Abstract

Familial Mediterranean Fever (FMF) is the first described and most prevalent monogenic autoinflammatory periodic fever syndrome worldwide. The disease is caused by pathogenic variants in the MEFV (Mediterranean fever) gene, which lead to dysregulated innate immune responses and a persistent hyperinflammatory state. Despite extensive genetic characterization, the molecular mechanisms linking MEFV mutations to aberrant inflammation remain incompletely understood. Moreover, substantial clinical heterogeneity—manifested as incomplete penetrance, variable expressivity, and modulation by additional autoinflammatory genes—indicates that FMF pathogenesis extends beyond classical Mendelian inheritance. Emerging evidence suggests that epigenetic mechanisms, including DNA methylation, histone modifications, and microRNA regulation, may contribute to phenotypic variability, disease severity, and therapeutic response; however, available data are limited and occasionally conflicting. This review provides a comprehensive and up-to-date overview of the genetic, molecular, and epigenetic factors implicated in FMF, highlights unresolved controversies, and proposes future research priorities aimed at elucidating disease mechanisms and improving clinical management.

INTRODUCTION

Familial Mediterranean Fever (FMF) is a monogenic autoinflammatory disorder predominantly affecting individuals of Mediterranean descent, including Turks, Armenians, Arabs, and non-Ashkenazi Jews.¹ It is the most common hereditary periodic fever syndrome worldwide and is characterized by recurrent episodes of fever, serositis, and arthritis (Figure 1). Among its complications, AA amyloidosis is the most serious and represents the leading cause of mortality in FMF patients. Daily prophylactic administration of colchicine remains the cornerstone of treatment, effectively preventing the development of amyloidosis.²

Pathogenic variants in the MEFV gene play a central role in FMF pathogenesis. This gene encodes pyrin, a protein critical for regulating the inflammatory response by modulating the inflammasome complex.^2,3 Despite extensive research, the precise mechanisms underlying pyrin inflammasome overactivation in FMF remain incompletely understood.

This review provides an updated and comprehensive overview of the genetics, epigenetics, and pathogenesis of FMF.

FMF results from pathogenic variants in the MEFV gene, which encodes the pyrin protein.^4,5 These variants lead to a gain-of-function effect in pyrin.⁶ Pyrin functions as an inflammasome-forming protein.⁷

Inflammasomes are multiprotein complexes that play a critical role in the innate immune response to pathogens.⁸ Unlike the adaptive immune system, the innate immune system does not recognize pathogen-specific molecules; instead, it detects conserved molecular patterns shared by pathogens—pathogen-associated molecular patterns (PAMPs)—or alterations arising from cellular damage, known as damage-associated molecular patterns (DAMPs).⁹ By monitoring the cytosol, inflammasomes trigger an inflammatory response upon detection of PAMPs or DAMPs.¹⁰

One notable inflammasome is the pyrin inflammasome. Because pyrin inflammasome overactivation underlies FMF pathogenesis, this review first summarizes its structure, function, and activation, along with recent advances in the field. Subsequently, we examine the pyrin inflammasome specifically in patients with FMF, highlighting emerging findings and hypotheses that provide new insights into disease pathophysiology. This discussion is followed by an overview of the intriguing relationship between FMF and Yersinia, a connection that has reshaped current understanding of FMF epidemiology and biology. Finally, we address the genetic landscape of FMF and explore epigenetic regulatory mechanisms that may contribute to phenotypic variability.

PYRIN INFLAMMASOME

Structure

The basic structure of an inflammasome consists of a sensor that detects pathogenic insults, an adaptor protein that bridges the sensor and the executioner, and an executioner that initiates the inflammatory cascade.¹¹ In the pyrin inflammasome, these components correspond to pyrin (sensor), [apoptosis-associated (ASC) speck-like protein containing a caspase recruitment domain (CARD)] (adaptor), and caspase-1 (executioner), respectively.

Pyrin, also known as tripartite motif–containing protein 20 or marenostrin, is a pattern recognition receptor that monitors cytosolic homeostasis and senses alterations within the cytosol, referred to as homeostasis-altering molecular processes.¹² Structurally, pyrin comprises an N-terminal pyrin domain (PYD), a zinc finger domain (B-box), a central helical scaffold (CHS), and a C-terminal B30.2 domain (Figure 2).^13,14

The PYD domain of pyrin interacts with the PYD domain of ASC, promoting ASC oligomerization. Oligomerized ASC subsequently engages procaspase-1 via its CARD domain, leading to autocatalytic cleavage and activation of caspase-1.¹⁵

Function and activation

The activation of the pyrin inflammasome under physiological conditions is illustrated in Figure 3.

Under normal conditions, pyrin remains in an inactive state, which is maintained by the small GTPase RhoA.⁷ RhoA functions as a “guard” of the pyrin inflammasome.⁷ Rather than interacting directly with pyrin, RhoA inhibits inflammasome activation through the serine–threonine protein kinases PKN1 and PKN2.¹⁶ Specifically, RhoA activates PKN1 and PKN2, which then bind to pyrin and phosphorylate serine residues at positions 208 and 242.^16,17 This phosphorylation facilitates the binding of the 14-3-3 chaperone to pyrin, thereby preventing pyrin inflammasome activation.¹⁶

Bacteria and bacterial toxins, such as the clostridial toxin TcdB, can alter RhoA activity, effectively “disarming” this regulatory guard.⁷ This disruption reduces pyrin phosphorylation and the binding of 14-3-3 proteins to pyrin.⁷ The decreased association of 14-3-3 proteins relieves pyrin inhibition, leading to activation of the pyrin inflammasome. This mechanism represents the primary pathway through which the pyrin inflammasome senses bacterial toxins and homeostatic disturbances.¹⁶

Upon activation, pyrin interacts with ASC via homotypic PYD–PYD interactions, promoting ASC oligomerization.^16,18 The CARD domain of oligomerized ASC then stimulates autocatalytic cleavage of procaspase-1 into active caspase-1, the principal executioner of inflammasome-induced inflammatory responses. Active caspase-1 cleaves proinflammatory cytokines interleukin (IL)-1β and IL-18 into their mature forms, triggering an exaggerated immune response largely mediated by neutrophils.^19,20

