Integrated analyses of a major histocompatibility complex, methylation and transcribed ultra-conserved regions in systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease which affects different organs and systems that, has a complex genetic inheritance, and is affected by both epigenetic and environmental risk factors. Previous studies on SLE have lacked the statistical power and genetic resolution to fully determine the influence of major histocompatibility complex (MHC) on SLE. In this study, in order to determine this influence, a total of 15 patients with SLE and 15 healthy controls were enrolled. MHC region capture technology, hMeDIP-chip, transcribed ultra-conserved region (T-UCR) microarray and bioinformatics analysis were utilized for both groups. The results revealed methylated CpG enrichment at 6 loci in the MHC segment of SLE. We found 4 single-nucleotide polymorphisms (SNPs) in the CpG promoter of human leukocyte antigen-B (HLA-B) and 2 SNPs in chr6:29521110‑29521833. No significant GO term or KEGG pathway enrichment was noted for an immune-correlated process in the SLE patients for the corresponding CpG-methylated genes. In this study, T-UCR was not discovered in the MHC segment. The analysis of SNPs (rs1050683, rs12697943, rs17881210, rs1065378, rs17184255 and rs16895070) and gene expression in peripheral blood lymphocytes indicated that these SNPs were associated with the occurrence of SLE. Further studies are warranted to examine the roles of these SNPs in the pathogenesis of SLE. Integrative analysis technology provided a view of the molecular signaling pathways in SLE.

Long Noncoding RNA HCP5, a Hybrid HLA Class I Endogenous Retroviral Gene: Structure, Expression, and Disease Associations

“…Hypomethylation of HCP5 was associated with autoantibody production against dsDNA, Sjogren’s syndrome-related antigen A (SSA), Smith (Sm) antigen, and ribonucleoprotein (RNP) in SLE [122,126], with gene expression and humoral immune response to influenza [124], with hypomethylated PSORS1C1-associated allopurinol-induced severe cutaneous adverse reactions in Han Chinese [127], accelerated aging in chronic HIV infection [123], endometrial receptivity [125], sexual bias in the human placental sexome [128,129], age-related monocyte and T cell gene expression [121], lung adenocarcinoma [130], and with hypomethylated POU5F1 -associated ankylosing spondylitis [131]. In contrast to the more common observation of hypomethylation, HCP5 hypermethylation was associated with obesity and BMI in an epigenome-wide association study of adiposity in Ghanaian African migrants using whole blood to measure DNA methylation [64].…”

“…Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease of unknown etiology that can affect most organs and is characterized by the development of autoantibodies associated with specific clinical manifestations implicated in the pathogenesis of lupus nephritis and decreased survival [122,126]. The genetic risk factors suggested for SLE include alleles in IRF5, STAT4, BLK, TNFAIP3, TNIP1 , FCGR2B , and other genes [132].…”

Highlighting transcribed ultraconserved regions in human diseases

“…The relation between T-UCRs and systemic lupus erythematosus (SLE), which is an autoimmune disease with complex pathways, was studied by H. Lin et al (2016). The study aimed to investigate the influence of three factors-major histocompatibility complex (MHC), methylation of CpG islands and T-UCRs expression-on SLE regulation.…”

“…Although this study integrating T-UCRs with MHC and the immune-correlated process, it did not correlate T-UCRs with common clinicopathological features of SLE patients. But differentially expressed T-UCRs were found in patients and must be better investigated (H. Lin et al, 2016).…”