Genetic and Epigenetic Features of Familial Mediterranean Fever: What is New?

Familial Mediterranean Fever and Genetic

Abstract views: 56 / PDF downloads: 64




Familial Mediterranean Fever, FMF, MEFV gene, miRNAs


Familial Mediterranean Fever (FMF) is a hereditary autoinflammatory disorder characterized by recurrent fever episodes and systemic inflammation, primarily attributed to mutations in the Mediterranean Fever (MEFV) gene.
Genetic studies have identified various mutations in the MEFV gene, with notable variants such as V726A, M694V, M694I, M680I, and E148Q predominating in affected populations. The MEFV gene encodes the pyrin protein, crucial for inflammasome assembly and subsequent inflammatory responses. While biallelic mutations are typical in FMF, monoallelic carriers also exhibit phenotypic variability, suggesting the involvement of additional genetic and environmental factors. Epigenetic mechanisms, particularly DNA methylation and histone modifications, play pivotal roles in regulating gene expression and inflammatory pathways in FMF. Studies investigating DNA methylation patterns of the MEFV gene have yielded conflicting results regarding their association with disease severity and colchicine responsiveness. Furthermore, histone modifications, including acetylation and methylation, have been implicated in inflammasome activation and FMF pathophysiology, offering potential therapeutic targets.
MicroRNAs (miRNAs), crucial regulators of gene expression, have emerged as key players in FMF pathogenesis. Dysregulated miRNA expression profiles in FMF patients, particularly those homozygous for specific mutations, suggest their involvement in immune dysregulation and cytokine modulation. Moreover, miRNAs hold promise as diagnostic biomarkers and therapeutic targets, with potential implications for personalized treatment strategies.


Alghamdi M. Familial Mediterranean fever, review of the literature. Clin Rheumatol. 2017;36(8):1707-1713. doi:10.1007/s10067-017-3715-5

Ben-Chetrit E, Touitou I. Familial mediterranean Fever in the world. Arthritis Rheum. 2009;61(10):1447-1453. doi:10.1002/art.24458

Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study. Medicine (Baltimore). 2005;84(1):1-11. doi:10.1097/

Cobankara V, Fidan G, Türk T, Zencir M, Colakoglu M, Ozen S. The prevalence of familial Mediterranean fever in the Turkish province of Denizli: a field study with a zero patient design. Clin Exp Rheumatol. 2004;22(4 Suppl 34):S27-S30.

Sarkisian T, Ajrapetian H, Beglarian A, Shahsuvarian G, Egiazarian A. Familial Mediterranean Fever in Armenian population. Georgian Med News. 2008;(156):105-111.

Livneh A. Reported at familial mediterranean fever and beyond: The 4th International Congress on Systemic Autoinflammatory Diseases, November 6-10, 2005, Bethesda, Maryland.

Li J, Wang W, Zhong L, et al. Familial Mediterranean Fever in Chinese Children: A Case Series. Front Pediatr. 2019;7:483. Published 2019 Nov 19. doi:10.3389/fped.2019.00483

Wu D, Shen M, Zeng X. Familial Mediterranean fever in Chinese adult patients. Rheumatology (Oxford). 2018;57(12):2140-2144. doi:10.1093/rheumatology/key218

Debeljak M, Toplak N, Abazi N, et al. The carrier rate and spectrum of MEFV gene mutations in central and southeastern European populations. Clin Exp Rheumatol. 2015;33(6 Suppl 94):S19-S23.

Samuels J, Aksentijevich I, Torosyan Y, et al. Familial Mediterranean fever at the millennium. Clinical spectrum, ancient mutations, and a survey of 100 American referrals to the National Institutes of Health. Medicine (Baltimore). 1998;77(4):268-297. doi:10.1097/00005792-199807000-00005

Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. The International FMF Consortium. Cell. 1997;90(4):797-807. doi:10.1016/s0092-8674(00)80539-5

French FMF Consortium. A candidate gene for familial Mediterranean fever. Nat Genet. 1997;17(1):25-31. doi:10.1038/ng0997-25

