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. 2011 Aug 7:12:105.
doi: 10.1186/1471-2350-12-105.

Analysis of MEFV exon methylation and expression patterns in familial Mediterranean fever

Asli K Kirectepe  1 , Ozgur Kasapcopur, Nil Arisoy, Gokce Celikyapi Erdem, Gulen Hatemi, Huri Ozdogan, Eda Tahir Turanli
Affiliations

Analysis of MEFV exon methylation and expression patterns in familial Mediterranean fever

Asli K Kirectepe et al. BMC Med Genet. .

Abstract

Background: MEFV mutations and decreased expression level of the gene are related to FMF pathology. DNA methylation at CpG islands is a well-known mechanism for transcriptional silencing. MEFV has a CpG island, spanning a part of the first intron and the whole of the second exon of the gene covering 998 bp region. Here, we tested the hypothesis that the MEFV transcript level in FMF patients correlates with its methylation level, and methylation, by allowing transcription silencing, has a role in FMF ethiopathogenesis.

Methods: The study group was composed of pediatric FMF patients (N = 51) and age-gender matched healthy controls (N = 21). The relative expression level of MEFV was assessed via quantitative real-time PCR (qRT-PCR) and bisulfite sequencing (BS) was performed to analyse the methylation level quantitatively.

Results: MEFV expression in FMF patients were decreased compared to healthy controls (P = 0.031). Methylation level of exon 2 of MEFV was found to be slightly higher in FMF patients compared to healthy controls (76% versus 74%) (P = 0.049). The expression level of the MEFV was negatively correlated with the methylation level of the CpG island in both FMF and healthy controls groups (cor = -0.29, P = 0.041) but more so in the FMF only group (cor = -0.36, P = 0.035).

Conclusions: In this study, the relation between reduced MEFV expression level and FMF was confirmed. Observed slight increase in methylation in FMF patients, and correlation of methylation with expression might be indicative of its role in FMF, however a larger dataset is needed to confirm our preliminary findings.

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Figures

Figure 1
Figure 1
Expression Level of MEFV in FMF patients and Healthy Controls. Expression levels were measured by quantitative real time PCR analysis. RNA was obtained from peripheral leukocytes as described in materials and methods. B2M gene was used as reference gene and ΔCT method were used to relative quantification. MEFV mRNA level was analyzed in 51 FMF patients and 11 healthy controls. The bars represent standard deviations. Two tail Student's t-test was used to compare the MEFV expression levels. The expression was significantly lower in FMF patients compared to healthy controls (P = 0.031).
Figure 2
Figure 2
MEFV Methylation Levels in FMF Patients and Healthy Controls. MEFV second exon methylation percentage in FMF patients and healthy controls. Bisulfite sequencing was performed in 30 FMF patients and 21 healthy controls genomic DNAs that were obtained from peripheral leukocytes. The bars represent standard deviations. Statistical analysis was done using one tail Student's t-test. Methylation level was observed slightly but significantly higher in FMF patients compared to healthy controls (P = 0.049).
Figure 3
Figure 3
Correlation Between Expression and Methylation Levels of MEFV. Negative correlation between expression and methylation levels of MEFV was observed using Spearman pairwise correlation analysis. (A) Correlation between MEFV mRNA expression and methylation levels in FMF patients (cor = -0.36, P= 0.035). (B) Negative correlation was also obtained between expression and methylation levels of MEFV when both groups analysed (cor = -0.29, p = 0.041).
Figure 4
Figure 4
Expression and Methylation Levels of MEFV in FMF Patients with Lowest Expression Level and Healthy Controls with Highest Expression Level. MEFV expression and methylation levels were compared between FMF patients with lowest expression level (N = 4) and healthy controls with highest expression level (N = 4). The expression level is given as 2-ΔCTX 100. Error bars represent standard deviation.
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