In addition to cytokine activation, caspase-1 cleaves the pore-forming protein Gasdermin-D, producing its active form and inducing inflammatory cell death, known as pyroptosis.²¹ Enhanced pyroptosis further amplifies inflammation by promoting the release of cytokines and alarmins such as S100A8/A9 and S100A12.²² Recent studies have also demonstrated that neutrophil extracellular traps are formed as a consequence of heightened neutrophil activation in patients with FMF.²³

PYRIN INFLAMMASOME IN FAMILIAL MEDITERRANEAN FEVER

Figure 4 summarizes the current understanding of the pyrin inflammasome in FMF. Despite advances in elucidating pyrin inflammasome activation and downstream signaling, the precise mechanisms underlying its overactivation in patients with FMF remain incompletely understood.^7,16 Current evidence suggests the involvement of distinct yet interconnected regulatory nodes, including the B30.2 domain, cytoskeletal dynamics, and autophagic pathways.^12,24,25

Structural regulation: the B30.2 and central helical scaffold domains

Most FMF-causing variants are located in exon 10 of the MEFV gene, which encodes the B30.2 domain of pyrin.¹³ Although the precise role of the B30.2 domain in pyrin inflammasome activation remains unclear, Weinert et al.²⁴ identified a shallow cavity containing hydrophobic clusters within B30.2, which they proposed as a potential ligand-binding site. They further observed that approximately two-thirds of pathogenic variants in the B30.2 coding region cluster near this cavity, suggesting that these variants likely alter its ligand-binding activity.²⁴

Chae et al.²⁵ and Arakelov et al.²⁶ reported that the B30.2 domain directly interacts with caspase-1, exerting an inhibitory effect on its activation. Studies indicate that FMF-causing variants in B30.2 weaken this interaction, thereby relieving caspase-1 inhibition.²⁷ Another study demonstrated that β2-microglobulin binds the B30.2 domain and promotes inflammasome activation, leading to caspase-1 activation.²⁸ This study also identified a negative feedback mechanism mediated by the p20 subunit of caspase-1, which binds B30.2 and reduces pyrin’s interaction with β2-microglobulin. FMF-associated MEFV variants were shown to diminish this inhibitory effect, contributing to enhanced inflammasome activation.²⁸

Recently, Chirita et al.¹⁴ demonstrated that the B30.2 domain is dispensable for pyrin activation. Instead, it negatively regulates pyrin activation, acting downstream of pyrin dephosphorylation and upstream of ASC speck oligomerization.¹⁴ Weinert et al.²⁴ showed that the remaining one-third of B30.2 variants cluster opposite the peptide-binding cavity. They hypothesized that these variants alter the spatial orientation between B30.2 and the central coiled-coil domain (a subdomain of CHS) and subsequently confirmed this hypothesis in a follow-up study.²⁹ Chirita et al.¹⁴ further demonstrated that variants in exons 3–8, which encode the CHS domain, mimic the effects of FMF-causing B30.2 variants. They also proposed that CHS and B30.2 function together to negatively regulate caspase-1 activation.¹⁴

Taken together, these findings suggest that B30.2 acts as a negative regulator of pyrin inflammasome activation in coordination with CHS. FMF-causing pathogenic variants located in exons 10 and 3–8 disrupt this inhibitory mechanism, resulting in pyrin inflammasome overactivation. Although the negative regulatory roles of B30.2 and CHS have been demonstrated, the precise molecular mechanisms remain unclear. Elucidating this regulation is of critical importance, as it may enhance understanding of FMF pathogenesis and inform the development of novel therapeutic strategies.

Cytoskeletal regulation and motility

Colchicine, the primary treatment for FMF, is well known for its effects on the cytoskeleton, prompting researchers to investigate the potential role of cytoskeletal dynamics in FMF pathogenesis. Figure 5 illustrates cytoskeletal organization in FMF. The pyrin inflammasome has long been recognized to associate with cytoskeletal components.

In 2001, Mansfield et al.³⁰ demonstrated that pyrin colocalizes with microtubules and the actin cytoskeleton via its N-terminal domain. Subsequently, Shoham et al.³¹ reported that pyrin interacts with proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1), a regulator of cytoskeletal organization. In addition to its role in cytoskeletal regulation, PSTPIP1 binds the B-box domain of pyrin, promoting pyrin activation downstream of dephosphorylation and upstream of ASC oligomerization.³²

In 2016, Van Gorp et al.³³ and Gao et al.³⁴ confirmed that pyrin interacts with microtubules and demonstrated that an intact microtubular network is essential for both pyrin dephosphorylation and subsequent activation of the pyrin inflammasome. They^33,34 further showed that microtubules function downstream of pyrin dephosphorylation and upstream of ASC oligomerization. Moreover, Van Gorp et al.³³ and Magnotti et al.³⁵ reported that, although FMF-associated pathogenic variants do not disrupt the physical interaction between pyrin and microtubules, these variants circumvent the requirement for an intact microtubular system in pyrin inflammasome activation.

Recently, CDC42 (cell division cycle 42), a well-established regulator of the cytoskeleton^36,37 was identified as a critical component of the pyrin pathway. Mechanistically, CDC42 promotes microtubule-dependent pyrin assembly, acting downstream of pyrin dephosphorylation and upstream of ASC oligomerization.^38,39 The essential role of CDC42 in FMF pathogenesis is further supported by evidence showing that CDC42 deletion prevents inflammatory cell death in disease models.³⁹

Furthermore, pyrin inflammasome activation appears to regulate inflammatory cell migration. Several studies have shown that pyrin colocalizes with polymerizing actin at the leading edge of migrating monocytes.^40,41 The functional significance of this interaction is underscored by pyrin knockdown models, which exhibit impaired migratory capacity.⁴¹ Recently, Akbaba et al.⁴² reported that pyrin inflammasome activation specifically enhances inflammatory cell migration in FMF patients, distinguishing them from patients with cryopyrin-associated periodic syndromes (CAPS) and healthy controls.

Alternative regulatory mechanisms

Chae et al.⁴³ demonstrated the involvement of the NF-κB pathway in FMF pathogenesis. Their study⁴³ revealed that pyrin can serve as a substrate for caspase-1, and the cleavage product of pyrin translocates to the nucleus, where it enhances NF-κB activity by promoting IκB degradation. Additionally, caspase-1–mediated pyrin cleavage was found to be elevated in FMF patients. These observations were corroborated by Fayez et al.,²⁷ whose in silico analysis of pyrin and caspase-1 supported the findings of Chae et al.⁴³

Another regulatory mechanism affected by disease-causing MEFV variants is pyrin-mediated autophagy. Kimura et al.⁴⁴ demonstrated that pyrin functions as an autophagy receptor, recognizing and promoting the autophagy of NOD-like receptor pyrin domain–containing 1 (NLRP1), NOD-like receptor pyrin domain–containing 3 (NLRP3), and pro–caspase-1. Pathogenic MEFV variants were associated with reduced autophagy of these inflammasome components. Consistent with these findings, Skendros et al.⁴⁵ and Mitroulis et al.⁴⁶ reported diminished autophagy of inflammasome components in FMF patients.

