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Risk of childhood asthma is associated with CpG-site polymorphisms, regional DNA methylation and mRNA levels at the GSDMB/ORMDL3 locus

Acevedo, Nathalie; Reinius, Lovisa E; Greco, Dario; Gref, Anna; Orsmark-Pietras, Christina LU ; Persson, Helena LU ; Pershagen, Göran; Hedlin, Gunilla; Melén, Erik and Scheynius, Annika, et al. (2015) In Human Molecular Genetics 24(3). p.90-875
Abstract

Single-nucleotide polymorphisms (SNPs) in GSDMB (Gasdermin B) and ORMDL3 (ORMDL sphingolipid biosynthesis regulator 3) are strongly associated with childhood asthma, but the molecular alterations contributing to disease remain unknown. We investigated the effects of asthma-associated SNPs on DNA methylation and mRNA levels of GSDMB and ORMDL3. Genetic association between GSDMB/ORMDL3 and physician-diagnosed childhood asthma was confirmed in the Swedish birth-cohort BAMSE. CpG-site SNPs (rs7216389 and rs4065275) showed differences in DNA methylation depending on carrier status of the risk alleles, and were significantly associated with methylation levels in two CpG sites in the 5' UTR (untranslated region) of ORMDL3. In the Swedish... (More)

Single-nucleotide polymorphisms (SNPs) in GSDMB (Gasdermin B) and ORMDL3 (ORMDL sphingolipid biosynthesis regulator 3) are strongly associated with childhood asthma, but the molecular alterations contributing to disease remain unknown. We investigated the effects of asthma-associated SNPs on DNA methylation and mRNA levels of GSDMB and ORMDL3. Genetic association between GSDMB/ORMDL3 and physician-diagnosed childhood asthma was confirmed in the Swedish birth-cohort BAMSE. CpG-site SNPs (rs7216389 and rs4065275) showed differences in DNA methylation depending on carrier status of the risk alleles, and were significantly associated with methylation levels in two CpG sites in the 5' UTR (untranslated region) of ORMDL3. In the Swedish Search study, we found significant differences in DNA methylation between asthmatics and controls in five CpG sites; after adjusting for lymphocyte and neutrophil cell counts, three remained significant: one in IKZF3 [IKAROS family zinc finger 3 (Aiolos); cg16293631] and two in the CpG island (CGI) of ORMDL3 (cg02305874 and cg16638648). Also, cg16293631 and cg02305874 correlated with mRNA levels of ORMDL3. The association between methylation and asthma was independent of the genotype in rs7216389, rs4065275 and rs12603332. Both SNPs and CpG sites showed significant associations with ORMDL3 mRNA levels. SNPs influenced expression independently of methylation, and the residual association between methylation and expression was not mediated by these SNPs. We found a differentially methylated region in the CGI shore of ORMDL3 with six CpG sites less methylated in CD8(+) T-cells. In summary, this study supports that there are differences in DNA methylation at this locus between asthmatics and controls; and both SNPs and CpG sites are independently associated with ORMDL3 expression.

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keywords
Adolescent, Asthma, Child, CpG Islands, DNA Methylation, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Ikaros Transcription Factor, Infant, Male, Membrane Proteins, Neoplasm Proteins, Polymorphism, Single Nucleotide, Prospective Studies, RNA, Messenger, Sweden
in
Human Molecular Genetics
volume
24
issue
3
pages
16 pages
publisher
Oxford University Press
external identifiers
  • scopus:84922444776
ISSN
0964-6906
DOI
10.1093/hmg/ddu479
language
English
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no
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8c7bc0fa-ce26-4de4-a3d0-157645748dff
date added to LUP
2016-04-14 14:26:00
date last changed
2017-10-22 05:13:54
@article{8c7bc0fa-ce26-4de4-a3d0-157645748dff,
  abstract     = {<p>Single-nucleotide polymorphisms (SNPs) in GSDMB (Gasdermin B) and ORMDL3 (ORMDL sphingolipid biosynthesis regulator 3) are strongly associated with childhood asthma, but the molecular alterations contributing to disease remain unknown. We investigated the effects of asthma-associated SNPs on DNA methylation and mRNA levels of GSDMB and ORMDL3. Genetic association between GSDMB/ORMDL3 and physician-diagnosed childhood asthma was confirmed in the Swedish birth-cohort BAMSE. CpG-site SNPs (rs7216389 and rs4065275) showed differences in DNA methylation depending on carrier status of the risk alleles, and were significantly associated with methylation levels in two CpG sites in the 5' UTR (untranslated region) of ORMDL3. In the Swedish Search study, we found significant differences in DNA methylation between asthmatics and controls in five CpG sites; after adjusting for lymphocyte and neutrophil cell counts, three remained significant: one in IKZF3 [IKAROS family zinc finger 3 (Aiolos); cg16293631] and two in the CpG island (CGI) of ORMDL3 (cg02305874 and cg16638648). Also, cg16293631 and cg02305874 correlated with mRNA levels of ORMDL3. The association between methylation and asthma was independent of the genotype in rs7216389, rs4065275 and rs12603332. Both SNPs and CpG sites showed significant associations with ORMDL3 mRNA levels. SNPs influenced expression independently of methylation, and the residual association between methylation and expression was not mediated by these SNPs. We found a differentially methylated region in the CGI shore of ORMDL3 with six CpG sites less methylated in CD8(+) T-cells. In summary, this study supports that there are differences in DNA methylation at this locus between asthmatics and controls; and both SNPs and CpG sites are independently associated with ORMDL3 expression.</p>},
  author       = {Acevedo, Nathalie and Reinius, Lovisa E and Greco, Dario and Gref, Anna and Orsmark-Pietras, Christina and Persson, Helena and Pershagen, Göran and Hedlin, Gunilla and Melén, Erik and Scheynius, Annika and Kere, Juha and Söderhäll, Cilla},
  issn         = {0964-6906},
  keyword      = {Adolescent,Asthma,Child,CpG Islands,DNA Methylation,Female,Genetic Association Studies,Genetic Predisposition to Disease,Humans,Ikaros Transcription Factor,Infant,Male,Membrane Proteins,Neoplasm Proteins,Polymorphism, Single Nucleotide,Prospective Studies,RNA, Messenger,Sweden},
  language     = {eng},
  month        = {02},
  number       = {3},
  pages        = {90--875},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  title        = {Risk of childhood asthma is associated with CpG-site polymorphisms, regional DNA methylation and mRNA levels at the GSDMB/ORMDL3 locus},
  url          = {http://dx.doi.org/10.1093/hmg/ddu479},
  volume       = {24},
  year         = {2015},
}