title: A functional SNP associated with atopic dermatitis controls cell type-specific methylation of the VSTM1 gene locus.
abstract: 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.
  
  
  
  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).
  
  
  
  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 × 10-6for rs612529 for association to atopic dermatitis (AD).
  
  
  
  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.
authors.affiliation: Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), 8A Biomedical Grove #04-06, Singapore, 138648, Republic of Singapore.
authors.forename: Dilip
authors.initials: D
authors.lastname: Kumar
authors.affiliation: Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), 8A Biomedical Grove #04-06, Singapore, 138648, Republic of Singapore.
authors.forename: Kia Joo
authors.initials: KJ
authors.lastname: Puan
authors.affiliation: Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), 8A Biomedical Grove #04-06, Singapore, 138648, Republic of Singapore.
authors.forename: Anand Kumar
authors.initials: AK
authors.lastname: Andiappan
authors.affiliation: Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), 8A Biomedical Grove #04-06, Singapore, 138648, Republic of Singapore.
authors.forename: Bernett
authors.initials: B
authors.lastname: Lee
authors.affiliation: Laboratory of Translational Immunology, Department of Immunology, University Medical Center Utrecht, P.O. box 85090, Utrecht, 3508 AB, The Netherlands.
authors.forename: Geertje H A
authors.initials: GH
authors.lastname: Westerlaken
authors.affiliation: Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), 8A Biomedical Grove #04-06, Singapore, 138648, Republic of Singapore.
authors.forename: Doreen
authors.initials: D
authors.lastname: Haase
authors.affiliation: Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), 8A Biomedical Grove #04-06, Singapore, 138648, Republic of Singapore.
authors.forename: Rossella
authors.initials: R
authors.lastname: Melchiotti
authors.affiliation: Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), 8A Biomedical Grove #04-06, Singapore, 138648, Republic of Singapore.
authors.forename: Zhuang
authors.initials: Z
authors.lastname: Li
authors.affiliation: Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), 8A Biomedical Grove #04-06, Singapore, 138648, Republic of Singapore.
authors.forename: Nurhashikin
authors.initials: N
authors.lastname: Yusof
authors.affiliation: Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), 8A Biomedical Grove #04-06, Singapore, 138648, Republic of Singapore.
authors.forename: Josephine
authors.initials: J
authors.lastname: Lum
authors.affiliation: Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), 8A Biomedical Grove #04-06, Singapore, 138648, Republic of Singapore.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Koh
authors.affiliation: Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), 8A Biomedical Grove #04-06, Singapore, 138648, Republic of Singapore.
authors.forename: Shihui
authors.initials: S
authors.lastname: Foo
authors.affiliation: Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), 8A Biomedical Grove #04-06, Singapore, 138648, Republic of Singapore.|Department of Pathology, Singapore General Hospital, Singapore, Republic of Singapore.
authors.forename: Joe
authors.initials: J
authors.lastname: Yeong
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
authors.forename: Alexessander Couto
authors.initials: AC
authors.lastname: Alves
authors.affiliation: Department of Environmental Health, National Institute for Health and Welfare, Kuopio, Finland.
authors.forename: Juha
authors.initials: J
authors.lastname: Pekkanen
authors.affiliation: Institute of Dermatology and Department of Dermatology at No.1 Hospital, Anhui Medical University, Hefei, Anhui, China.
authors.forename: Liang Dan
authors.initials: LD
authors.lastname: Sun
authors.affiliation: Genome Institute of Singapore (GIS), Agency for Science, Technology and Research of Singapore (A*STAR), Singapore, Republic of Singapore.
authors.forename: Astrid
authors.initials: A
authors.lastname: Irwanto
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford, UK.|Department of Oncology, Cancer and Haematology Centre, Churchill Hospital, Oxford, UK.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Fairfax