Mortensen et al.⁴⁷ demonstrated that pyrin inflammasome activation reduces the secretion of IL-1 receptor antagonist, thereby diminishing anti-inflammatory capacity and suggesting a novel mechanism contributing to FMF pathogenesis.

Integrated model of pathogenesis

Collectively, current evidence suggests that B30.2/CHS dysregulation, cytoskeletal alterations, and impaired autophagy converge on a common pathogenic node: the loss of negative regulation between pyrin dephosphorylation and ASC oligomerization. Because the cytoskeleton modulates pyrin activation at the same step as the B30.2 and CHS domains (downstream of dephosphorylation), we propose a functional coupling between these systems. Specifically, the B30.2 domain likely depends on precise cytoskeletal configurations to exert its inhibitory effect. FMF-associated variants impair B30.2/CHS function and disrupt this cytoskeleton-dependent regulation. In combination with reduced autophagic clearance, these defects lower the activation threshold of the pyrin inflammasome, promoting excessive ASC oligomerization and driving the hyperinflammatory phenotype observed in FMF.

FAMILIAL MEDITERRANEAN FEVER AND YERSINIA

Pyrin functions as a pattern recognition receptor that senses perturbations in cellular homeostasis, including those induced by microbial processes.¹² Studies have shown that various bacterial toxins modulate pyrin inflammasome–mediated immune responses by targeting Rho GTPases.⁷ Notable toxins that regulate this guard mechanism and thereby influence pyrin inflammasome activation include the T6SS of Burkholderia cenocepacia;^7,19,48 TcdA and TcdB of Clostridium difficile;^7,49 VopS of Vibrio parahaemolyticus;⁷ and YopE, YopT, and YopM of Yersinia pestis.^50,51 Among these, Y. pestis holds particular significance.

Toxins produced by Y. pestis differentially regulate the pyrin inflammasome. YopE and YopT inhibit Rho GTPases, thereby disrupting phagocytosis⁵² and activating the pyrin inflammasome.^50,53-55 In contrast, YopM exploits RhoA-activated kinases to phosphorylate pyrin, suppressing pyrin inflammasome–mediated inflammatory responses.^50,51,56,57

For decades, researchers have sought to explain the high carrier frequency of FMF-associated variants among Mediterranean populations, interpreting it as a possible outcome of selective advantage against a historical disease.^58,59 Y. pestis, the plague-causing bacterium, has emerged as a plausible driver of positive selection in FMF carriers for several reasons:

Y. pestis suppresses pyrin inflammasome–mediated inflammation via YopM.^50,51,56,57

FMF-associated variants confer a gain of function, resulting in overactivation of the pyrin inflammasome.⁶

Historical plague epidemics were widespread throughout the Mediterranean region.⁶⁰

In 2020, Park et al.⁶¹ provided strong evidence supporting this hypothesis. Their key findings were:

Haplotype analysis indicated recent positive selection of FMF-associated variants in the studied population.

Mutant pyrin exhibited reduced binding affinity to YopM compared with wild-type pyrin.

FMF patients mounted a stronger immune response against Y. pestis than healthy individuals.

Other microorganisms, including Mycobacterium tuberculosis⁶² and Brucella melitensis,⁶³ have also been proposed as contributors to the positive selection of FMF variants; however, the evidence supporting these claims remains limited.

GENETICS OF FAMILIAL MEDITERRANEAN FEVER

The MEFV gene and inheritance patterns

FMF is an autoinflammatory disorder caused by pathogenic variants in the MEFV gene. The causative locus for FMF was first identified in 1997 by the International FMF Consortium and the French FMF Consortium.^4,5 The MEFV gene encodes pyrin, a protein that regulates the inflammasome and IL-1β processing, directly linking MEFV variants to innate immune dysregulation. Since its discovery, MEFV has remained one of the most extensively studied autoinflammatory genes for elucidating mechanisms of dysregulated innate immunity.⁶⁴

Historically, FMF has been considered an autosomal recessive disorder. Biallelic pathogenic MEFV variants, particularly prevalent in populations such as Turks, Armenians, Arabs, and non-Ashkenazi Jews,⁶⁵ are strongly associated with disease. However, clinical penetrance is incomplete, and heterozygous carriers may also manifest typical FMF phenotypes, suggesting a spectrum between recessive and dominant-like inheritance patterns.⁶⁶ Recent evidence supports a continuum of inheritance mechanisms, influenced by variant-specific functional effects as well as genetic and environmental modifiers. This incomplete penetrance and variable expressivity are particularly evident when comparing FMF phenotypes across diverse geographic and ethnic backgrounds.

Variant spectrum and genotype–phenotype correlations

The MEFV gene exhibits extensive genetic variability, with over 400 variants currently cataloged in Infevers.⁶⁷ However, only a small subset of these variants accounts for the majority of FMF cases. The most frequent and clinically significant variants are p.M694V, p.V726A, and p.M680I. Among them, p.M694V is consistently associated with early-onset disease, severe clinical phenotype, colchicine resistance, and a high-risk of amyloidosis. In contrast, p.V726A and p.M680I, although enriched in Mediterranean populations, are generally linked to milder phenotypes compared with p.M694V.⁶⁵

Variants such as p.E148Q and p.R202Q have recently been reclassified as low-penetrance or likely benign, with expert consensus groups advising against their reporting as pathogenic in clinical settings. Large-scale cohort studies continue to confirm that genotype remains the strongest predictor of disease severity, although environmental and epigenetic factors also modulate clinical outcomes.

