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).