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

https://doi.org/10.1016/j.jdermsci.2020.05.006Get rights and content

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.

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)

  • K. Danielsen et al.

    Is the prevalence of psoriasis increasing? A 30-year follow-up of a population-based cohort

    Br. J. Dermatol.

    (2013)
  • M.A. Lowes et al.

    Pathogenesis and therapy of psoriasis

    Nature

    (2007)
  • A.K. Maunakea et al.

    Intragenic DNA methylation modulates alternative splicing by recruiting MeCP2 to promote exon recognition

    Cell Res.

    (2013)
  • C. Genetic et al.

    A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1

    Nat. Genet.

    (2010)
  • L. Chen et al.

    HLA-Cw6 and psoriasis

    Br. J. Dermatol.

    (2018)
  • J.E. Gudjonsson et al.

    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)
  • X. Fan et al.

    Childhood psoriasis: a study of 277 patients from China

    J. Eur. Acad. Dermatol. Venereol.

    (2007)
  • R. Queiro et al.

    Age at disease onset: a key factor for understanding psoriatic disease

    Rheumatology (Oxford)

    (2014)
  • Y. Jin et al.

    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)
  • E. Mallon et al.

    HLA-C and guttate psoriasis

    Br. J. Dermatol.

    (2000)
  • X. Fan et al.

    Comparison of clinical features of HLA-Cw*0602-positive and -negative psoriasis patients in a han Chinese population

    Acta Derm. Venereol.

    (2007)
  • P. Wolf et al.

    Desired response to phototherapy vs photoaggravation in psoriasis: what makes the difference?

    Exp. Dermatol.

    (2016)
  • A.M. Al-Heresh et al.

    Tumour necrosis factor-alpha polymorphism and the HLA-Cw*0602 allele in psoriatic arthritis

    Rheumatology (Oxford)

    (2002)
  • S. Indhumathi et al.

    The HLA-C*06 allele as a possible genetic predisposing factor to psoriasis in South Indian tamils

    Arch. Dermatol. Res.

    (2016)
  • L. Eder et al.

    The association of HLA-class I genes and the extent of atherosclerotic plaques in patients with psoriatic disease

    J. Rheumatol.

    (2016)
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