
N2 - 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.
AB - 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.
KW - Atopic dermatitis
KW - Expression quantitative trait loci (eQTL)
KW - Monocytes
KW - Neutrophils
KW - Reactive oxygen species (ROS)
KW - Signal inhibitory receptor on leukocytes-1 (SIRL-1)
KW - VSTM1
UR - http://www.scopus.com/inward/record.url?scp=85013270072&partnerID=8YFLogxK
U2 - 10.1186/s13073-017-0404-6
DO - 10.1186/s13073-017-0404-6
M3 - Article
C2 - 28219444
AN - SCOPUS:85013270072
SN - 1756-994x
VL - 9
JO - Genome Medicine
JF - Genome Medicine
IS - 1
M1 - 18
ER -