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Deep intronic 9q21.11 polymorphism contributes to atopic dermatitis risk through methylation regulated expression of tight junction protein 2

Eliza Lim YY1, Yie Sio Y1, Say YH1,2,3†, Reginald K3, Tim Chew F1

1Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore
2Department of Biomedical Science, Faculty of Science, Universiti Tunku Abdul Rahman (UTAR) Kampar Campus, Kampar, Perak, Malaysia
3Department of Biological Sciences, School of Medical and Life Sciences, Sunway University, Malaysia

J Investig Allergol Clin Immunol 2025; Vol. 35(3)
doi: 10.18176/jiaci.0978

Background: Atopic dermatitis (AD) is a chronic inflammatory itchy skin condition. Genomic- and epigenetic wide association studies provide insights into the genetic susceptibility and potential underlying disease pathogenesis.
Objectives: This study sought to functionally characterise an AD-associated single nucleotide polymorphism (SNP) located deep intronic of the tight junction protein 2 (TJP2) gene (9q21.11 locus), identified through a genome-wide association study (GWAS).
Methods: The association between the 9q21.11 locus (rs7872806) and AD was identified through a GWAS of 956 cases and 723 controls. TJP2 expression in peripheral blood mononuclear cells (PBMCs) was assessed against the rs7872806 genotypes. Allele-specific methylation was evaluated at CpG sites 10kb up- and down-stream of the 9q21.11 locus. Effects of DNA methylation on TJP2 expression was validated via in vitro methylation and 5-aza-2’-deoxycytidine-induced transcriptional activation studies. Trans-epidermal water loss measurements were used to determine skin barrier function.
Results: The major allele of rs7872806 was determined to increase AD risk by 2.64-fold (adjusted p-value=2.40 x 10-18, OR=0.38), associated with increased methylation levels at cg13920460 site (p<0.001) and lower TJP2 expression in PBMCs (Pearson’s p=1.09 x 10-6, Pearson’s R=-0.313, p<0.001). Methylation inhibition by 5-aza-2’-deoxycytidine increased TJP2 promoter activity by up to 85%. Elimination of the cg13920460 methylation site increased expression by approximately 25%. The rs7872806 major allele was also found to be associated with increased trans-epidermal water loss (p<0.001).
Conclusion: Epigenetic influence at CpG site cg13920460 is associated with rs7872806 located deep intronic at 9q21.11. The SNP confers susceptibility to AD through altering TJP2 expression and promoting trans-epidermal water loss.

Key words: Atopic dermatitis, Genome-wide association studies, Epigenetics, Methylation, Expression quantitative trait loci, Tight junction protein, Transepidermal water loss, Epidermal hyperplasia