Introduction
Ankylosing spondylitis (AS) is a common chronic rheumatic arthritis, characterized with progressive bone proliferation of axial skeleton and sacroiliac joints. The exactly pathogenesis of AS is still obscure now, but studies indicated that gene and environmental interaction plays roles in the development and progression of AS (1, 2). Twins and family based studies estimated the heritability of AS is about 90% (2-4). The human leukocyte antigen (HLA)-B27, which is encoded in class 1 major histocompatibility complex region, is the strongest risk factor of AS (4). Recent genome-wide association and case-control studies indicated that endoplasmic reticulum aminopeptidase 1 (ERAP1 ) is significant associated with AS through cooperating with HLA-B27 (5). The total of 114 loci are established to associate with AS; however these genetic variants are reported to only accounting for about 30% of genetic risk (6). Recent studies indicated that epigenetics may partly account for the inter-individual variance of heterogeneity.
DNA methylation as a most common reported epigenetic modification plays pivotal roles in various life courses, as growth and differentiation, through programmed gene expression regulation in the genome. DNA methylation is the addition of a methyl group to 5’ position of a cytosine DNA base in the middle of cytosine-guanine dinucleotide (CpG) (7). The abnormal DNA methylation in the gene promoter is generally associated with transcriptional silencing and linked to ranges of diseases (8, 9). Recently, increasing number of epigenome-wide association studies (EWAS) indicated that DNA methylation plays pivotal roles in the mechanism of rheumatic diseases as systematic lupus erythematosus, rheumatoid arthritis, and AS (10-14). One EWAS found 1915 altered DNA methylation loci of AS. Besides, candidate targeted gene methylation studies also reported differential methylation loci of AS patients. Methylation of SOCS-1 gene was detected in serum of HLA-B27 positive AS patients but not B27 positive controls, and significantly associated with higher serum cytokines and severity of clinical manifestations of AS patients (15). Hypermethylation and decreased expression of DNMT1 and BCL11 B genes were both reported to associate with AS (16, 17). Nevertheless, study focus on DNA methylation and AS is still scarce and urgent.
ERAP1 is a polymorphic aminopeptidase within the endoplasmic reticulum, known as “molecular ruler” to trim peptides to nine amino acids in length for binding to HLA class I molecules on antigen-presenting cells for subsequent interaction with CD8+ T cells (18, 19). Recent single nucleotide polymorphism studies of our team and other scholars also proved that ERAP1 plays pivotal roles in the pathogenesis of AS through cooperating with HLA-B27 (5, 14). Taken into account of these factors, we designed a two stage case-controlled study to evaluate the promoter methylation and transcriptional profile ofERAP1gene, respectively, in peripheral blood mononuclear cells of AS patients and healthy controls (HCs).