Van Gorp H, Huang L, Saavedra P, et al. Blood-based test for diagnosis and functional subtyping of familial Mediterranean fever. Ann Rheum Dis. 2020;79(7):960-968. doi:10.1136/annrheumdis-2019-216701

Touitou I. The spectrum of Familial Mediterranean Fever (FMF) mutations. Eur J Hum Genet. 2001;9(7):473-483. doi:10.1038/sj.ejhg.5200658

Ben-Zvi I, Herskovizh C, Kukuy O, Kassel Y, Grossman C, Livneh A. Familial Mediterranean fever without MEFV mutations: a case-control study. Orphanet J Rare Dis. 2015;10:34. Published 2015 Mar 25. doi:10.1186/s13023-015-0252-7

Chaaban A, Salman Z, Karam L, Kobeissy PH, Ibrahim JN. Updates on the role of epigenetics in familial mediterranean fever (FMF). Orphanet J Rare Dis. 2024;19(1):90. Published 2024 Feb 26. doi:10.1186/s13023-024-03098-w

Marek-Yagel D, Berkun Y, Padeh S, et al. Clinical disease among patients heterozygous for familial Mediterranean fever. Arthritis Rheum. 2009;60(6):1862-1866. doi:10.1002/art.24570

Rowczenio DM, Iancu DS, Trojer H, et al. Autosomal dominant familial Mediterranean fever in Northern European Caucasians associated with deletion of p.M694 residue-a case series and genetic exploration. Rheumatology (Oxford). 2017;56(2):209-213. doi:10.1093/rheumatology/kew058

Stoffels M, Szperl A, Simon A, et al. MEFV mutations affecting pyrin amino acid 577 cause autosomal dominant autoinflammatory disease. Ann Rheum Dis. 2014;73(2):455-461. doi:10.1136/annrheumdis-2012-202580

Rowczenio DM, Youngstein T, Trojer H, et al. British kindred with dominant FMF associated with high incidence of AA amyloidosis caused by novel MEFV variant, and a review of the literature. Rheumatology (Oxford). 2020;59(3):554-558. doi:10.1093/rheumatology/kez334

Jéru I, Hentgen V, Cochet E, et al. The risk of familial Mediterranean fever in MEFV heterozygotes: a statistical approach. PLoS One. 2013;8(7):e68431. Published 2013 Jul 3. doi:10.1371/journal.pone.0068431

Grossman C, Kassel Y, Livneh A, Ben-Zvi I. Familial Mediterranean fever (FMF) phenotype in patients homozygous to the MEFV M694V mutation. Eur J Med Genet. 2019;62(6):103532. doi:10.1016/j.ejmg.2018.08.013

Shinar Y, Livneh A, Langevitz P, et al. Genotype-phenotype assessment of common genotypes among patients with familial Mediterranean fever. J Rheumatol. 2000;27(7):1703-1707.

Davies K, Lonergan B, Patel R, Bukhari M. Symptomatic patients with P369S-R408Q mutations: familial Mediterranean fever or mixed auto-inflammatory syndrome?. BMJ Case Rep. 2019;12(7):e228858. Published 2019 Jul 1. doi:10.1136/bcr-2018-228858

Yamagami K, Nakamura T, Nakamura R, et al. Familial Mediterranean fever with P369S/R408Q exon3 variant in pyrin presenting as symptoms of PFAPA. Mod Rheumatol. 2017;27(2):356-359. doi:10.1080/14397595.2017.1267173

Kandur Y, Kocakap DBS, Alpcan A, Tursun S. Clinical significance of MEFV gene variation R202Q. Clin Rheumatol. 2022;41(1):271-274. doi:10.1007/s10067-021-05906-1

Sgouropoulou V, Farmaki E, Papadopoulos T, Tzimouli V, Pratsidou-Gertsi J, Trachana M. Sequence analysis in Familial Mediterranean Fever patients with no confirmatory genotype. Rheumatol Int. 2022;42(1):15-22. doi:10.1007/s00296-021-04913-4

Migita K, Uehara R, Nakamura Y, et al. Familial Mediterranean fever in Japan. Medicine (Baltimore). 2012;91(6):337-343. doi:10.1097/MD.0b013e318277cf75

