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Methylation and expression profiles of monocytes in monozygotic twins: role in Myasthenia Gravis [methylation profiling]

ABSTRACT: Myasthenia gravis (MG) is a relatively rare autoimmune neuromuscular disorder. Monozygotic twin studies indicate that discordance rate in MG is about 70-60%, suggesting that despite identical DNA unknown factors contribute to disease development. The aim of the current study was to identify novel disease-associated genes in purified monocytes, including both genes associated with predisposition or with disease course, using the unique model of MZ twins. Thus the transcriptome and methylome were compared between twins discordant and concordant for the diseases, as well as MG singletons, and healthy controls. Several transcripts associated with immune homeostasis and inflammation resolution were highlighted in the current study. High similarity between the healthy and the MG discordant twins found, suggest that genetic predisposition may have a stronger contribution then previously assumed. In addition, results suggest that numerous small changes in expression and DNA methylation might contribute to disease onset making it more difficult to pick up

ORGANISM(S): Homo sapiens

PROVIDER: GSE85647 | GEO | 2017/11/22

SECONDARY ACCESSION(S): PRJNA338998

REPOSITORIES: GEO

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Project description:Myasthenia gravis (MG) is an autoimmune disease affecting the neuromuscular junction, whose clinical hallmark is muscle weakness and early fatigability. Azathioprine (AZA) is commonly used in Myasthenia Gravis therapy. AZA is a purine antagonist, which inhibits the cell cycle in the resting and DNA synthesis phases. It is usually used as an immunosuppressant to block T- and B-cell proliferation. AZA, bioconverted to 6-mercaptopurine by glutathione S-transferase (GST), can be metabolized either through the hypoxanthine phosphoribosyl transferase pathway to active 6-thioguanine nucleotides (6-TGN) or through the thiopurine S-methyltransferase (TPMT) pathway to inactive methyl-thiopurine metabolites. The incorporation of active 6-TGNs into DNA, causing breaks in DNA strands resulting in interference with RNA production and thereby protein synthesis, is responsible for the drug effect. The response to AZA is determined by which metabolic pathway is being favored. While balanced use of both HPRT and TPMT pathways results in responsiveness to AZA, hyperactivity of TPMT skews the balance towards the TPMT pathway and results in unresponsiveness to AZA with no pharmacological effect. In contrast, low TPMT activity skews the balance towards the HPRT pathway, resulting in increasing side-effects due to the accumulation of 6-TGNs. Current treatments for MG therapy are often inadequate because less than 40% of patients achieve complete remission with available drugs. This reflects the lack of drugs acting on target sites for which there is strong evidence of pathogenicity and the inability to identify responder patients. No criteria for responsiveness are available, exposing patients to unpredictable failures and unpredictable side effects. These individuals are at particular risk for adverse drug reaction (ADRs) or therapeutic failure. Genetic profiling with the Affymetrix drug metabolizing enzymes and transports genotyping array offers the ability to determine 1,931 variants and 225 genes involved in drug metabolism and disposition. Accordingly, the study of well-known drug-metabolizing genes can be involved in the specific metabolic pathway of a drug, which is more likely to define genotype-phenotype association and thereby genotype profiles relevant to drug response that can be applied as predictive biomarkers for pharmacological treatment.

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Methylation and expression profiles of monocytes in monozygotic twins: role in Myasthenia Gravis [methylation profiling]

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