DNA methylation of the filaggrin gene adds to the risk of eczema associated with loss‐of‐function variants. (25th September 2012)

• Record Type: Journal Article
• Authors: Ziyab, A.H.; Karmaus, W.; Holloway, J.W.; Zhang, H; Ewart, S.; Arshad, S.H.
• Is Part Of: Journal of the European Academy of Dermatology and Venereology. Volume 27:Number 3(2013:Mar.)
• Page Start: e420
• Page End: e423
• Publication Date: 2012-09-25
• Subjects: Dermatology -- Periodicals; Sexually transmitted diseases -- Periodicals; 616.5
• DOI: 10.1111/jdv.12000
• Languages: English
• ISSNs: 0926-9959

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p> <bold>Background </bold> Loss‐of‐function variants within the filaggrin gene (<italic>FLG</italic>) 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.</p> <p> <bold>Objectives </bold> To investigate whether genetic variants and adjacent differential DNA methylation within the <italic>FLG</italic> gene synergistically act on the development of eczema.</p> <p> <bold>Methods </bold> A subsample (<italic>n </italic>= 245, only females aged 18 years) of the Isle of Wight birth cohort participants (<italic>n </italic>= 1456) had available information for <italic>FLG</italic> variants R501X, 2282del4 and S3247X and DNA methylation levels for 10 CpG sites within the <italic>FLG</italic> gene. Log‐binomial regression was used to estimate the risk ratios (RRs) of eczema associated with <italic>FLG</italic> variants at different methylation levels.</p> <p> <bold>Results </bold> The period prevalence of eczema was 15.2% at age 18 years and 9.0% of participants were carriers (heterozygous) of <italic>FLG</italic> variants. Of the 10 CpG sites spanning the genomic region of <italic>FLG</italic>, methylation levels of CpG site 'cg07548383' showed a significant interaction with <italic>FLG</italic> 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 <italic>FLG</italic> genotype (<italic>P</italic>‐value = 0.0008).</p> <p> <bold>Conclusions </bold> Our novel results indicated that the association between <italic>FLG</italic> loss‐of‐function variants and eczema is modulated by DNA methylation. Simultaneously assessing the joint effect of genetic and epigenetic factors within the <italic>FLG</italic> gene further highlights the importance of this genomic region for eczema manifestation.</p> </abstract>