Abstract
Increasing evidence suggests a contribution of epigenetic processes in promoting cancer and autoimmunity. Myasthenia gravis (MG) is an autoimmune disease mediated, in approximately 80% of the patients, by antibodies against the nicotinic acetylcholine receptor (AChR+). Moreover, epithelial tumours (thymomas) are present in about 10-20% of the patients, and there is indication that changes in DNA methylation might contribute to the risk and progression of thymomas. However, the role of epigenetics in MG is still not completely clarified. In the present study we investigated if a common polymorphism (-579G>T: rs1569686) in the promoter of the DNMT3B gene coding for the DNA methyltransferase 3B, an enzyme that mediates DNA methylation, increases the risk to develop MG or MG-associated thymomas. The study polymorphism was selected based on recent reports and a literature meta-analysis suggesting association with increased risk of various types of cancer. We screened 324 AChR+ MG patients (140 males and 184 females, mean age 56.0 ± 16.5 years) and 735 healthy matched controls (294 males and 441 females, mean age 57.3 ± 15.6 years). 94 of the total MG patients had a thymoma. While there was no association with the whole cohort of MG patients, we found a statistically significant association of the DNMT3B -579T allele (OR = 1.51; 95% CI=1.1-2.1, P = 0.01) and the TT homozygous genotype (OR = 2.59; 95% CI=1.4-4.9, P = 0.006) with the risk of thymoma. No association was observed in MG patients without thymoma, even after stratification into clinical subtypes. Present results suggest that the DNMT3B -579T allele might contribute to the risk of developing thymoma in MG patients, particularly in homozygous TT subjects.
Highlights
Increasing evidence suggests a contribution of epigenetic modifications in complex diseases such as cancer and autoimmune disorders [1,2,3]
Allele and genotype frequencies generated by the DNMT3B -579G>T polymorphism in patients and controls are shown in Tables 2 and 3, respectively
After stratification of Myasthenia gravis (MG) patients into three subgroups according to thymic pathology, the comparison of each of the three subgroups with controls revealed a significant association of the DNMT3B -579T allele with increased thymoma risk (OR = 1.5; 95% confidence intervals (CIs) = 1.1-2.1, P = 0.01)
Summary
Increasing evidence suggests a contribution of epigenetic modifications in complex diseases such as cancer and autoimmune disorders [1,2,3]. Several epigenetic mechanisms are known, including DNA methylation, covalent modifications of histone tails, and nucleosome positioning, all interacting to determine chromatin folding and the relative accessibility of a given genetic locus to activating and suppressing transcription factors [4], and non coding RNAs affecting gene expression levels [5]. Most of the studies performed so far in autoimmune diseases have focused on DNA methylation impairments in systemic lupus erythematosus and rheumatoid arthritis [3]. There is increasing evidence of methylation changes and/or impaired DNMTs activity in other autoimmune disorders such as Sjögren’s syndrome, multiple sclerosis, systemic sclerosis, psoriasis, and autoimmune thyroid diseases [3,7,8]
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