Genetic complexity: modifiers, epigenetics, and overlap

Beyond inheritance patterns, the genotype–phenotype relationship in FMF has garnered considerable attention due to its role in explaining the clinical complexity and heterogeneity of the disease. Patients carrying identical MEFV variants, particularly those with low penetrance, may exhibit a wide spectrum of disease courses, ranging from subclinical carriers to severe, colchicine-resistant FMF. This heterogeneity is partially attributable to the influence of modifier genes and environmental factors. Among genetic modifiers, polymorphisms in SAA1 have been strongly associated with an increased risk of amyloidosis.^68,69 In addition, recent studies have highlighted the contribution of epigenetic mechanisms, including DNA methylation and non-coding RNA regulation, in modulating pyrin inflammasome activity and MEFV expression.⁷⁰

Further complexity arises from the clinical and genetic overlap between FMF and other monogenic autoinflammatory diseases. In FMF-prevalent regions, particularly Türkiye, individuals clinically diagnosed with FMF but lacking biallelic MEFV variants have been found to carry pathogenic variants in other autoinflammatory genes. For example, Karacan et al.⁷¹ reported families with FMF-like phenotypes harboring either a homozygous MVK variant or a heterozygous TNFRSF1A variant, highlighting the potential for misclassification and the need for comprehensive genetic evaluation in atypical cases. This overlap illustrates a broader challenge in autoinflammatory disease classification, where genetic and phenotypic spectra intersect.⁷²

Collectively, these findings underscore that FMF genetics cannot be interpreted in isolation but must be considered within the interconnected network of autoinflammatory pathways.⁶⁴ They highlight the multilayered nature of FMF genetics, encompassing classical MEFV variants, modifier genes, epigenetic regulation, and overlapping disease genes that together shape the clinical phenotype.

Emerging concepts: somatic mosaicism

The advent of next-generation sequencing (NGS) has broadened the spectrum of MEFV variants, enabling the detection of rare and novel alleles as well as cases of somatic mosaicism, which have been increasingly reported in other autoinflammatory disorders, including CAPS (NLRP3) and VEXAS (UBA1).^73-75 A particularly emerging area of interest is somatic MEFV variants.⁷⁶ Although uncommon, somatic mosaicism has been proposed as a contributor to late-onset or atypical FMF, especially in cases where conventional germline testing fails to account for the phenotype. Somatic pathogenic variants may function similarly to low-penetrance germline alleles, modulating disease onset and severity; however, their detection requires high-depth sequencing methods that are not routinely applied in clinical practice. Current evidence remains limited, and further studies are required to clarify their role in FMF pathogenesis and clinical heterogeneity.

Diagnostic strategies in clinical practice

Genetic testing for FMF follows a stepwise, sequencing-based approach that balances efficiency with diagnostic accuracy. In patients from high-prevalence populations presenting with classical FMF symptoms, the first step typically involves targeted genotyping panels covering the most common founder variants, including p.M694V, p.M680I, p.V726A, and p.M694I. If these tests are negative or identify only a single heterozygous variant, Sanger sequencing of exon 10—where the majority of pathogenic variants cluster—is recommended.

When results remain inconclusive, particularly in atypical presentations or in populations with broader allelic heterogeneity, NGS multigene panel sequencing targeting genes associated with autoinflammatory diseases is indicated. NGS enables identification of rare or novel MEFV variants and helps exclude alternative autoinflammatory disorders when multigene panels are applied. Whole-exome or whole-genome sequencing may be justified in unresolved cases, although these approaches frequently reveal variants of uncertain significance. In select cases, especially adult-onset disease with atypical features, high-depth sequencing to detect somatic mosaicism may be considered in research or specialized clinical settings.

At each stage, careful interpretation using reference databases such as Infevers, combined with clinical scoring systems, is essential to avoid overcalling benign polymorphisms as pathogenic. This diagnostic pathway emphasizes that genetic findings must always be interpreted in the context of clinical presentation, a principle central to modern rheumatology genetics.

EPIGENETIC REGULATIONS IN FAMILIAL MEDITERRANEAN FEVER

The Genotype–phenotype gap

The existence of patient groups whose genotypes do not conform to the classical autosomal recessive model of FMF has prompted investigation into additional contributors to disease expression. Such groups include:

Patients carrying only a single pathogenic variant.^77,78

Patients without any identifiable pathogenic variant.⁷⁹

Healthy individuals harboring two pathogenic variants.⁷⁸

Populations with the same ethnic background exhibiting different disease courses across countries.^80-82

These observations have directed attention toward epigenetic regulation as a potential modifier of FMF pathogenesis. Epigenetic mechanisms alter gene expression without changing the underlying DNA sequence.⁸³ They encompass biochemical processes such as acetylation, methylation, and ubiquitination, as well as posttranscriptional regulation mediated by microRNAs (miRNAs).⁸³

DNA methylation and chromatin architecture

Several studies have evaluated the methylation status of the MEFV gene and reported increased methylation,^84-86 particularly in exon 2, accompanied by reduced MEFV expression in FMF patients. Kirectepe et al.⁸⁴ demonstrated a negative correlation between MEFV methylation levels and gene expression. Similarly, Zekry et al.⁸⁶ reported that higher MEFV methylation was associated with increased disease severity. Erdem et al.⁸⁵ investigated the functional consequences of exon 2 methylation and identified alternative splicing of this exon as a key outcome. Furthermore, they observed altered subcellular localization of pyrin lacking exon 2, which localized predominantly to the cytoplasm rather than the nucleus, suggesting a potential mechanism for FMF in the absence of pathogenic variants.

Beyond MEFV-specific changes, global DNA methylation patterns in FMF patients have been assessed. Caldiran et al.⁸⁷ reported increased global methylation levels in FMF patients, with a positive correlation between global methylation and disease severity. They also demonstrated reduced expression of the NLRP13 inflammasome, attributable to hypermethylation of its promoter region. Notably, FMF patients with amyloidosis exhibited higher NLRP13 methylation than both FMF patients without amyloidosis and healthy controls, suggesting that this epigenetic alteration may contribute to amyloidogenesis and could merit screening in FMF patients.

Caldiran et al.⁸⁸ reported increased methylation of specific histone marks in FMF patients. These modifications reflected a combination of proinflammatory and anti-inflammatory influences, which the authors interpreted as indicative of heightened inflammatory activity accompanied by a compensatory regulatory response.

More recently, Röring et al.⁸⁹ assessed chromatin accessibility in FMF patients compared with healthy controls using ATAC-sequencing. They found that FMF patients exhibited a greater number of regions with reduced chromatin accessibility, particularly near genes involved in cellular regulatory processes. Integration with transcriptomic data, which demonstrated downregulation of immune-related pathways, suggested that these chromatin changes may represent a compensatory mechanism aimed at counterbalancing the chronic hyperinflammatory state observed in FMF.

