A Pathway Analysis Based on Genome-Wide DNA Methylation of Chinese Patients with Graves’ Orbitopathy

Abstract

Background The pathogenesis Graves' Orbitopathy (GO) is not yet fully understood. Here, we conducted a pathway analysis based on genome-wide DNA methylation data of Chinese GO patients to explore GO-related pathways and potential feature genes. Methods Six GO patients and 6 age-matched control individuals were recruited, and a genome-scale screen of DNA methylation was measured using their peripheral blood sample. After extracting the differentially methylated regions (DMRs), we classified DMRs into three clusters with respect to median absolute deviation (MAD) for GO and control group, respectively. Then the extract tests were performed to identify significant pathways by comparing the counts of genes in each cluster between GO and control group in a pathway. For each significant pathway, we calculated the Methylation-based Inference of Regulatory Activity (MIRA) score to infer the regulatory activity of genes involved in the pathway. Furthermore, we took the significant pathways as the subsets and applied Random forests (RF) method to extract GO-related feature genes. Results We identified four potential significant pathways associated with the occurrence and development of GO disease. There were Toxoplasmosis, Axon guidance, Focal adhesion, and Proteoglycans in cancer (p<0.001 or p=0.007). The identified genes involved in the significant pathways, such as LDLR (p=0.019), CDK5 (p=0.036), and PIK3CB (p=0.020), were found to be correlated with GO phenotype. Conclusion Our study suggested pathway analyses can help understand the potential relationships between the DNA methylation level of some certain genes and their regulation in Chinese GO patients.

Adipose/Connective Tissue From Thyroid-Associated Ophthalmopathy Uncovers Interdependence Between Methylation and Disease Pathogenesis: A Genome-Wide Methylation Analysis

“…DNA methylation is a stable but modifiable epigenetic process whereby a methyl group is transferred onto the C5 position of a cytosine on DNA sequences and regulates gene expression in response to environmental stimulation. Changed methylation levels are observed in the peripheral blood samples of TAO patients ( Xin et al, 2019 ); however, its regulatory pattern in genome of orbital tissues remains to be evaluated.…”

“…The enriched GO of hyper- and hypomethylated genes shared similar functions, including cell adhesion, proliferation and migration, while their enriched pathways were associated with inflammation and nervous system in common. Previous study of function enrichment analysis in peripheral blood samples of TAO patients revealed that identified genes are involved with functions of axon guidance, focal adhesion and so on ( Xin et al, 2019 ). Similar results are found in orbital tissue, and multiple unique functions were also exhibited in our study.…”

“…Moreover, aberrant DNA methylation has been reported to be highly associated with a range of ophthalmic diseases, including myopia ( Seow et al, 2019 ), glaucoma ( Johnson et al, 2018 ), cataract ( Liu et al, 2020 ), age-related macular degeneration ( Baird and Wei, 2013 ), and uveitis ( Wei et al, 2020 ). In terms of TAO, although the DNA methylation profile of peripheral blood has been detected in TAO patients ( Xin et al, 2019 ), research on the role of methylation modification in the pathogenesis of TAO is still needed.…”

Effect of the Abnormal Expression of BMP-4 in the Blood of Diabetic Patients on the Osteogenic Differentiation Potential of Alveolar BMSCs and the Rescue Effect of Metformin: A Bioinformatics-Based Study

“…In this study, differentially expressed genes were subjected to RF analysis using the R v3.6.1 tool (https://www.r-project .org) and ranked based on the mean decrease Gini (MDG) coefficient. MDG was used to quantify the contribution of the difference in the expression of each gene to the overall difference between the two groups [21], and comparison of MDGs provided a basis for extraction of the major risk genes.…”

Preliminary evidence of the association between DNAm and orbital volumetry in GO

“…Several factors, including genetic susceptibility, and multiple environmental factors, such as gender, age, and smoking, have been demonstrated to be involved in the development of GO (2). Our previous study identified several genomic loci that had significant differences in DNA methylation (DNAm) patterns associated with GO (3,4). BOLL, MBP, and CDK5 are potential genes associated with GO, according to the genome-scale screening of DNAm and the single methylation sequencing validation using enlarged samples (5).…”