Koné Paut I, Dubuc M, Sportouch J, Minodier P, Garnier JM, Touitou I. Phenotype-genotype correlation in 91 patients with familial Mediterranean fever reveals a high frequency of cutaneomucous features. Rheumatology (Oxford). 2000;39(11):1275-1279. doi:10.1093/rheumatology/39.11.1275

Tchernitchko D, Legendre M, Cazeneuve C, Delahaye A, Niel F, Amselem S. The E148Q MEFV allele is not implicated in the development of familial Mediterranean fever. Hum Mutat. 2003;22(4):339-340. doi:10.1002/humu.9182

Topaloglu R, Ozaltin F, Yilmaz E, et al. E148Q is a disease-causing MEFV mutation: a phenotypic evaluation in patients with familial Mediterranean fever. Ann Rheum Dis. 2005;64(5):750-752. doi:10.1136/ard.2004.026963

Eyal O, Shinar Y, Pras M, Pras E. Familial Mediterranean fever: Penetrance of the p.[Met694Val];[Glu148Gln] and p.[Met694Val];[=] genotypes. Hum Mutat. 2020;41(11):1866-1870. doi:10.1002/humu.24090

Touitou I, Picot MC, Domingo C, et al. The MICA region determines the first modifier locus in familial Mediterranean fever. Arthritis Rheum. 2001;44(1):163-169. doi:10.1002/1529-0131(200101)44:1<163::AID-ANR20>3.0.CO;2-Z

Bakkaloglu A, Duzova A, Ozen S, et al. Influence of Serum Amyloid A (SAA1) and SAA2 gene polymorphisms on renal amyloidosis, and on SAA/C-reactive protein values in patients with familial mediterranean fever in the Turkish population. J Rheumatol. 2004;31(6):1139-1142.

Waddington CH. The epigenotype. 1942. Int J Epidemiol. 2012;41(1):10-13. doi:10.1093/ije/dyr184

Dupont C, Armant DR, Brenner CA. Epigenetics: definition, mechanisms and clinical perspective. Semin Reprod Med. 2009;27(5):351-357. doi:10.1055/s-0029-1237423

Lotfy R, Ali O, Zarouk W, El-Bassyouni H, Nour El-Din G. Epigenetics and familial mediterranean fever. Azhar Int J Pharm Med Sci. 2021;1(2):1–12.

Zhang L, Lu Q, Chang C. Epigenetics in Health and Disease. Adv Exp Med Biol. 2020;1253:3-55. doi:10.1007/978-981-15-3449-2_1

Lim WJ, Kim KH, Kim JY, Jeong S, Kim N. Identification of DNA-Methylated CpG Islands Associated With Gene Silencing in the Adult Body Tissues of the Ogye Chicken Using RNA-Seq and Reduced Representation Bisulfite Sequencing. Front Genet. 2019;10:346. Published 2019 Apr 16. doi:10.3389/fgene.2019.00346

Ulum YA, Peynircioglu BB, Batu E, Guler C, Karadag O, Ertenli A, et al. MEFV gene methylation pattern analysis in familial Mediterranean fever patients with altered expression levels. Pediatr Rheumatol. 2015;13(1):P113. doi: 10.1186/1546-0096-13-S1-P113

Kirectepe AK, Kasapcopur O, Arisoy N, et al. Analysis of MEFV exon methylation and expression patterns in familial Mediterranean fever. BMC Med Genet. 2011;12:105. Published 2011 Aug 7. doi:10.1186/1471-2350-12-105

Doğan E, Gürsoy S, Bozkaya G, Çamlar SA, Kılıçarslan ÖA, Soylu A, et al. The effects of epigenetic regulation on phenotypic expressivity in Turkish patients with familial mediterranean fever. Indian J Rheumatol. 2019;14(4):297. doi: 10.4103/injr.injr_24_19

