- •HLA-Cw*0602 is an important genetic biomarker in psoriasis (Ps).
- •Epigenetic changes, specifically the methylation contributed to the development of Ps.
- •Key methylation sites contributed to the carrying status of HLA-Cw*0602 were evaluated.
- •Methylation loci in gene body and CGI may affect the methylation levels in HLA-Cw*0602 carriers.
HLA-Cw*0602 has long been established as one of the most important genetic biomarkers in psoriasis. However, the epigenetic and gene expression differences between HLA-Cw*0602 carriers and non-carriers has not yet been investigated.
We aim to explore the whole-genome methylation and gene expression differences between HLA-Cw*0602 carriers and non-carriers.
HLA imputation was performed to get landscape of variants in this region. Genome-wide DNA methylation was compared between positive and negative HLA-Cw*0602 groups. Eleven methylation loci were selected for further validation in additional 43 cases. For differentially methylated genes, GO and KEGG were used to annotate gene functions.
We imputed 29,948 variants based on the constructed HLA reference panels, and obtained 42 HLA-Cw*0602 carriers and 72 non-carriers. Significant methylation differences were detected at 4321 sites (811 hypo- and 3510 hypermethylated). The cg02607779 (KLF7, P = 0.001), cg06936779 (PIP5K1A, P = 0.002), cg03860400 (BTBD10, P = 0.017) and cg26112390 (GOLGA2P5, P = 0.019) were identified and validated to be the significant CpGs contributed to different HLA-C*0602 groups. Among the hypo- and hypermethylated sites, the top CpGs were in gene body and CpG island.
We performed the first whole-genome study on methylation differences between psoriatic individuals with or without HLA-Cw*0602, and found the key methylation sites which may contribute to the carrying status of HLA-Cw*0602. Methylation loci located in gene body and CpG island are more likely to affect the methylation levels in HLA-Cw*0602 carriers. This integrated analysis shed light on novel insights into the pathogenic mechanisms of genomic methylation in different HLA genotypes of psoriasis.
Abbreviations:Ps (psoriasis), DNAm (DNA methylation), HLA (histocompatibility leukocyte antigens), MHC (major histocompatibility complex), MAF (minor allele frequency), HWE (Hardy-Weinberg equilibrium), BS-seq (Bisulfite Sequencing), NCBI (National Center for Biotechnology Information), FDR (false-discovery rate), DMSs (differentially methylated sites), IGR (intergenic region), CGI (CpG island), KLF7 (Krüppel-like factor 7), KLFs (Krüppel-like transcription factors), BTBD10 (BTB/POZ domain-containing protein 10), GMRP1 (glucose metabolism-related protein 1)
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Published online: May 31, 2020
Accepted: May 12, 2020
Received in revised form: May 7, 2020
Received: January 11, 2020
© 2020 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.