Background/Purpose: Familial Mediterranean fever (FMF) is an autoinflammatory disease most commonly associated with biallelic mutations in the MEFV gene. Patients carrying the same pathogenic variant in MEFV can exhibit a broad spectrum of clinical phenotypes. Identifying factors contributing to this clinical variability is essential for understanding disease mechanisms. DNA methylation has been proposed as a potential modifier of MEFV mutations and clinical presentation. However, prior studies exploring this hypothesis included heterogeneous cohorts, lacked genome-wide methylation analyses, and yielded inconsistent findings. We aimed to investigate the role of DNA methylation in FMF using a genome-wide DNA methylation approach.

Methods: We conducted a cross-sectional, genome-wide DNA methylation analysis using whole blood samples from pediatric FMF patients and age- and ethnicity-matched healthy controls (2:1 ratio), all recruited from Istanbul University Medical School. To minimize confounding, we included only patients homozygous for the M694V mutation and from the same geographical region. DNA methylation profiling was performed using the Illumina Infinium MethylationEPIC v2.0 BeadChip array, covering over 930,000 CpG sites. Data analysis was conducted in R (v4.4.0), adjusting for age, sex, and cell composition.

Results: We identified 22 differentially methylated CpG sites in 32 FMF patients compared with 16 healthy controls. Of these, 18 were hypomethylated—including a CpG site within the MEFV gene—and four were hypermethylated. Notably, several differentially methylated CpGs were located in genes encoding zinc finger proteins, a family of transcriptional regulators. Of the 22 CpGs, 13 were found on chromosome 16, where MEFV is located. Three hypomethylated CpGs were within 1.1 kb of the MEFV transcription start site, two of which overlapped with enhancer regions, suggesting a potential regulatory role. Cell-type–specific analysis revealed significant differential methylation in NK cells, CD8⁺ T cells, and CD4⁺ T cells in FMF patients compared with controls.

Conclusion: Our findings suggest that DNA methylation changes may contribute to the pathogenesis of FMF. The enrichment of differentially methylated sites near MEFV on chromosome 16 and in immune cell subsets supports a role for epigenetic regulation in disease expression. These results highlight DNA methylation as a potential modifier of FMF and a promising target for future biomarker development and personalized therapeutic strategies.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/genome-wide-dna-methylation-analysis-in-familial-mediterranean-fever/