Ankara Eğitim ve Araştırma Hastanesi Tıp Dergisi

1304-6187

Sağlık Bakanlığı Ankara Eğitim ve Araştırma Hastanesi

The MEFV variants in patients with familial Mediterranean fever and their clinical correlations

Varan

Özkan

Küçük

Hamit

Babaoğlu

Hakan

Ataş

Nuh

Bilici Salman

Reyhan

Satış

Hasan

Öztürk

Mehmet Akif

Haznedaroğlu

Şeminur

Göker

Berna

Tufan

Abdurrahman

07 31 2019

52 2 162 166 01 04 2019 03 31 2019

2003

Ankara Eğitim ve Araştırma Hastanesi Tıp Dergisi

Background: Familial Mediterranean Fever (FMF) is themost common auto-inflammatory disease characterized by recurrent attacks. FMFwas found to be correlated with the mutation in MEFV gene. The mutation in theMEFV gene located at the short arm of the 16th chromosome impairs the encodingof the pyrin protein. Until now, numerous variants of the MEFV gene have beenidentified. Patients with M694V homozygous mutation have been reported to havea more severe disease. However, there is no clear study of clinical correlationin other variants. In this study, we aimed to investigate the frequency andclinical correlation of MEFV gene variants.Methods: Electronicmedical records of FMF cohort were retrospectively analyzed. FMF cohort wasestablished in year 2010 and since then all patients who fulfilled Tel-Hashomercriteria Demographicinformation, attack characteristics, treatment information and MEFV geneoutcomes of the patients were analysed using the records. In MEFV geneanalysis, M694V, M694I, M680I, V726A, R761H, A744S, F479L, P369S, R202Q andE148Q variants are evaluated.Results: A total of 605 patients were included inthe study. In patients who had M694V mutation, arthritis and erysipelas wereobserved more frequently (p=0.04, p=0.008). Increased family history of FMF wasidentified in patients with M694V mutation (p<0.001). In patients with M694V mutation, it was foundthat age of onset of FMF symptoms, age of diagnosis, and age of treatmentinitiation were younger (p=0.003, p=0.014, p=0.025). In patients with M694V homozygous,frequency of amyloidosis was higher (p<0.001). The risk of developingamyloidosis was higher in M694V homozygous (Odds ratio 7.46, 95% confidenceinterval: 2.92-19.05).Conclusions: In conclusion, homozygous M694V mutationleads to severe disease. There was no clinical variability in other MEFV genevariants.

Familial Mediterranean Fever MEFV gene

1. Gershoni-Baruch R, Brik R, Shinawi M, Livneh A (2002) The differential contribution of MEFV mutant alleles to the clinical profile of familial Mediterranean fever. Eur J Hum Genet 10 (2):145-149. doi:10.1038/sj.ejhg.5200776

2. Ben-Chetrit E, Touitou I (2012) The impact of MEFV gene identification on FMF: an appraisal after 15 years. Clin Exp Rheumatol 30 (3 Suppl 72):S3-6

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

4. Tufan A, Babaoglu MO, Akdogan A et al. (2007) Association of drug transporter gene ABCB1 (MDR1) 3435C to T polymorphism with colchicine response in familial Mediterranean fever. J Rheumatol 34 (7):1540-1544

5. Chae JJ, Cho YH, Lee GS et al. (2011) Gain-of-function Pyrin mutations induce NLRP3 protein-independent interleukin-1beta activation and severe autoinflammation in mice. Immunity 34 (5):755-768. doi:10.1016/j.immuni.2011.02.020

6. Martinon F, Burns K, Tschopp J (2002) The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 10 (2):417-426

7. Infevers (2018) The registry of familial Mediterranean fever (FMF) and hereditary autoinflammatory disorders mutations. http://fmf.igh.cnrs.fr/ISSAID/infevers/.