Zekry ME, Sallam AM, AbdelHamid SG, Zarouk WA, El-Bassyouni HT, El-Mesallamy HO. Genetic and Epigenetic Regulation of MEFV Gene and Their Impact on Clinical Outcome in Auto-Inflammatory Familial Mediterranean Fever Patients. Curr Issues Mol Biol. 2023;45(1):721-737. Published 2023 Jan 13. doi:10.3390/cimb45010048

Vento-Tormo R, Álvarez-Errico D, Garcia-Gomez A, et al. DNA demethylation of inflammasome-associated genes is enhanced in patients with cryopyrin-associated periodic syndromes. J Allergy Clin Immunol. 2017;139(1):202-211.e6. doi:10.1016/j.jaci.2016.05.016

Cedar H, Bergman Y. Linking DNA methylation and histone modification: patterns and paradigms. Nat Rev Genet. 2009;10(5):295-304. doi:10.1038/nrg2540

Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res. 2011;21(3):381-395. doi:10.1038/cr.2011.22

Fellous A, Lefranc L, Jouaux A, Goux D, Favrel P, Rivière G. Histone Methylation Participates in Gene Expression Control during the Early Development of the Pacific Oyster Crassostrea gigas. Genes (Basel). 2019;10(9):695. Published 2019 Sep 10. doi:10.3390/genes10090695

Alaskhar Alhamwe B, Khalaila R, Wolf J, et al. Histone modifications and their role in epigenetics of atopy and allergic diseases. Allergy Asthma Clin Immunol. 2018;14:39. Published 2018 May 23. doi:10.1186/s13223-018-0259-4

Gkoutsias A, Makis A. The role of epigenetics in childhood autoimmune diseases with hematological manifestations. Pediatr Investig. 2022;6(1):36-46. Published 2022 Feb 21. doi:10.1002/ped4.12309

Araki Y, Mimura T. The Histone Modification Code in the Pathogenesis of Autoimmune Diseases. Mediators Inflamm. 2017;2017:2608605. doi:10.1155/2017/2608605

Ma X, Wang X, Zheng G, et al. Critical Role of Gut Microbiota and Epigenetic Factors in the Pathogenesis of Behçet's Disease. Front Cell Dev Biol. 2021;9:719235. Published 2021 Oct 5. doi:10.3389/fcell.2021.719235

Liu CC, Huang ZX, Li X, et al. Upregulation of NLRP3 via STAT3-dependent histone acetylation contributes to painful neuropathy induced by bortezomib. Exp Neurol. 2018;302:104-111. doi:10.1016/j.expneurol.2018.01.011

Mezher N, Mroweh O, Karam L, Ibrahim JN, Kobeissy PH. Experimental models in Familial Mediterranean Fever (FMF): Insights into pathophysiology and therapeutic strategies. Exp Mol Pathol. 2024;135:104883. doi:10.1016/j.yexmp.2024.104883

O'Brien J, Hayder H, Zayed Y, Peng C. Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation. Front Endocrinol (Lausanne). 2018;9:402. Published 2018 Aug 3. doi:10.3389/fendo.2018.00402

Okuyan HM, Begen MA. miRNAs as attractive diagnostic and therapeutic targets for Familial Mediterranean Fever. Mod Rheumatol. 2021;31(5):949-959. doi:10.1080/14397595.2020.1868674

Lindsay MA. microRNAs and the immune response. Trends Immunol. 2008;29(7):343-351. doi:10.1016/

Balci-Peynircioglu B, Akkaya-Ulum YZ, Akbaba TH, Tavukcuoglu Z. Potential of miRNAs to predict and treat inflammation from the perspective of Familial Mediterranean Fever. Inflamm Res. 2019;68(11):905-913. doi:10.1007/s00011-019-01272-6

Amarilyo G, Pillar N, Ben-Zvi I, et al. Analysis of microRNAs in familial Mediterranean fever. PLoS One. 2018;13(5):e0197829. Published 2018 May 22. doi:10.1371/journal.pone.0197829

Kahraman CY, Egin ME, Tatar A, Turkez H, Mardinoglu A. The Assessment of Selected miRNA Profile in Familial Mediterranean Fever. Biomed Res Int. 2021;2021:6495700. Published 2021 Oct 13. doi:10.1155/2021/6495700