Posttranscriptional regulation: microRNAs (miRNAs)

In a study examining demethylation of inflammasome-associated genes in autoinflammatory disorders, Vento-Tormo et al.⁹⁰ reported no significant differences between FMF patients and healthy controls. This outcome may reflect study limitations, including a very small FMF sample size (n = 5) and the fact that most patients (60%) were receiving anti–IL-1 therapy. Larger studies with appropriate adjustment for such confounders are therefore warranted.

MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression posttranscriptionally,⁹¹ represent another major epigenetic mechanism studied in FMF. Multiple studies have consistently reported altered miRNA expression in FMF patients compared with healthy controls.^92-101 Differences have also been observed across clinical and genetic subgroups. For instance, Akkaya-Ulum et al.⁹² reported distinct inflammatory miRNA profiles among homozygous patients, heterozygous patients, and healthy carriers, while Kahraman et al.¹⁰¹ observed differential expression of specific miRNAs between homozygous and heterozygous individuals. Wada et al.¹⁰⁰ further demonstrated variation according to genotype and exon-specific mutations. Several studies also reported differential miRNA expression based on disease severity⁹⁷ and attack status.⁹⁹ Additionally, Tümerdem et al.⁹⁸ identified miRNAs targeting the NFKB and NR3C pathways that were differentially expressed in colchicine-resistant versus colchicine-responsive patients.

Several studies have investigated the functional role of miRNAs in FMF using advanced experimental approaches. Akkaya-Ulum et al.¹⁰² demonstrated that miR-197-3p, previously reported as downregulated in FMF, exerts anti-inflammatory effects in functional assays. Using 3′UTR luciferase experiments, they identified IL-1R as a direct target of this miRNA and proposed that reduced miR-197-3p expression may contribute to FMF pathogenesis.

Similarly, Akbaba et al.¹⁰³ reported downregulated expression of miR-30e-3p in FMF patients. Functional transfection assays suggested its anti-inflammatory role, and 3′UTR luciferase and Western blot analyses identified IL-1β as a direct target. These findings indicate that miR-30e-3p could serve as a potential diagnostic and therapeutic marker in FMF.

Koga et al.¹⁰⁴ reported significantly reduced levels of miR-204-3p in FMF patients during attacks. Lipopolysaccharide stimulation similarly suppressed miR-204-3p in macrophages, and its inhibition increased TLR4-related cytokine production. Bioinformatics analyses suggested that miR-204-3p targets genes involved in the TLR pathway via regulation of PIK3γ, which was confirmed by luciferase assays demonstrating that miR-204-3p suppresses PIK3γ. Transfection of FMF monocytes further showed that miR-204-3p inhibition increased IL-6 and IL-12p40 expression. The authors proposed miR-204-3p as a potential diagnostic and therapeutic target in FMF.

Latsoudis et al.¹⁰⁵ reported that miR-4520a expression is significantly elevated in MEFV-variant carriers compared with healthy controls. In silico analyses suggested that miR-4520a negatively regulates autophagy-related genes via the RHEB/mTOR pathway. These findings are consistent with protein-level studies demonstrating impaired autophagy in FMF patients.^44-46

Limitations and future perspectives

Despite significant advances in understanding epigenetic regulation in FMF, several key gaps remain. Existing studies have not established causal links between epigenetic alterations and MEFV pathogenic variants, nor have they clearly demonstrated their impact on clinical phenotype. Furthermore, confounding factors such as colchicine treatment, inflammatory status, and tissue specificity complicate the interpretation of current epigenetic data.

Prospective studies with larger cohorts and concordance analyses are therefore needed to delineate the phenotypic consequences of epigenetic modifications. A clearer understanding of these mechanisms may ultimately provide opportunities for the development of targeted therapeutic strategies, as well as improved diagnostic and prognostic tools in FMF.

CONCLUSION

FMF is the prototypical monogenic autoinflammatory disease, arising from pathogenic variants in the MEFV gene. Although it is well established that these variants lead to overactivation of the pyrin inflammasome and a resultant hyperinflammatory state, the precise mechanisms underlying this overactivation remain incompletely understood. Evidence from the literature suggests that alterations in pyrin ligand-binding activity, particularly within the B30.2 and CHS domains, together with disruptions in cytoskeletal regulation, constitute key pathogenic events in FMF. These alterations, which affect the same stage of pyrin inflammasome activation and produce similar downstream consequences, are likely interrelated components of a unified pathogenic mechanism.

While pathogenic MEFV variants are central to FMF, incomplete penetrance and variable clinical expression reflect additional layers of genetic and epigenetic regulation. In patients with atypical clinical features, pathogenic variants in other autoinflammatory genes should be considered. Current studies on epigenetic regulation in FMF remain insufficient to fully explain their impact on disease pathogenesis and phenotypic variability, highlighting the need for rigorously designed investigations. A deeper understanding of these regulatory mechanisms has the potential to improve diagnostic accuracy, guide personalized therapeutic strategies, and inform prognosis in FMF patients.

Authorship Contributions: Concept- S.U., O.C.K., I.K., K.P.; Design- S.U., O.C.K., I.K., K.P.; Supervision- S.U.; Materials- S.U.; Data Collection or Processing- S.U.; Analysis and/or Interpretation- S.U., O.C.K., I.K.; Literature Review- O.C.K., I.K.; Writing- S.U., O.C.K., I.K., K.P.; Critical Review- S.U., O.C.K.

Conflict of Interest: One of the authors, Serdal Uğurlu, is a member of the editorial board of the Balkan Medical Journal. However, he was not involved in any stage of the editorial decision-making process for this manuscript. The manuscript was evaluated independently by editors from other institutions. The other authors declare no conflicts of interest.

Funding: The authors declared that this study received no financial support.

Peer-Review: Serdal Uğurlu is a member of the Editorial Board of the Balkan Medical Journal. However, he was not involved in the editorial decision of the manuscript at any stage.