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford, UK.|Department of Oncology, Cancer and Haematology Centre, Churchill Hospital, Oxford, UK.
authors.forename: Vivek
authors.initials: V
authors.lastname: Naranbhai
authors.affiliation: Institute of Medical Biology (IMB), A*STAR (Agency for Science, Technology and Research), Singapore, Republic of Singapore.
authors.forename: John E A
authors.initials: JE
authors.lastname: Common
authors.affiliation: National Skin Center, Singapore, Republic of Singapore.
authors.forename: Mark
authors.initials: M
authors.lastname: Tang
authors.affiliation: Institute of Molecular & Cellular Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, 138648, Republic of Singapore.|Department of Physiology, NUS Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore.
authors.forename: Chin Keh
authors.initials: CK
authors.lastname: Chuang
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.|Center for Life Course Epidemiology, Faculty of Medicine, University of Oulu, P.O. Box 5000, 90014, Oulu, Finland.|Biocenter Oulu, University of Oulu, P.O. Box 5000, Aapistie 5A, 90014, Oulu, Finland.|Unit of Primary Care, Oulu University Hospital, Kajaanintie 50, 90029 OYS, P.O. Box 20, 90220, Oulu, Finland.
authors.forename: Marjo-Riitta
authors.initials: MR
authors.lastname: Jarvelin
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford, UK.
authors.forename: Julian C
authors.initials: JC
authors.lastname: Knight
authors.affiliation: Institute of Dermatology and Department of Dermatology at No.1 Hospital, Anhui Medical University, Hefei, Anhui, China.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Biological Sciences, National University of Singapore, Singapore, Republic of Singapore.
authors.forename: Fook Tim
authors.initials: FT
authors.lastname: Chew
authors.affiliation: Genome Institute of Singapore (GIS), Agency for Science, Technology and Research of Singapore (A*STAR), Singapore, Republic of Singapore.
authors.forename: Shyam
authors.initials: S
authors.lastname: Prabhakar
authors.affiliation: Genome Institute of Singapore (GIS), Agency for Science, Technology and Research of Singapore (A*STAR), Singapore, Republic of Singapore.
authors.forename: Liu
authors.initials: L
authors.lastname: Jianjun
authors.affiliation: Department of Otolaryngology, National University of Singapore, Singapore, Republic of Singapore.|Biological Sciences, National University of Singapore, Singapore, Republic of Singapore.
authors.forename: De Yun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), 8A Biomedical Grove #04-06, Singapore, 138648, Republic of Singapore.
authors.forename: Francesca
authors.initials: F
authors.lastname: Zolezzi
authors.affiliation: Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), 8A Biomedical Grove #04-06, Singapore, 138648, Republic of Singapore.
authors.forename: Michael
authors.initials: M
authors.lastname: Poidinger
authors.affiliation: Institute of Medical Biology (IMB), A*STAR (Agency for Science, Technology and Research), Singapore, Republic of Singapore.
authors.forename: E Birgitte
authors.initials: EB
authors.lastname: Lane
authors.affiliation: Laboratory of Translational Immunology, Department of Immunology, University Medical Center Utrecht, P.O. box 85090, Utrecht, 3508 AB, The Netherlands. L.Meyaard@umcutrecht.nl.
authors.forename: Linde
authors.initials: L
authors.lastname: Meyaard
authors.affiliation: Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), 8A Biomedical Grove #04-06, Singapore, 138648, Republic of Singapore. Olaf_Rotzschke@immunol.a-star.edu.sg.
authors.forename: Olaf
authors.initials: O
authors.lastname: Rötzschke
mesh_terms: D044466:Asian People / Q000235:genetics; D019175:DNA Methylation; D003876:Dermatitis, Atopic / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D009000:Monocytes / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011971:Receptors, Immunologic / Q000235:genetics*; D055815:Young Adult
chemical_list: D011971:Receptors, Immunologic; C550469:VSTM1 protein, human
keywords: Atopic dermatitis; Expression quantitative trait loci (eQTL); Monocytes; Neutrophils; Reactive oxygen species (ROS); Signal inhibitory receptor on leukocytes-1 (SIRL-1); VSTM1