8. Fujikura K (2015) Global epidemiology of Familial Mediterranean fever mutations using population exome sequences. Mol Genet Genomic Med 3 (4):272-282. doi:10.1002/mgg3.140

9. Olgun A, Akman S, Kurt I, Tuzun A, Kutluay T (2005) MEFV mutations in familial Mediterranean fever: association of M694V homozygosity with arthritis. Rheumatol Int 25 (4):255-259. doi:10.1007/s00296-003-0433-x

10. Yalcinkaya F, Cakar N, Misirlioglu M et al. (2000) Genotype-phenotype correlation in a large group of Turkish patients with familial mediterranean fever: evidence for mutation-independent amyloidosis. Rheumatology (Oxford) 39 (1):67-72

11. Ece A, Cakmak E, Uluca U et al. (2014) The MEFV mutations and their clinical correlations in children with familial Mediterranean fever in southeast Turkey. Rheumatol Int 34 (2):207-212. doi:10.1007/s00296-013-2858-1

12. Jarjour RA (2010) Familial Mediterranean fever in Syrian patients: MEFV gene mutations and genotype-phenotype correlation. Mol Biol Rep 37 (1):1-5. doi:10.1007/s11033-009-9475-9

13. Dewalle M, Domingo C, Rozenbaum M et al. (1998) Phenotype-genotype correlation in Jewish patients suffering from familial Mediterranean fever (FMF). Eur J Hum Genet 6 (1):95-97. doi:10.1038/sj.ejhg.5200170

14. Livneh A, Langevitz P, Zemer D et al. (1997) Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum 40 (10):1879-1885. doi:10.1002/1529-0131(199710)40:10<1879::AID-ART23>3.0.CO;2-M

15. Taskiran EZ, Cetinkaya A, Balci-Peynircioglu B, Akkaya YZ, Yilmaz E (2012) The effect of colchicine on pyrin and pyrin interacting proteins. J Cell Biochem 113 (11):3536-3546. doi:10.1002/jcb.24231

16. Kasifoglu T, Bilge SY, Sari I et al. (2014) Amyloidosis and its related factors in Turkish patients with familial Mediterranean fever: a multicentre study. Rheumatology (Oxford) 53 (4):741-745. doi:10.1093/rheumatology/ket400

17. Chae JJ, Wood G, Masters SL et al. (2006) 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 103 (26):9982-9987. doi:10.1073/pnas.0602081103

18. Pasa S, Altintas A, Devecioglu B et al. (2008) Familial Mediterranean fever gene mutations in the Southeastern region of Turkey and their phenotypical features. Amyloid 15 (1):49-53. doi:10.1080/13506120701815456

19. Coskun S, Kurtgoz S, Keskin E, Sonmez F, Bozkurt G (2015) Frequency of mutations in Mediterranean fever gene, with gender and genotype-phenotype correlations in a Turkish population. J Genet 94 (4):629-635

20. Bonyadi MJ, Gerami SM, Somi MH, Dastgiri S (2015) MEFV mutations in Northwest of Iran: a cross sectional study. Iran J Basic Med Sci 18 (1):53-57

21. Cekin N, Akyurek ME, Pinarbasi E, Ozen F (2017) MEFV mutations and their relation to major clinical symptoms of Familial Mediterranean Fever. Gene 626:9-13. doi:10.1016/j.gene.2017.05.013

22. Cattan D, Dervichian M, Thomas M, Dode C, Touitou I (2001) MEFV mutations and phenotype-genotype correlations in North African Jews and Armenians with familial Mediterranean fever. Isr Med Assoc J 3 (11):803-804

23. Samuels J, Aksentijevich I, Torosyan Y et al. (1998) 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) 77 (4):268-297

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

25. Cazeneuve C, Sarkisian T, Pecheux C et al. (1999) MEFV-Gene analysis in armenian patients with Familial Mediterranean fever: diagnostic value and unfavorable renal prognosis of the M694V homozygous genotype-genetic and therapeutic implications. Am J Hum Genet 65 (1):88-97. doi:10.1086/302459

26. Soylemezoglu O, Arga M, Fidan K et al. (2010) Unresponsiveness to colchicine therapy in patients with familial Mediterranean fever homozygous for the M694V mutation. J Rheumatol 37 (1):182-189. doi:10.3899/jrheum.090273

27. Akpolat T, Ozkaya O, Ozen S (2012) Homozygous M694V as a risk factor for amyloidosis in Turkish FMF patients. Gene 492 (1):285-289. doi:10.1016/j.gene.2011.10.012

28. Touitou I, Sarkisian T, Medlej-Hashim M et al. , International Study Group for Phenotype-Genotype Correlation in Familial Mediterranean F (2007) Country as the primary risk factor for renal amyloidosis in familial Mediterranean fever. Arthritis Rheum 56 (5):1706-1712. doi:10.1002/art.22507

29. Ong FS, Vakil H, Xue Y et al. (2013) The M694V mutation in Armenian-Americans: a 10-year retrospective study of MEFV mutation testing for familial Mediterranean fever at UCLA. Clin Genet 84 (1):55-59. doi:10.1111/cge.12029