Genetic and Epigenetic Regulation of MEFV Gene and Their Impact on Clinical Outcome in Auto-Inflammatory Familial Mediterranean Fever Patients

Abstract

Epigenetic modifications play a pivotal role in autoimmune/inflammatory disorders and could establish a bridge between personalized medicine and disease epidemiological contexts. We sought to investigate the role of epigenetic modifications beside genetic alterations in the MEFV gene in familial Mediterranean fever (FMF). The study comprised 63 FMF patients diagnosed according to the Tel Hashomer criteria: 37 (58.7%) colchicine-responders, 26 (41.3%) non-responders, and 19 matched healthy controls. MEFV mutations were detected using a CE/IVD-labeled 4-230 FMF strip assay. DNA methylation of MEFV gene exon 2 was measured using bisulfite modification and related to pyrin level, phenotypic picture, MEFV mutations, disease severity, serum amyloid A (SAA), CRP, ESR, disease severity, and colchicine response. Our results showed that FMF patients exhibited significantly higher methylation percentage (p < 0.001) and lower pyrin levels (p < 0.001) compared to the control. The MEFV gene M694I mutation was the most commonly reported mutation (p < 0.004). High methylation percentage of the MEFV exon 2 and low pyrin concentration were correlated with disease severity, high SAA, ESR levels, H-pylori, and renal calculi. In conclusion, this study highlights the relation between high methylation percentage, reduced pyrin level, and different biomarkers in FMF, which underscores their role in the pathogenesis of FMF and could be considered as potential therapeutic targets.

Updates on the role of epigenetics in familial mediterranean fever (FMF)

“…DNA methylation is the most common epigenetic mechanism. This process involves the addition of a methyl group from S-adenosyl-L-methionine (SAM) by DNA methyltransferases (DNMTs) to the fifth position of a cytosine to form 5-methylcytosine (5mC) [ 33 ], thus leading to changes in function without directly manipulating the DNA sequence itself. Most DNA methylation occurs in regions known as CpG islands, which are located mainly within promoters of different genes, hence leading to a decrease in the expression levels of the respective genes [ 34 ].…”

“…The MEFV gene has a 998-base pair (bp) CpG island that covers a part of the first intron and the entire exon 2 of the gene [ 36 ]. In this respect, it is expected that methylation of the MEFV gene might lead to phenotypic variability, and patients with a methylated variant of MEFV exon 2 may exhibit a more severe form of FMF [ 33 ]. However, this hypothesis was not confirmed due to inconsistencies in findings linking MEFV methylation and disease severity.…”

“…While the results showed that the colchicine nonresponders had a greater methylation level of exon 2 of the MEFV gene than did the colchicine responders, these results were deemed to be nonsignificant. As such, it was difficult to reach a conclusion regarding the effectiveness of colchicine in patients suffering from methylation, and additional studies need to be conducted to confirm this observation [ 33 ].…”