Epigenome-wide association data implicates DNA methylation-mediated genetic risk in psoriasis

Abstract

BackgroundPsoriasis is a chronic inflammatory skin disease characterized by epidermal hyperproliferation and altered keratinocyte differentiation and inflammation and is caused by the interplay of genetic and environmental factors. Previous studies have revealed that DNA methylation (DNAm) and genetic makers are closely associated with psoriasis, and strong evidences have shown that DNAm can be controlled by genetic factors, which attracted us to evaluate the relationship among DNAm, genetic makers, and disease status.MethodsWe utilized the genome-wide methylation data of psoriatic skin (PP, N = 114) and unaffected control skin (NN, N = 62) tissue samples in our previous study, and we performed whole-genome genotyping with peripheral blood of the same samples to evaluate the underlying genetic effect on skin DNA methylation. Causal inference test (CIT) was used to assess whether DNAm regulate genetic variation and gain a better understanding of the epigenetic basis of psoriasis susceptibility.ResultsWe identified 129 SNP-CpG pairs achieving the significant association threshold, which constituted 28 unique methylation quantitative trait loci (MethQTL) and 34 unique CpGs. There are 18 SNPs were associated with psoriasis at a Bonferoni-corrected P < 0.05, and these 18 SNPs formed 93 SNP-CpG pairs with 17 unique CpG sites. We found that 11 of 93 SNP-CpG pairs, composed of 5 unique SNPs and 3 CpG sites, presented a methylation-mediated relationship between SNPs and psoriasis. The 3 CpG sites were located on the body of C1orf106, the TSS1500 promoter region of DMBX1 and the body of SIK3.ConclusionsThis study revealed that DNAm of some genes can be controlled by genetic factors and also mediate risk variation for psoriasis in Chinese Han population and provided novel molecular insights into the pathogenesis of psoriasis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0297-z) contains supplementary material, which is available to authorized users.

Best practices in DNA methylation: lessons from inflammatory bowel disease, psoriasis and ankylosing spondylitis

“…As expected, the differentially methylated genes identified in the skin are mostly associated with epidermal and keratinocyte differentiation, and cellular regeneration [39, 74–76]. Four skin biopsy-based studies identified members of the S100A family, part of the epidermal differentiation complex, as top differentially methylated hits [39, 40, 75–78]. Many studies have failed to identify differences in skin biopsies in affected non-inflamed skin compared to healthy controls [39, 75, 76].…”

“…IL13 , ALOX5AP , PTHLH and TNFSF11 ) [38, 70, 75, 76]). This was observed in Zhou et al (2017) where 3 unique CpG sites were identified with 11 associated SNP-CpG pairs within C1orf106 , DMBX1 and SIK3 [39, 40, 64]. C1orf106 regulates adherence junction stability, although the key gene at this locus remains unclear [79].…”

“…When combined with gene expression data, cell-specific differences were identified, including IL13, ALOX5AP, PTHLH and TNFSF11.Zhou (1) [39]CC114 psoriasis patients62 HCSkin biopsies PP and PNIllumina Methylation 450K BeadChip; Sequenom Epityper system129 SNP-CpG pairs achieved statistical significance between psoriatic and healthy control peripheral blood, constituting 28 unique meQTLs and 34 unique CpGs. 11 SNP-CpG pairs passed CIT constituting 3 unique CpG sites within C1orf106, DMBX1 and SIK3.Zhou (2) [40]CC114 Psoriasis patients (41 PP+PN)62 HCskin biopsies; Previous methylation dataIllumina Methylation 450K BeadChip1514 DMP were identified between PP and PN, only 426 DMP were identified between PP and PN, and none between PN and NN. During replication, 9 sites reached significance ( CYP2S1 , ECE1 , EIF2C2 , MAN1C1 , DLGAP4 , S100A9 , S100A7A and S100A5 ), but none replicated in PBMCs.Pollock [41]CC23 psoriasis patients without PsA; 13 PsA individuals18 HCSpermIllumina Infinium Human Methylation 450K BeadChip2467 DMP identified between PsA and healthy controls, compared to 574 DMP between psoriasis and controls.…”

Overview of the molecular determinants contributing to the expression of Psoriasis and Psoriatic Arthritis phenotypes

“…Concerning the contribution of DNA methylation to Ps or PsA, deregulation of the global methylation pattern has been found in psoriatic lesions 83‐85 . In particular, the promoting region of Epidermal Differentiation Complex ( EDC locus, 1q21.3) genes has been found hypomethylated.…”

In silico analysis of CpG islands and miRNAs potentially regulating the JAK-STAT signalling pathway

“…It seems that new methods to suppress the JAK-STAT pathway could involve the use of epigenetic mechanisms of the expression of genes connected with the said pathway. The epigenetic strategies were described as a new possibility to treat, for instance, cancers [ 14 , 15 ], mental diseases [ 16 ] and psoriasis [ 17 , 18 ].…”