Elsevier

Clinica Chimica Acta

Volume 414, 24 December 2012, Pages 36-40
Clinica Chimica Acta

Association between sequence variations of the Mediterranean fever gene and fibromyalgia syndrome in a cohort of Turkish patients

https://doi.org/10.1016/j.cca.2012.07.019Get rights and content

Abstract

Objective

Fibromyalgia syndrome (FMS) is a common chronic widespread pain syndrome mainly affecting women. Genetic risk factors are known to contribute to the etiology of the syndrome. Clinical features show that FMS and familial Mediterranean fever (FMF) have some overlapping symptoms. Mediterranean fever (MEFV) gene has already been identified as being responsible for FMF. The aim of this study was to explore the frequency and clinical significance of missense mutations and a common polymorphism of MEFV gene in a cohort of Turkish patients with FMS.

Methods

The study included 187 patients with FMS and 190 healthy controls. Genomic DNA was isolated and genotyped using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analyses for the five MEFV gene mutations (M694V, M680I, V726A, E148Q and P369S) and one polymorphism (R202Q).

Results

There were statistically significant differences of the MEFV gene mutation carrier rates and allele frequencies between FMS patients and healthy controls (p = 0.002, OR: 2.3, 95% CI: 1.35–4.16 and p = 0.003, OR: 2.2, 95% CI: 1.28–3.75, respectively). There was also a significant difference between MEFV mutation carriers and non-carriers with respect to the clinical characteristic of morning fatigue (p = 0.045). The genotype and allele frequencies of R202Q polymorphism of MEFV gene showed statistically significant differences between FMS patients and healthy controls (p < 0.0001 and p < 0.0001, respectively) and especially the homozygous AA genotype was significantly higher in FMS patients than in healthy controls (p = 0.0003; OR: 7.43, 95% CI: 2.14–39.75). While 13 of the 44 FMS patients with MEFV mutation had R202Q polymorphism, none of the 22 controls with MEFV mutation had R202Q polymorphism. Stratification analysis according to clinical features for this disease reveals that morning fatigue and irritable bowel syndrome had associations with R202Q polymorphism (p = 0.022 and p = 0.031 respectively).

Conclusion

The results of this study suggest that MEFV gene mutations and polymorphism are positively associated with predisposition to develop FMS. Further studies with larger populations will be required to confirm these findings.

Highlights

► Genetic and environmental factors play significant roles in the development of FMS ► Clinical features of FMF show some overlapping symptoms with FMS ► As a result MEFV gene sequence variations are positively associated with FMS

Introduction

Fibromyalgia syndrome (FMS) is a chronic, generalized pain condition, defined by widespread musculoskeletal pain for more than 3 months and the presence of ≥ 11 tender points [1]. FMS is also characterized by fatigue, sleep disturbance and often accompanied by a variety of associated symptoms such as irritable bowel syndrome, headache, and mood disorders [2]. The prevalence of FMS in the general population is estimated at 2%, where 85% of the affected are females [3]. FMS has a prevalence that may range between 0.66% and 10.5% for the adult population [3], [4]. The prevalence of this syndrome was reported to be 3.6% in women aged 20–64 in the city of Trabzon, Turkey [4]. FMS is currently considered as a complex disorder, with interplay between sensory abnormalities, central nervous system dysfunction, psychological factors, and environmental triggers [5]. Although the etiology of FMS remains unclear, it is likely that both genetic and environmental factors play significant roles in the development of FMS [6]. Significant familial aggregation, convincing demonstrations of genetic linkages and associations demonstrate an underlying genetic basis for FMS [7]. Many studies have examined the potential contribution of the candidate gene polymorphisms to FMS susceptibility, but these studies have produced diverse results [8]. Identifying the genes responsible for this substantial genetic contribution to risk should provide a better understanding of the complex mechanisms underlying FMS and other chronic pain diseases.

Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by recurrent attacks of fever and inflammation in the peritoneum, synovium, or pleura, and accompanied by pain [9], [10]. Clinical features show that FMS and FMF have some overlapping symptoms, such as chronic lower body pain, points of tenderness, and widespread pain. To date, some scientific investigations seeking to determine the genes associated with FMS had been published for Turkish populations [11], [12], [13], [14], [15], [16]. These investigations were mainly related to serotonergic system genes, but no study has attempted to correlate the Mediterranean fever (MEFV) gene with FMS.

It was demonstrated that rare missense variants of the MEFV gene were, collectively, associated with risk of FMS and are present in a subset of 15% of FMS patients [17]. In persons with MEFV gene mutations, it was suggested that upregulation of the inflammatory response most likely favors inflammation in general and as such predisposes MEFV mutant carriers to inflammatory diseases [18]. The up-regulation of the inflammatory response in carriers of MEFV mutations can also affect the severity of the accompanying chronic diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS), Behcet's disease (BD), palindromic rheumatism (PR) and ulcerative colitis (UC) [19], [20], [21], [22], [23]. Patients with the inflammatory burden of these chronic diseases appear to be highly susceptible to develop a more severe disease if they also have a mutated MEFV.

The MEFV gene is located on the short arm of chromosome 16p13.3, comprises 10 exons [24] and encodes a 781‐amino acid protein called marenostrin or pyrin. Pyrin is only expressed in neutrophils and monocytes, the cell types involved in innate immune responses. Pyrin has a key role in the regulation of inflammasome activity and pro‐interleukin-1β (proIL-1β) processing [25], [26]. At present, more than 180 gene polymorphisms (mutations/polymorphisms) (http://fmf.cnrs.fr/infevers/), primarily clustered in exon 10, have been identified in affected individuals: 70 with known clinical effect and more than 110 with minimal, or without influence on the phenotype. Of these mutations, five account for more than 70% of FMF cases (i.e., V726A, M694V, M694I, M680I, and E148Q) and have different frequencies in classically affected populations [27]. R202Q has also been associated with FMF causative rare mutations in Mediterranean populations [28].

We hypothesized that MEFV mutations may contribute to the development of FMS. Considering that FMF is very common in Turkey, it is important to investigate MEFV mutations and impact of these mutations on FMS. Therefore, we investigated whether the MEFV gene might be involved in the pathogenesis of FMS. We adopted a case–control design, to compare the frequencies of missense mutations (M694V, M680I, V726A, E148Q and P369S) and a common polymorphism (R202Q) between patients with FMS and healthy controls, and to compare disease severity between mutation carriers and non-carriers.

Section snippets

Study population

The study population comprised 187 unrelated FMS patients (mean age 43.47 ± 10.790 years; 3 males, 184 females) recruited consecutively from those whom were treated and followed‐up in the Physical Medicine and Rehabilitation Department of Gaziosmanpasa University Research Hospital, Tokat, Turkey. All patients met the American College of Rheumatology criteria for FMS (widespread pain present for > 3 months, and tenderness in at least 11 of 18 tender point sites) [1]. A total of 190 unrelated healthy

MEFV gene mutations in FMS patients

We investigated whether the MEFV gene mutations might be involved in the pathogenesis of FMS because of its overlapping symptoms with FMF. Table 1 shows the demographic and clinical characteristics of FMS patients according to the presence (carrier) or absence (non-carrier) of MEFV mutations. So many clinic and demographic features (gender, age, height, weight, BMI, sleep disturbances, fatigue, difficulty concentrating, headache, paresthesia, feeling of stiffness, feeling of swelling in soft

Discussion

There is a growing interest in the genetics of FMS, which is a common rheumatologic condition characterized by chronic widespread musculoskeletal pain and tenderness at multiple sites on palpation [1]. To date, some scientific investigations, seeking to determine the genes associated with FMS, had been published for Turkish population [11], [12], [13], [14], [15], [16]. These investigations were mainly related to serotonergic system genes, but no study has attempted to correlate FMS with genes

Conclusions

The results of this study suggest that MEFV gene mutations and polymorphism are positively associated with predisposition to develop FMS. Further studies with larger populations will be required to confirm these findings.

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