REFERENCES

1. Alghamdi M. Familial Mediterranean fever, review of the literature. Clin Rheumatol. 2017;36:1707-1713.
2. Ozdogan H, Ugurlu S. Familial Mediterranean Fever. Presse Med. 2019;48:e61-e76.
3. Schnappauf O, Chae JJ, Kastner DL, Aksentijevich I. The Pyrin Inflammasome in Health and Disease. Front Immunol. 2019;10:1745.
4. French FMF Consortium. A candidate gene for familial Mediterranean fever. Nat Genet. 1997;17:25-31.
5. 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;90:797-807.
6. Chae JJ, Cho YH, Lee GS, et al. Gain-of-function Pyrin mutations induce NLRP3 protein-independent interleukin-1β activation and severe autoinflammation in mice. 2011;34:755-768.
7. Xu H, Yang J, Gao W, et al. Innate immune sensing of bacterial modifications of Rho GTPases by the Pyrin inflammasome. 2014;513:237-241.
8. Rathinam VA, Fitzgerald KA. Inflammasome complexes: emerging mechanisms and effector functions. 2016;165:792-800.
9. Jo EK, Kim JK, Shin DM, Sasakawa C. Molecular mechanisms regulating NLRP3 inflammasome activation. Cell Mol Immunol. 2016;13:148-159.
10. Man SM, Kanneganti TD. Regulation of inflammasome activation. Immunol Rev. 2015;265:6-21.
11. Latz E, Xiao TS, Stutz A. Activation and regulation of the inflammasomes. Nat Rev Immunol. 2013;13:397-411.
12. Liston A, Masters SL. Homeostasis-altering molecular processes as mechanisms of inflammasome activation. Nat Rev Immunol. 2017;17:208-214.
13. Woo JS, Imm JH, Min CK, Kim KJ, Cha SS, Oh BH. Structural and functional insights into the B30.2/SPRY domain. EMBO J. 2006;25:1353-1363.
14. Chirita D, Bronnec P, Magnotti F, et al. Mutations in the B30.2 and the central helical scaffold domains of pyrin differentially affect inflammasome activation. Cell Death Dis. 2023;14:213.
15. Richards N, Schaner P, Diaz A, et al. Interaction between pyrin and the apoptotic speck protein (ASC) modulates ASC-induced apoptosis. J Biol Chem. 2001;276:39320-39329.
16. Park YH, Wood G, Kastner DL, Chae JJ. Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS. Nat Immunol. 2016;17:914-921.
17. Jéru I, Papin S, L’hoste S, et al. Interaction of pyrin with 14.3.3 in an isoform-specific and phosphorylation-dependent manner regulates its translocation to the nucleus. Arthritis Rheum. 2005;52:1848-1857.
18. Vajjhala PR, Kaiser S, Smith SJ, et al. Identification of multifaceted binding modes for pyrin and ASC pyrin domains gives insights into pyrin inflammasome assembly. J Biol Chem. 2014;289:23504-23519.
19. Gavrilin MA, Abdelaziz DH, Mostafa M, et al. Activation of the pyrin inflammasome by intracellular Burkholderia cenocepacia. J Immunol. 2012;188:3469-3477.
20. Srinivasula SM, Poyet JL, Razmara M, Datta P, Zhang Z, Alnemri ES. The PYRIN-CARD protein ASC is an activating adaptor for caspase-1. J Biol Chem. 2002;277:21119-21122.
21. Shi J, Zhao Y, Wang K, et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. 2015;526:660-665.
22. Jorch SK, McNally A, Berger P, et al. Complex regulation of alarmins S100A8/A9 and secretion via gasdermin D pores exacerbates autoinflammation in familial Mediterranean fever. J Allergy Clin Immunol. 2023;152:230-243.
23. Apostolidou E, Skendros P, Kambas K, et al. Neutrophil extracellular traps regulate IL-1β-mediated inflammation in familial Mediterranean fever. Ann Rheum Dis. 2016;75:269-277.
24. Weinert C, Grütter C, Roschitzki-Voser H, Mittl PR, Grütter MG. The crystal structure of human pyrin b30.2 domain: implications for mutations associated with familial Mediterranean fever. J Mol Biol. 2009;394:226-236.
25. Chae JJ, Wood G, Masters SL, et al. The B30.2 domain of pyrin, the familial Mediterranean fever protein, interacts directly with caspase-1 to modulate IL-1beta production. Proc Natl Acad Sci U S A. 2006;103:9982-9987.
26. Arakelov G, Arakelov V, Nazaryan K. Complex formation dynamics of native and mutated pyrin’s B30.2 domain with caspase-1. 2018;86:676-683.
27. Fayez AG, Eldeen GN, Zarouk WA, et al. Dynamic disequilibrium-based pathogenicity model in mutated pyrin’s B30.2 domain-Casp1/p20 complex. J Genet Eng Biotechnol. 2022;20:31.
28. Samukawa S, Yoshimi R, Kirino Y, Nakajima H. The PRY/SPRY domain of pyrin/TRIM20 interacts with β2-microglobulin to promote inflammasome formation. Sci Rep. 2021;11:23613.
29. Weinert C, Morger D, Djekic A, Grütter MG, Mittl PR. Crystal structure of TRIM20 C-terminal coiled-coil/B30.2 fragment: implications for the recognition of higher order oligomers. Sci Rep. 2015;5:10819.
30. Mansfield E, Chae JJ, Komarow HD, et al. The familial Mediterranean fever protein, pyrin, associates with microtubules and colocalizes with actin filaments. 2001;98:851-859.
31. Shoham NG, Centola M, Mansfield E, et al. Pyrin binds the PSTPIP1/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway. Proc Natl Acad Sci U S A. 2003;100:13501-13506.
32. Yu JW, Fernandes-Alnemri T, Datta P, et al. Pyrin activates the ASC pyroptosome in response to engagement by autoinflammatory PSTPIP1 mutants. Mol Cell. 2007;28:214-227.
33. Van Gorp H, Saavedra PH, de Vasconcelos NM, et al. Familial Mediterranean fever mutations lift the obligatory requirement for microtubules in Pyrin inflammasome activation. Proc Natl Acad Sci U S A. 2016;113:14384-14389.
34. Gao W, Yang J, Liu W, Wang Y, Shao F. Site-specific phosphorylation and microtubule dynamics control Pyrin inflammasome activation. Proc Natl Acad Sci U S A. 2016;113:E4857-E4866.
35. Magnotti F, Lefeuvre L, Benezech S, et al. Pyrin dephosphorylation is sufficient to trigger inflammasome activation in familial Mediterranean fever patients. EMBO Mol Med. 2019;11:e10547.
36. Hall A. Rho GTPases and the actin cytoskeleton. 1998;279:509-514.
