Significance of MEFV gene R202Q polymorphism in Turkish familial Mediterranean fever patients
Highlights
► R202Q is a common polymorphism of MEFV gene. ► A high association was found between R202Q polymorphism and FMF. ► R202Q polymorphism can be included in routine molecular diagnosis of FMF patients.
Introduction
Familial Mediterranean fever (FMF, OMIM ID: 249100) is the most frequent periodic syndrome characterized by recurrent attacks of polyserositis. Fever, abdominal pain, chest pain, and arthritis/arthralgia are the leading symptoms. Amyloidosis is the most severe complication of FMF. Of the known hereditary periodic fevers, FMF is the most prevalent and best characterized. It is an autosomal recessive disorder, which predominantly affects people living in or originating from areas around the Mediterranean basin, mainly Jews, Armenians, Turks and Arabs (Chen et al., 1998, Touitou et al., 1998). Mediterranean fever (MEFV) gene has already been identified as being responsible for FMF (The International FMF Consortium, 1997).
The prevalence of FMF reaches a high of 1 in 200 individuals: 1 in 256 to 1 in 500 in non-Ashkenazi Jews and 1 in 1073 in the Turkish population (Daniels et al., 1995, Ozen et al., 1998). The carrier frequency among North African Jews is 1 in 5 to 1 in 10 and 1 in 5 among Ashkenazi Jews (Daniels et al., 1995). Among Armenians it is expected to be as high as 1 in 3 (Torosyan et al., 2000) and in Turkey the carrier rate is found to be 1 in 5 (Yilmaz et al., 2001).
The MEFV gene is located on the short arm of chromosome 16p13.3, comprises 10 exons (Pras et al., 1992) and encodes a 781‐amino acid protein called marenostrin or pyrin. Pyrin is only expressed in neutrophils and monocytes, which are 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 (Papin et al., 2007, Ting et al., 2006). 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 (Yepiskoposyan and Harutyunyan, 2007).
The association between the disease and many MEFV gene mutations, such as M694V, M694I and V726A, has been clearly established. However, controversy exists regarding the role of some amino acid substitutions, particularly for R202Q, where glutamine (Q) substitutes for arginine (R). It was demonstrated that R202Q (c.605G>A) polymorphism might be a disease-causing mutation at least in some FMF patients (Ozturk et al., 2008). R202Q has also been associated with FMF causative rare mutations in Mediterranean populations (Aldea et al., 2004). The aim of this study was to explore the frequency and clinical significance of the R202Q polymorphism in exon 2 of the MEFV gene in a cohort of Turkish patients with FMF.
Section snippets
Subjects
The study group consisted of 191 unrelated patients with FMF (79 male and 112 female; mean age: 29.38 ± 13.043 standard deviation [SD] years; range, 5–68), and 150 (73 male and 77 female; mean age: 33.87 ± 13.904 SD years; range, 11–87) unrelated healthy controls. All FMF patients were treated and followed up in the Internal Medicine Department at Gaziosmanpasa University Research Hospital, Tokat, Turkey and fulfilled the Tel Hashomer criteria of FMF for classification (Livneh et al., 1997). All
Results
The demographic characteristics of 191 FMF patients were shown in Table 1. No statistically significant association was observed between clinical and demographic features of FMF patients (gender, mean age, mean age at disease onset, mean age at diagnosis, fever, family history of FMF, abdominal pain, pleurisy, erythema, amyloidosis, colchicine use, response to colchicine, peritonitis, arthritis, operation for appendicitis) and MEFV gene R202Q polymorphism (data not shown). Allelic and genotypic
Discussion
The frequencies of four common mutations of MEFV gene (M694V, M680I, V726A and E148Q) were published to be between 28.57–51.4%, 7.56–15.8%, 4.9–9.7% and 3.5–16.3% respectively in Turkish FMF patients (Coker et al., 2011). Among these common mutations M694V mutation was also the most common one in homozygous form in Turkish FMF patients with a frequency of 13.7% (Coker et al., 2011). According to the results of our study the frequency of R202Q polymorphism and homozygous R202Q in FMF patients
Conflicts of interest
None.
Acknowledgments
This study was supported by the Gaziosmanpasa University (Project No. 2008/15).
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