Koga T, Migita K, Sato T, et al. MicroRNA-204-3p inhibits lipopolysaccharide-induced cytokines in familial Mediterranean fever via the phosphoinositide 3-kinase γ pathway. Rheumatology (Oxford). 2018;57(4):718-726. doi:10.1093/rheumatology/kex451

Latsoudis H, Mashreghi MF, Grün JR, et al. Differential Expression of miR-4520a Associated With Pyrin Mutations in Familial Mediterranean Fever (FMF). J Cell Physiol. 2017;232(6):1326-1336. doi:10.1002/jcp.25602

Akkaya-Ulum YZ, Balci-Peynircioglu B, Karadag O, et al. Alteration of the microRNA expression profile in familial Mediterranean fever patients. Clin Exp Rheumatol. 2017;35 Suppl 108(6):90-94.

Hortu HO, Karaca E, Sozeri B, et al. Evaluation of the effects of miRNAs in familial Mediterranean fever [published correction appears in Clin Rheumatol. 2019 Jan 7;:]. Clin Rheumatol. 2019;38(3):635-643. doi:10.1007/s10067-017-3914-0

Abdelkawy RFM, Kholoussi S, Eissa E, Hamed K, Raouf HA, El-Bassyouni HT. Differential expression of micro RNAs and their association with the inflammatory markers in familial mediterranean fever patients. Biomed Pharmacol J. 2021;14(3):1351–1358. doi: 10.13005/bpj/2236.

Ehlers L, Rolfes E, Lieber M, et al. Treat-to-target strategies for the management of familial Mediterranean Fever in children. Pediatr Rheumatol Online J. 2023;21(1):108. Published 2023 Sep 26. doi:10.1186/s12969-023-00875-y

Ben-Zvi I, Kukuy O, Giat E, et al. Anakinra for Colchicine-Resistant Familial Mediterranean Fever: A Randomized, Double-Blind, Placebo-Controlled Trial. Arthritis Rheumatol. 2017;69(4):854-862. doi:10.1002/art.39995

De Benedetti F, Gattorno M, Anton J, et al. Canakinumab for the Treatment of Autoinflammatory Recurrent Fever Syndromes. N Engl J Med. 2018;378(20):1908-1919. doi:10.1056/NEJMoa1706314

Phase 2 Study to Evaluate the Safety and Efficacy of RIST4721 in Subjects With Familial Mediterranean Fever. Identifier NCT05448391, U.S. National Library of Medicine (2023).

El Hasbani G, Jawad A, Uthman I. Update on the management of colchicine resistant Familial Mediterranean Fever (FMF). Orphanet J Rare Dis. 2019;14(1):224. Published 2019 Oct 15. doi:10.1186/s13023-019-1201-7

Pepoyan A, Balayan M, Manvelyan A, et al. Probiotic Lactobacillus acidophilus Strain INMIA 9602 Er 317/402 Administration Reduces the Numbers of Candida albicans and Abundance of Enterobacteria in the Gut Microbiota of Familial Mediterranean Fever Patients. Front Immunol. 2018;9:1426. Published 2018 Jun 26. doi:10.3389/fimmu.2018.01426

Jing W, Zhang X, Sun W, Hou X, Yao Z, Zhu Y. CRISPR/CAS9-Mediated Genome Editing of miRNA-155 Inhibits Proinflammatory Cytokine Production by RAW264.7 Cells. Biomed Res Int. 2015;2015:326042. doi:10.1155/2015/326042

Karpuzoglu EM, Kisla Ekinci RM, Balci S, Bisgin A, Yilmaz M. Altered expression of apoptosis-related, circulating cell-free miRNAs in children with familial Mediterranean fever: a cross-sectional study. Rheumatol Int. 2021;41(1):103-111. doi:10.1007/s00296-020-04541-4




How to Cite

Erkuş, E. (2024). Genetic and Epigenetic Features of Familial Mediterranean Fever: What is New? Familial Mediterranean Fever and Genetic. Journal of European Internal Medicine Professionals, 2(2).



Review or Metaanalysis