Dataset Information

Associations of BAFF rs2893321 polymorphisms with myasthenia gravis susceptibility.

ABSTRACT:

Background

Myasthenia gravis (MG) is an autoimmune diseases characterized by fatigue and weakness of skeletal muscles. B-lymphocyte-activating factor (BAFF), an essential factor for B cell differentiation and development, is important in the progression of MG. The current study aimed to investigate the association between single nucleotide polymorphism rs2893321 in BAFF with MG susceptibility in Chinese Han population.

Methods

One hundred forty-nine patients with MG and 148 healthy controls were recruited. Using improved multiple ligase detection reaction technology, the polymorphisms of rs2893321 between groups and among MG subgroups have been compared.

Results

A significant differences between the MG group and the healthy control group was observed. Additionally, rs2893321 was found to be associated with gender and age in patients with MG.

Conclusion

Genetic variations of rs2893321 in BAFF might be associated with susceptibility to MG in the Chinese Han population.

SUBMITTER: Deng H

PROVIDER: S-EPMC6822419 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Publications

Associations of BAFF rs2893321 polymorphisms with myasthenia gravis susceptibility.

Deng Hui H Wang Jianjian J Kong Xiaotong X Zhang Huixue H Wang Tianfeng T Tian Wenqi W Yi Tingting T Wang Lihua L

BMC medical genetics 20191030 1

<h4>Background</h4>Myasthenia gravis (MG) is an autoimmune diseases characterized by fatigue and weakness of skeletal muscles. B-lymphocyte-activating factor (BAFF), an essential factor for B cell differentiation and development, is important in the progression of MG. The current study aimed to investigate the association between single nucleotide polymorphism rs2893321 in BAFF with MG susceptibility in Chinese Han population.<h4>Methods</h4>One hundred forty-nine patients with MG and 148 health ...[more]

PMID: 31666013

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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.

Project description:BackgroundMyasthenia gravis (MG) is an autoimmune disorder caused by antibodies that target the postsynaptic muscle membrane. Recent evidence suggests that genetic variants and long noncoding RNAs (lncRNAs) play crucial roles in the pathogenesis of MG. The purpose of this study was to investigate the associations between lncRNA-related single-nucleotide polymorphisms (SNPs) and MG susceptibility in Chinese populations.MethodsFirst, we identified lncRNA mutation hotspot regions based on the improved Kolmogorov‒Smirnov test and the cumulative hypergeometric distribution principle. Next, we further identified lncRNA mutation hotspot SNPs by calculating conservative scores. Finally, experiments were conducted to verify the associations between lncRNA mutation hotspot SNPs and MG susceptibility. A total of 82 patients with MG and 82 healthy controls were recruited for genotyping of lncRNA mutation hotspot SNPs using the SNaPshot technique. Quantitative real-time PCR was used to investigate lncRNA expression in 34 patients with MG and 37 healthy controls.ResultsIn the multistep calculation, 14 candidate SNPs of 3 lncRNAs (AL031686.1, NONHSAT028539.2 and AC245014.3) in MG were identified as mutation hotspot SNPs. The genotyping results of the 14 SNPs in our study revealed no statistically significant differences in the frequencies of genotypes and alleles between patients with MG and controls. However, in the lncRNA AL031686.1, rs1000383 and rs6094353 were in perfect linkage disequilibrium (LD) and were associated with an increased risk of ocular MG. Additionally, rs6094347 was associated with an increased risk of ocular MG. Nevertheless, no SNP was found to be associated with factors such as sex, age, the presence or absence of thymoma, or the genetic model of MG. Further experiments revealed that NONHSAT028539.2 expression was upregulated in peripheral blood mononuclear cells (PBMCs) from patients with MG compared with those from healthy controls.ConclusionIn our study, we did not find an association between the 14 mutation hotspot SNPs of lncRNAs and susceptibility to MG. However, we observed that the rs6094347 and rs1000383/rs6094353 polymorphisms in the lncRNA AL031686.1 were associated with the risk of ocular MG.

Dataset Information

Associations of BAFF rs2893321 polymorphisms with myasthenia gravis susceptibility.

Background

Methods

Results

Conclusion

Publications

Associations of BAFF rs2893321 polymorphisms with myasthenia gravis susceptibility.

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