Highlights
- •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.
Abstract
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.
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)Keywords
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References
- Is the prevalence of psoriasis increasing? A 30-year follow-up of a population-based cohort.Br. J. Dermatol. 2013; 168: 1303-1310
- Pathogenesis and therapy of psoriasis.Nature. 2007; 445: 866-873
- A subset of methylated CpG sites differentiate psoriatic from normal skin.J. Invest. Dermatol. 2012; 132: 583-592
- Whole-genome DNA methylation in skin lesions from patients with psoriasis vulgaris.J. Autoimmun. 2013; 41: 17-24
- Epigenome-wide association analysis identified nine skin DNA methylation loci for psoriasis.J. Invest. Dermatol. 2016; 136: 779-787
- Intragenic DNA methylation modulates alternative splicing by recruiting MeCP2 to promote exon recognition.Cell Res. 2013; 23: 1256-1269
- A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.Nat. Genet. 2010; 42: 985-990
- HLA-Cw6 and psoriasis.Br. J. Dermatol. 2018; 178: 854-862
- Psoriasis patients who are homozygous for the HLA-Cw*0602 allele have a 2.5-fold increased risk of developing psoriasis compared with Cw6 heterozygotes.Br. J. Dermatol. 2003; 148: 233-235
- Distinct clinical differences between HLA-Cw*0602 positive and negative psoriasis patients--an analysis of 1019 HLA-C- and HLA-B-typed patients.J. Invest. Dermatol. 2006; 126: 740-745
- Childhood psoriasis: a study of 277 patients from China.J. Eur. Acad. Dermatol. Venereol. 2007; 21: 762-765
- Age at disease onset: a key factor for understanding psoriatic disease.Rheumatology (Oxford). 2014; 53: 1178-1185
- Combined effects of HLA-Cw6 and cigarette smoking in psoriasis vulgaris: a hospital-based case-control study in China.J. Eur. Acad. Dermatol. Venereol. 2009; 23: 132-137
- HLA-C and guttate psoriasis.Br. J. Dermatol. 2000; 143: 1177-1182
- Comparison of clinical features of HLA-Cw*0602-positive and -negative psoriasis patients in a han Chinese population.Acta Derm. Venereol. 2007; 87: 335-340
- Desired response to phototherapy vs photoaggravation in psoriasis: what makes the difference?.Exp. Dermatol. 2016; 25: 937-944
- Tumour necrosis factor-alpha polymorphism and the HLA-Cw*0602 allele in psoriatic arthritis.Rheumatology (Oxford). 2002; 41: 525-530
- Observations of psoriasis in the absence of therapeutic intervention identifies two unappreciated morphologic variants, thin-plaque and thick-plaque psoriasis, and their associated phenotypes.J. Invest. Dermatol. 2006; 126: 2397-2403
- The HLA-C*06 allele as a possible genetic predisposing factor to psoriasis in South Indian tamils.Arch. Dermatol. Res. 2016; 308: 193-199
- The association of HLA-class I genes and the extent of atherosclerotic plaques in patients with psoriatic disease.J. Rheumatol. 2016; 43: 1844-1851
- HLA-Cw6-positive patients with psoriasis show improved response to methotrexate treatment.Clin. Exp. Dermatol. 2017; 42: 651-655
- HLA-C*06 and response to ustekinumab in caucasian patients with psoriasis: outcome and long-term follow-up.J. Am. Acad. Dermatol. 2016; 74: 374-375
- The power of NGS technologies to delineate the genome organization in cancer: from mutations to structural variations and epigenetic alterations.Cancer Metastasis Rev. 2011; 30: 199-210
- DNA methylation, genotype and gene expression: who is driving and who is along for the ride?.Genome Biol. 2013; 14: 126
- Epigenome-wide association data implicates DNA methylation-mediated genetic risk in psoriasis.Clin Epigenetics. 2016; 8: 131
