Genomic DNA methylation in HLA-Cw*0602 carriers and non-carriers of psoriasis

Background: 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.

Objective: We aim to explore the whole-genome methylation and gene expression differences between HLA-Cw*0602 carriers and non-carriers.

Methods: 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.

Results: 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.

Conclusion: 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.