Original ArticleGenomic DNA methylation in HLA-Cw*0602 carriers and non-carriers of psoriasis
Introduction
Psoriasis (Ps) is a chronic immune-mediated skin disorder with a strong and albeit polygenic genetic basis affecting 0.09%–11.4% population worldwide [1], making it a serious global problem. The clinical manifestation, areas of skin lesions and response to the treatment in Ps patients may vary greatly due to the complex interactions between genetics, environmental factors and immune pathways [2]. Increasing evidence have clearly suggested that epigenetic mechanisms, specifically the methylation of cytosine residue at CpG dinucleotides, contributed to the development of Ps [[3], [4], [5]], mainly due to the effect of DNA methylation (DNAm) on the transcriptional regulation and the control of promoter / exon usage and alternative splicing [6].
Histocompatibility leukocyte antigens (HLA) is one of the most important regions for almost all immune-related diseases, including Ps [7]. The HLA-associated susceptibility to diseases varies according to the allele or haplotype carried by the person, for example, the HLA-Cw6, with a percentage ranging from 10.5%–77.2% in Ps patients [8]. What’s more, it is reported that people with homozygous allele of HLA-Cw*0602 have more than 2.5 times potential to get Ps than with heterozygous allele [9]. The presence of HLA-Cw*0602 has been shown to affect different aspects of Ps, ranging from genetic susceptibility, clinical manifestation, comorbidity, and treatment efficacy. Multiple studies have proven HLA-Cw*0602 allele to be strongly associated with early-onset Ps [10,11], positive family history [12], more frequent remissions during pregnancy [10], and development of Ps in individuals with smoking and stressful life [13]. Ps is a heterogeneous disease with distinct phenotypes. In addition to the chronic plaque type, the associations of guttate Ps [14,15], photosensitive Ps [16], palmoplantar pustulosis [15] and psoriatic arthritis [17] with HLA-Cw*0602 have also been identified in several studies. The clinical morphology and severity of Ps may be predetermined genetically [18]. HLA-Cw*0602 carriers were shown to have more extensive plaques on their arms, leg and trunk, and have a significantly higher incidence of the Koebner phenomenon [11,15,19]. Ps patients with HLA-Cw*0602 allele had higher levels of erythrocyte sedimentation rate over time and were more likely to suffer from more severe atherosclerosis [20]. Besides the clinical features, HLA-Cw*0602 genotype status has also been linked to the treatment effect, such as the response to methotrexate [21], and biologics like ustekinumab [22]. However, HLA-Cw*0602-negative patients were reported to exhibit higher treatment-limiting adverse events [21].
Several lines of evidences supported the notion that genetic sequence variations like polymorphisms or mutations can not only be linked with the change of function in a gene, but also determine the gene's methylation state in human tissues and cultured cells [[23], [24], [25]]. For example, changes in HLA-Ⅰ gene expression induced by epigenetic changes were observed in normal cells and multiple tumors [[26], [27], [28]]. In Ps patients, Zhou et al. revealed that DNAm of several genes can be controlled by genetic factors and also mediate risk variation for Ps in Chinese Han population [25]. Although HLA-Cw*0602 has long been established as one of the most important genetic biomarkers in Ps, to our knowledge, the epigenetic and gene expression differences between HLA-Cw*0602 carriers and non-carriers has not yet been investigated, resulting in limited progress in Ps associations of the methylation in the major histocompatibility complex (MHC) region. To this end, we speculated that different epigenetic background existed in HLA-Cw*0602 carriers and non-carriers of Ps patients, and divided them into positive and negative group depending on the HLA-Cw*0602 genotype status. We aimed to investigate the epigenetic changes utilizing the genome-wide methylation data of psoriatic skin (N = 114) and whole-genome genotyping with peripheral blood of the same samples based on a HLA imputation method with our newly built Han-MHC reference panel [29], and to search the methylation markers that potentially mediate genetic risk for Ps.