37. Nobes CD, Hall A. Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. 1995;81:53-62.
38. Nishitani-Isa M, Mukai K, Honda Y, et al. Trapping of CDC42 C-terminal variants in the Golgi drives pyrin inflammasome hyperactivation. J Exp Med. 2022;219:e20211889.
39. Spel L, Zaffalon L, Hou C, Nganko N, Chapuis C, Martinon F. CDC42 regulates PYRIN inflammasome assembly. Cell Rep. 2022;41:111636.
40. Waite AL, Schaner P, Hu C, et al. Pyrin and ASC co-localize to cellular sites that are rich in polymerizing actin. Exp Biol Med (Maywood). 2009;234:40-52.
41. Balci-Peynircioglu B, Akkaya-Ulum YZ, Avci E, et al. Potential role of pyrin, the protein mutated in familial Mediterranean fever, during inflammatory cell migration. Clin Exp Rheumatol. 2018;36:116-124.
42. Akbaba TH, Akkaya-Ulum YZ, Demir S, Ozen S, Balci-Peynircioglu B. The pyrin inflammasome aggravates inflammatory cell migration in patients with familial Mediterranean fever. Pediatr Res. 2022;91:1399-1404.
43. Chae JJ, Wood G, Richard K, et al. The familial Mediterranean fever protein, pyrin, is cleaved by caspase-1 and activates NF-kappaB through its N-terminal fragment. 2008;112:1794-1803.
44. Kimura T, Jain A, Choi SW, et al. TRIM-mediated precision autophagy targets cytoplasmic regulators of innate immunity. J Cell Biol. 2015;210:973-989.
45. Skendros P, Chrysanthopoulou A, Rousset F, et al. Regulated in development and DNA damage responses 1 (REDD1) links stress with IL-1β-mediated familial Mediterranean fever attack through autophagy-driven neutrophil extracellular traps. J Allergy Clin Immunol. 2017;140:1378-1387.e13.
46. Mitroulis I, Kourtzelis I, Kambas K, Chrysanthopoulou A, Ritis K. Evidence for the involvement of mTOR inhibition and basal autophagy in familial Mediterranean fever phenotype. Hum Immunol. 2011;72:135-138.
47. Mortensen SB, Hansen AE, Mogensen TH, et al. Pyrin inflammasome activation abrogates interleukin-1 receptor antagonist, suggesting a new mechanism underlying familial mediterranean fever pathogenesis. Arthritis Rheumatol. 2021;73:2116-2126.
48. Aubert DF, Xu H, Yang J, et al. A burkholderia type VI effector deamidates Rho GTPases to activate the Pyrin inflammasome and trigger inflammation. Cell Host Microbe. 2016;19(5):664-674.
49. 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;79:960-968.
50. Chung LK, Park YH, Zheng Y, et al. The yersinia virulence factor YopM hijacks host kinases to inhibit type III effector-triggered activation of the Pyrin inflammasome. Cell Host Microbe. 2016;20:296-306.
51. Ratner D, Orning MP, Proulx MK, et al. The yersinia pestis effector YopM inhibits Pyrin inflammasome activation. PLoS Pathog. 2016;12:e1006035.
52. Black DS, Bliska JB. The RhoGAP activity of the Yersinia pseudotuberculosis cytotoxin YopE is required for antiphagocytic function and virulence. Mol Microbiol. 2000;37:515-527.
53. Medici NP, Rashid M, Bliska JB. Characterization of Pyrin dephosphorylation and inflammasome activation in macrophages as triggered by the yersinia effectors YopE and YopT. Infect Immun. 2019;87:e00822-18.
54. Shao F, Vacratsis PO, Bao Z, Bowers KE, Fierke CA, Dixon JE. Biochemical characterization of the Yersinia YopT protease: cleavage site and recognition elements in Rho GTPases. Proc Natl Acad Sci U S A. 2003;100:904-909.
55. Wang X, Parashar K, Sitaram A, Bliska JB. The GAP activity of type III effector YopE triggers killing of Yersinia in macrophages. PLoS Pathog. 2014;10:e1004346.
56. McDonald C, Vacratsis PO, Bliska JB, Dixon JE. The yersinia virulence factor YopM forms a novel protein complex with two cellular kinases. J Biol Chem. 2003;278:18514-18523.
57. Chung LK, Philip NH, Schmidt VA, et al. IQGAP1 is important for activation of caspase-1 in macrophages and is targeted by Yersinia pestis type III effector YopM. 2014;5:e01402-e01414.
58. Ben-Chetrit E, Touitou I. Familial mediterranean Fever in the world. Arthritis Rheum. 2009;61:1447-1453.
59. Ben-Chetrit E, Levy M. Familial Mediterranean fever. 1998;351:659-664.
60. , V., Plague and Empire in the Early Modern Mediterranean World: The Ottoman Experience. 2015: Cambridge University Press.
61. Park YH, Remmers EF, Lee W, et al. Ancient familial Mediterranean fever mutations in human pyrin and resistance to Yersinia pestis. Nat Immunol. 2020;21:857-867.
62. Ozen S, Balci B, Ozkara S, et al. Is there a heterozygote advantage for familial Mediterranean fever carriers against tuberculosis infections: speculations remain? Clin Exp Rheumatol. 2002;20:S57-S58.
63. Ross JJ. Goats, germs, and fever: Are the pyrin mutations responsible for familial Mediterranean fever protective against Brucellosis? Med Hypotheses. 2007;68:499-501.
64. Ozen S, Aksentijevich I. The past 25 years in paediatric rheumatology: insights from monogenic diseases. Nat Rev Rheumatol. 2024;20:585-593.
65. Lancieri M, Bustaffa M, Palmeri S, et al. An update on familial Mediterranean fever. Int J Mol Sci. 2023;24:9584.
66. Ben-Chetrit E, Touitou I. The significance of carrying MEFV variants in symptomatic and asymptomatic individuals. Clin Genet. 2024;106:217-223.
67. Milhavet F, Cuisset L, Hoffman HM, et al. The infevers autoinflammatory mutation online registry: update with new genes and functions. Hum Mutat. 2008;29:803-808.
68. Atoyan S, Hayrapetyan H, Sarkisian T, Ben-Chetrit E. MEFV and SAA1 genotype associations with clinical features of familial Mediterranean fever and amyloidosis in Armenia. Clin Exp Rheumatol. 2016;34:72-76.
69. Medlej-Hashim M, Delague V, Chouery E, et al. Amyloidosis in familial Mediterranean fever patients: correlation with MEFV genotype and SAA1 and MICA polymorphisms effects. BMC Med Genet. 2004;5:4.