- DNA methylation profiling of the human major histocompatibility complex: a pilot study for the human epigenome project.PLoS Biol. 2004; 2: e405
- Epigenetic mechanisms regulate MHC and antigen processing molecules in human embryonic and induced pluripotent stem cells.PLoS One. 2010; 5e10192
- Epigenetic changes within the promoter regions of antigen processing machinery family genes in Kazakh primary esophageal squamous cell carcinoma.Asian Pac J Cancer Prev. 2014; 15: 10299-10306
- Deep sequencing of the MHC region in the Chinese population contributes to studies of complex disease.Nat. Genet. 2016; 48: 740-746
- Integrative analyses reveal biological pathways and key genes in psoriasis.Br. J. Dermatol. 2017; 177: 1349-1357
- Imputing amino acid polymorphisms in human leukocyte antigens.PLoS One. 2013; 8e64683
- Overexpression of kruppel-like factor 7 regulates adipocytokine gene expressions in human adipocytes and inhibits glucose-induced insulin secretion in pancreatic beta-cell line.Mol. Endocrinol. 2006; 20: 844-856
- Mammalian kruppel-like factors in health and diseases.Physiol. Rev. 2010; 90: 1337-1381
- PPARdelta enhances keratinocyte proliferation in psoriasis and induces heparin-binding EGF-like growth factor.J. Invest. Dermatol. 2008; 128: 110-124
- Global gene expression analysis reveals evidence for decreased lipid biosynthesis and increased innate immunity in uninvolved psoriatic skin.J. Invest. Dermatol. 2009; 129: 2795-2804
- Integrative methylome and transcriptome analysis to dissect key biological pathways for psoriasis in Chinese han population.J. Dermatol. Sci. 2018; 91: 285-291
- KLF7 regulates satellite cell quiescence in response to extracellular signaling.Stem Cells. 2016; 34: 1310-1320
- The role of kruppel-like factor 4 in transforming growth factor-beta-induced inflammatory and fibrotic responses in human proximal tubule cells.Clin. Exp. Pharmacol. Physiol. 2015; 42: 680-686
- Induction and effector functions of T(H)17 cells.Nature. 2008; 453: 1051-1057
- TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function.Nature. 2008; 453: 236-240
- Phosphatidylinositol-4-phosphate 5-kinase 1alpha mediates extracellular calcium-induced keratinocyte differentiation.Mol. Biol. Cell. 2009; 20: 1695-1704
- Interrogating the protein interactomes of RAS isoforms identifies PIP5K1A as a KRAS-specific vulnerability.Nat. Commun. 2018; 9: 3646
- Molecular cloning and characterization of a novel human BTB domain-containing gene, BTBD10, which is down-regulated in glioma.Gene. 2004; 340: 61-69
- Glucose metabolism-related protein 1 (GMRP1) regulates pancreatic beta cell proliferation and apoptosis via activation of akt signalling pathway in rats and mice.Diabetologia. 2011; 54: 852-863
- Involvement of GMRP1, a novel mediator of akt pathway, in brain damage after intracerebral hemorrhage.Int J Clin Exp Pathol. 2013; 6: 224-229
- Reduced expression of BTBD10 in anterior horn cells with golgi fragmentation and pTDP-43-positive inclusions in patients with sporadic amyotrophic lateral sclerosis.Neuropathology. 2013; 33: 397-404
- DNA methylation age is not affected in psoriatic skin tissue.Clin Epigenetics. 2018; 10: 160
- Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis.Nat. Biotechnol. 2013; 31: 142-147
- Combined single-cell profiling of expression and DNA methylation reveals splicing regulation and heterogeneity.Genome Biol. 2019; 20
- CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing.Nature. 2011; 479: 74-U99
Article info
Publication history
Published online: May 31, 2020
Accepted:
May 12,
2020
Received in revised form:
May 7,
2020
Received:
January 11,
2020
Identification
Copyright
© 2020 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.
