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

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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; Persson, Helena; Pershagen, Göran; Hedlin, Gunilla; Melén, Erik; Scheynius, Annika; Kere, Juha; Söderhäll, Cilla.

In: Human Molecular Genetics, Vol. 24, No. 3, 01.02.2015, p. 875-90.

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Acevedo, N, Reinius, LE, Greco, D, Gref, A, Orsmark-Pietras, C, Persson, H, Pershagen, G, Hedlin, G, Melén, E, Scheynius, A, Kere, J & Söderhäll, C 2015, 'Risk of childhood asthma is associated with CpG-site polymorphisms, regional DNA methylation and mRNA levels at the GSDMB/ORMDL3 locus', Human Molecular Genetics, vol. 24, no. 3, pp. 875-90. https://doi.org/10.1093/hmg/ddu479

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Acevedo, Nathalie ; Reinius, Lovisa E ; Greco, Dario ; Gref, Anna ; Orsmark-Pietras, Christina ; Persson, Helena ; Pershagen, Göran ; Hedlin, Gunilla ; Melén, Erik ; Scheynius, Annika ; Kere, Juha ; Söderhäll, Cilla. / Risk of childhood asthma is associated with CpG-site polymorphisms, regional DNA methylation and mRNA levels at the GSDMB/ORMDL3 locus. In: Human Molecular Genetics. 2015 ; Vol. 24, No. 3. pp. 875-90.

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TY - JOUR

T1 - Risk of childhood asthma is associated with CpG-site polymorphisms, regional DNA methylation and mRNA levels at the GSDMB/ORMDL3 locus

AU - Acevedo, Nathalie

AU - Reinius, Lovisa E

AU - Greco, Dario

AU - Gref, Anna

AU - Orsmark-Pietras, Christina

AU - Persson, Helena

AU - Pershagen, Göran

AU - Hedlin, Gunilla

AU - Melén, Erik

AU - Scheynius, Annika

AU - Kere, Juha

AU - Söderhäll, Cilla

N1 - © The Author 2014. Published by Oxford University Press.

PY - 2015/2/1

Y1 - 2015/2/1

N2 - 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.

AB - 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.

KW - Adolescent

KW - Asthma

KW - Child

KW - CpG Islands

KW - DNA Methylation

KW - Female

KW - Genetic Association Studies

KW - Genetic Predisposition to Disease

KW - Humans

KW - Ikaros Transcription Factor

KW - Infant

KW - Male

KW - Membrane Proteins

KW - Neoplasm Proteins

KW - Polymorphism, Single Nucleotide

KW - Prospective Studies

KW - RNA, Messenger

KW - Sweden

U2 - 10.1093/hmg/ddu479

DO - 10.1093/hmg/ddu479

M3 - Article

VL - 24

SP - 875

EP - 890

JO - Human Molecular Genetics

T2 - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 3

ER -