70. 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;19:90.
71. Karacan İ, Uğurlu S, Tolun A, Tahir Turanlı E, Ozdogan H. Other autoinflammatory disease genes in an FMF-prevalent population: a homozygous MVK mutation and a novel heterozygous TNFRSF1A mutation in two different Turkish families with clinical FMF. Clin Exp Rheumatol. 2017;35:75-81.
72. Ben-Chetrit E, Gattorno M, Gul A, et al. Consensus proposal for taxonomy and definition of the autoinflammatory diseases (AIDs): a Delphi study. Ann Rheum Dis. 2018;77:1558-1565.
73. Assrawi E, Louvrier C, Lepelletier C, et al. Somatic mosaic NLRP3 mutations and inflammasome activation in late-onset chronic urticaria. J Invest Dermatol. 2020;140:791-798.e2.
74. Beck DB, Ferrada MA, Sikora KA, et al. Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease. N Engl J Med. 2020;383:2628-2638.
75. Tanaka N, Izawa K, Saito MK, et al. High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome: results of an international multicenter collaborative study. Arthritis Rheum. 2011;63:3625-3632.
76. Shinar Y, Tohami T, Livneh A, et al. Acquired familial Mediterranean fever associated with a somatic MEFV mutation in a patient with JAK2 associated post-polycythemia myelofibrosis. Orphanet J Rare Dis. 2015;10:86.
77. Marek-Yagel D, Berkun Y, Padeh S, et al. Clinical disease among patients heterozygous for familial Mediterranean fever. Arthritis Rheum. 2009;60:1862-1866.
78. Lachmann HJ, Sengül B, Yavuzşen TU, et al. Clinical and subclinical inflammation in patients with familial Mediterranean fever and in heterozygous carriers of MEFV mutations. Rheumatology (Oxford). 2006;45:746-750.
79. Padeh S, Livneh A, Pras E, et al. Familial Mediterranean fever in children presenting with attacks of fever alone. J Rheumatol. 2010;37:865-869.
80. Schwabe AD, Peters RS. Familial Mediterranean fever in armenians. Analysis of 100 cases. Medicine (Baltimore). 1974;53:453-462.
81. Ozen S, Aktay N, Lainka E, Duzova A, Bakkaloglu A, Kallinich T. Disease severity in children and adolescents with familial Mediterranean fever: a comparative study to explore environmental effects on a monogenic disease. Ann Rheum Dis. 2009;68:246-248.
82. Batu ED, Kara Eroğlu F, Tsoukas P, et al. Periodic fever, aphthosis, pharyngitis, and adenitis syndrome: analysis of patients from two geographic areas. Arthritis Care Res (Hoboken). 2016;68:1859-1865.
83. Weinhold B. Epigenetics: the science of change. Environ Health Perspect. 2006;114:A160-A167.
84. 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.
85. Erdem GC, Erdemir S, Abaci I, Aydin AKK, Everest E, Turanli ET. Alternatively spliced MEFV transcript lacking exon 2 and its protein isoform pyrin-2d implies an epigenetic regulation of the gene in inflammatory cell culture models. Genet Mol Biol. 2017;40:688-697.
86. 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;45:721-737.
87. Caldiran FY, Deveci K, Cacan E. NLRP13 inflammasome complex is hypermethylated in familial Mediterranean fever and global methylation correlates with the disease severity. Ann Hum Genet. 2023;87:115-124.
88. Caldiran F, Deveci K, Cacan E. Epigenetic insights into familial Mediterranean fever: increased RGS10 expression and histone modifications accompanies inflammation in familial Mediterranean fever disease. 2024;906:148222.
89. Röring RJ, Li W, Liu R, et al. Epigenetic, transcriptional, and functional characterization of myeloid cells in familial Mediterranean fever. 2024;27:109356.
90. 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;139:202-211.e6.
91. Bushati N, Cohen SM. microRNA functions. Annu Rev Cell Dev Biol. 2007;23:175-205.
92. 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 108:90-94.
93. Amarilyo G, Pillar N, Ben-Zvi I, et al. Analysis of microRNAs in familial Mediterranean fever. PLoS One. 2018;13:e0197829.
94. 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;41:103-111.
95. Sokkar MF, Eldeen GN, Lotfy RS, Kobesiy MM, El-Bassyouni HT, Zarouk WA. Altered expression of miR-17 and miR-148b in pediatric familial mediterranean fever patients. Clin Rheumatol. 2024;43:2661-2667.
96. Demİr F, Çebİ AH, Kalyoncu M. Assessment of circulating microribonucleic acids in patients with familial Mediterranean fever. Arch Rheumatol. 2019;35:52-59.
97. Akbaba TH, Akkaya-Ulum YZ, Tavukcuoglu Z, Bilginer Y, Ozen S, Balci-Peynircioglu B. Inflammation-related differentially expressed common miRNAs in systemic autoinflammatory disorders patients can regulate the clinical course. Clin Exp Rheumatol. 2021;39 Suppl 132:109-117.
98. Tümerdem BŞ, Akbaba TH, Batu ED, et al. Drug metabolism and inflammation related distinct miRNA signature of colchicine resistant familial Mediterranean fever patients. Int Immunopharmacol. 2023;124:111011.
99. Hortu HO, Karaca E, Sozeri B, et al. Evaluation of the effects of miRNAs in familial Mediterranean fever. Clin Rheumatol. 2019;38:635-643.
100. Wada T, Toma T, Matsuda Y, et al. Microarray analysis of circulating microRNAs in familial Mediterranean fever. Mod Rheumatol. 2017;27:1040-1046.
101. 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.
102. Akkaya-Ulum YZ, Akbaba TH, Tavukcuoglu Z, Chae JJ, Yilmaz E, Ozen S, Balci-Peynircioglu B. Familial Mediterranean fever-related miR-197-3p targets IL1R1 gene and modulates inflammation in monocytes and synovial fibroblasts. Sci Rep. 2021;11:685.
103. Akbaba TH, Akkaya-Ulum YZ, Batu ED, et al. Dysregulation of miRNA-30e-3p targeting IL-1β in an international cohort of systemic autoinflammatory disease patients. J Mol Med (Berl). 2023;101:757-766.
104. 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;57:718-726.
105. 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;232:1326-1336.