Section snippets
Study samples
Skin tissues from 114 psoriasis vulgaris were collected from the Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Anhui Province, China. The blood-derived genotype data came from the same patients. The features of samples were previously described elsewhere [5].Written informed consent were obtained from all the subjects under an Anhui Medical University approved protocol (Number: 2,015,007). The study was performed according to the Declaration of Helsinki
HLA imputation and HLA-Cw*0602 genotyping
We previously performed genotyping for all enrolled samples, which includes 8985 variants in the HLA region. For the strong linkage disequilibrium, these variants are informative on predicting HLA-Cw*0602 alleles. Our group have constructed a high accurate Han-MHC reference panel including both variants and HLA gene typing results. Based on this panel, we performed imputation with SNP2HLA computational strategy [31], and got 29,948 variants in the HLA region. After quality control, we
Discussion
MHC I molecules are present on almost all nucleated cells and are key molecules for immune surveillance, since they present intracellular peptides (both self and non-self peptides) to the immune system, which are also critical for CD8+ T-cells priming and subsequent cytolytic targeting of cells. However, the mechanisms through which this allele increases the risk of Ps remain poorly understood. In this study, we innovatively conducted an epigenetic background survey between HLA-Cw*0602 carriers
Declaration of Competing Interest
The authors have no conflict of interest to declare.
Acknowledgements
We are most grateful to all the participants for participating in this study. This work was supported by the Scientific Research of BSKY of Anhui Medical University (XJ201634), the Key Program of Outstanding Talents support of Anhui province (gxyqZD2017028) and the National Innovation and Entrepreneurship Training Program for College Students (201910366011).
References (50)
- et al.
A subset of methylated CpG sites differentiate psoriatic from normal skin
J. Invest. Dermatol.
(2012) - et al.
Whole-genome DNA methylation in skin lesions from patients with psoriasis vulgaris
J. Autoimmun.
(2013) - et al.
Epigenome-wide association analysis identified nine skin DNA methylation loci for psoriasis
J. Invest. Dermatol.
(2016) - et al.
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) - et al.
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) - et al.
HLA-C*06 and response to ustekinumab in caucasian patients with psoriasis: outcome and long-term follow-up
J. Am. Acad. Dermatol.
(2016) - et al.
PPARdelta enhances keratinocyte proliferation in psoriasis and induces heparin-binding EGF-like growth factor
J. Invest. Dermatol.
(2008) - et al.
Global gene expression analysis reveals evidence for decreased lipid biosynthesis and increased innate immunity in uninvolved psoriatic skin
J. Invest. Dermatol.
(2009) - et al.
Integrative methylome and transcriptome analysis to dissect key biological pathways for psoriasis in Chinese han population
J. Dermatol. Sci.
(2018) - et al.
Molecular cloning and characterization of a novel human BTB domain-containing gene, BTBD10, which is down-regulated in glioma
Gene
(2004)
Is the prevalence of psoriasis increasing? A 30-year follow-up of a population-based cohort
Br. J. Dermatol.
Pathogenesis and therapy of psoriasis
Nature
Intragenic DNA methylation modulates alternative splicing by recruiting MeCP2 to promote exon recognition
Cell Res.
A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1
Nat. Genet.
HLA-Cw6 and psoriasis
Br. J. Dermatol.
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.
Childhood psoriasis: a study of 277 patients from China
J. Eur. Acad. Dermatol. Venereol.
Age at disease onset: a key factor for understanding psoriatic disease
Rheumatology (Oxford)
Combined effects of HLA-Cw6 and cigarette smoking in psoriasis vulgaris: a hospital-based case-control study in China
J. Eur. Acad. Dermatol. Venereol.
HLA-C and guttate psoriasis
Br. J. Dermatol.
Comparison of clinical features of HLA-Cw*0602-positive and -negative psoriasis patients in a han Chinese population
Acta Derm. Venereol.
Desired response to phototherapy vs photoaggravation in psoriasis: what makes the difference?
Exp. Dermatol.
Tumour necrosis factor-alpha polymorphism and the HLA-Cw*0602 allele in psoriatic arthritis
Rheumatology (Oxford)
The HLA-C*06 allele as a possible genetic predisposing factor to psoriasis in South Indian tamils
Arch. Dermatol. Res.
The association of HLA-class I genes and the extent of atherosclerotic plaques in patients with psoriatic disease
J. Rheumatol.
Cited by (0)
- 1
These authors contribute equally to this article.