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DNA methylation of the filaggrin gene adds to the risk of eczema associated with loss-of-function variants

DNA methylation of the filaggrin gene adds to the risk of eczema associated with loss-of-function variants
DNA methylation of the filaggrin gene adds to the risk of eczema associated with loss-of-function variants
Background
Loss-of-function variants within the filaggrin gene (FLG) are associated with a dysfunctional skin barrier that contributes to the development of eczema. Epigenetic modifications, such as DNA methylation, are genetic regulatory mechanisms that modulate gene expression without changing the DNA sequence. Objectives? To investigate whether genetic variants and adjacent differential DNA methylation within the FLG gene synergistically act on the development of eczema.

Methods
A subsample (n?=?245, only females aged 18?years) of the Isle of Wight birth cohort participants (n?=?1456) had available information for FLG variants R501X, 2282del4 and S3247X and DNA methylation levels for 10 CpG sites within the FLG gene. Log-binomial regression was used to estimate the risk ratios (RRs) of eczema associated with FLG variants at different methylation levels.

Results
The period prevalence of eczema was 15.2% at age 18?years and 9.0% of participants were carriers (heterozygous) of FLG variants. Of the 10 CpG sites spanning the genomic region of FLG, methylation levels of CpG site 'cg07548383' showed a significant interaction with FLG sequence variants on the risk for eczema. At 86% methylation level, filaggrin haploinsufficient individuals had a 5.48-fold increased risk of eczema when compared to those with wild type FLG genotype (P-value?=?0.0008).

Conclusions
Our novel results indicated that the association between FLG loss-of-function variants and eczema is modulated by DNA methylation. Simultaneously assessing the joint effect of genetic and epigenetic factors within the FLG gene further highlights the importance of this genomic region for eczema manifestation.
0926-9959
e420-e423
Ziyab, A.H.
288d35a2-e782-49f8-b2e8-fdb0290a7c00
Karmaus, W.
d78616d6-bc9c-4664-a461-7c0d0be5e39e
Holloway, J.W.
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Zhang, H
c2a38ed5-39f1-4c00-beaf-9d80d9512cb3
Ewart, S.
9da730b1-7e8a-4889-8dc5-2703de288a34
Arshad, S.H.
917e246d-2e60-472f-8d30-94b01ef28958
Ziyab, A.H.
288d35a2-e782-49f8-b2e8-fdb0290a7c00
Karmaus, W.
d78616d6-bc9c-4664-a461-7c0d0be5e39e
Holloway, J.W.
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Zhang, H
c2a38ed5-39f1-4c00-beaf-9d80d9512cb3
Ewart, S.
9da730b1-7e8a-4889-8dc5-2703de288a34
Arshad, S.H.
917e246d-2e60-472f-8d30-94b01ef28958

Ziyab, A.H., Karmaus, W., Holloway, J.W., Zhang, H, Ewart, S. and Arshad, S.H. (2013) DNA methylation of the filaggrin gene adds to the risk of eczema associated with loss-of-function variants. Journal of the European Academy of Dermatology and Venereology, 27 (3), e420-e423. (doi:10.1111/jdv.12000). (PMID:23003573)

Record type: Article

Abstract

Background
Loss-of-function variants within the filaggrin gene (FLG) are associated with a dysfunctional skin barrier that contributes to the development of eczema. Epigenetic modifications, such as DNA methylation, are genetic regulatory mechanisms that modulate gene expression without changing the DNA sequence. Objectives? To investigate whether genetic variants and adjacent differential DNA methylation within the FLG gene synergistically act on the development of eczema.

Methods
A subsample (n?=?245, only females aged 18?years) of the Isle of Wight birth cohort participants (n?=?1456) had available information for FLG variants R501X, 2282del4 and S3247X and DNA methylation levels for 10 CpG sites within the FLG gene. Log-binomial regression was used to estimate the risk ratios (RRs) of eczema associated with FLG variants at different methylation levels.

Results
The period prevalence of eczema was 15.2% at age 18?years and 9.0% of participants were carriers (heterozygous) of FLG variants. Of the 10 CpG sites spanning the genomic region of FLG, methylation levels of CpG site 'cg07548383' showed a significant interaction with FLG sequence variants on the risk for eczema. At 86% methylation level, filaggrin haploinsufficient individuals had a 5.48-fold increased risk of eczema when compared to those with wild type FLG genotype (P-value?=?0.0008).

Conclusions
Our novel results indicated that the association between FLG loss-of-function variants and eczema is modulated by DNA methylation. Simultaneously assessing the joint effect of genetic and epigenetic factors within the FLG gene further highlights the importance of this genomic region for eczema manifestation.

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More information

Published date: March 2013
Organisations: Human Development & Health, Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 343258
URI: http://eprints.soton.ac.uk/id/eprint/343258
ISSN: 0926-9959
PURE UUID: 59efa3e5-34d4-4c94-984a-65337881bbab
ORCID for J.W. Holloway: ORCID iD orcid.org/0000-0001-9998-0464

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Date deposited: 02 Oct 2012 10:48
Last modified: 28 Apr 2022 01:42

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Contributors

Author: A.H. Ziyab
Author: W. Karmaus
Author: J.W. Holloway ORCID iD
Author: H Zhang
Author: S. Ewart
Author: S.H. Arshad

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