Abstract
BackgroundThe currently known risk loci could explain a small proportion of the heritability of ankylosing spondylitis (AS). Epigenetics might account for the missing heritability. We aimed to seek more novel AS-associated DNA methylation alterations and delineate the regulatory effect of DNA methylation and gene expression with integrated analysis of methylome and transcriptome.MethodsEpigenome-wide DNA methylation and mRNA expression were profiled in peripheral blood mononuclear cells (PBMCs) from 45 individuals (AS: health controls (HCs) = 30:15) with high-throughput array. The methylome was validated in an independent cohort (AS: HCs = 12:12). Pearson correlation analysis and causal inference tests (CIT) were conducted to determine potentially causative regulatory effects of methylation on mRNA expression.ResultsA total of 4794 differentially methylated positions (DMPs) were identified associated with AS, 2526 DMPs of which were validated in an independent cohort. Both cohorts highlighted T cell receptor (TCR) signaling and Th17 differentiation pathways. Besides, AS patients manifested increased DNA methylation variability. The methylation levels of 158 DMPs were correlated with the mRNA expression levels of 112 genes, which formed interconnected network concentrated on Th17 cell differentiation and TCR signaling pathway (LCK, FYN, CD3G, TCF7, ZAP70, CXCL12, and PLCG1). We also identified several cis-acting DNA methylation and gene expression changes associated with AS risk, which might regulate the cellular mechanisms underlying AS.ConclusionsOur studies outlined the landscapes of epi-signatures of AS and several methylation-gene expression-AS regulatory axis and highlighted the Th17 cell differentiation and TCR signaling pathway, which might provide innovative molecular targets for therapeutic interventions for AS.
Highlights
The currently known risk loci could explain a small proportion of the heritability of ankylosing spondylitis (AS)
Causal inference tests and transcription factor motif enrichment analysis The correlation analysis could not determine the direction of causality of the strong association between methylome and transcriptome; we conducted the causal inference tests (CIT) analysis to infer the cis-acting DNA methylation and gene expression changes associated with AS risk
We demonstrated the alteration of DNA methylome and gene transcriptome in peripheral blood mononuclear cells (PBMCs) underlying predisposition to AS
Summary
The currently known risk loci could explain a small proportion of the heritability of ankylosing spondylitis (AS). Despite the numerous diseaseassociated variants identified, they cumulatively explain only a small proportion (< 28%) of the heritability of the disease. Epigenetics refers to functional modifications to DNA without sequence alteration, which is heritable from one cell cycle to the potentially reversible, and is largely responsible for the cell-specific expression of genes [4]. The modifications include histone modifications, DNA methylation, and non-coding RNAs. DNA methylation, the best studied and understood epigenetic modification, plays a critical role in the regulation of gene transcription and nuclear organization and influences cellular function. Many environmental risk factors, such as diet, cigarette, and infection [5, 6], have been proved to be related to the development of AS disease. Since environmental factors influence DNA methylation profiles, it may provide an essential link between genes and the environment
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