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

Year 2019, Volume: 52 Issue: 2, 162 - 166, 31.07.2019

Özkan Varan , Hamit Küçük Hakan Babaoğlu , Nuh Ataş Reyhan Bilici Salman Hasan Satış Mehmet Akif Öztürk Şeminur Haznedaroğlu Berna Göker Abdurrahman Tufan

Abstract

Background: Familial Mediterranean Fever (FMF) is the
most common auto-inflammatory disease characterized by recurrent attacks. FMF
was found to be correlated with the mutation in MEFV gene. The mutation in the
MEFV gene located at the short arm of the 16th chromosome impairs the encoding
of the pyrin protein. Until now, numerous variants of the MEFV gene have been
identified. Patients with M694V homozygous mutation have been reported to have
a more severe disease. However, there is no clear study of clinical correlation
in other variants. In this study, we aimed to investigate the frequency and
clinical correlation of MEFV gene variants.

 

Methods: Electronic
medical records of FMF cohort were retrospectively analyzed. FMF cohort was
established in year 2010 and since then all patients who fulfilled Tel-Hashomer
criteria Demographic
information, attack characteristics, treatment information and MEFV gene
outcomes of the patients were analysed using the records. In MEFV gene
analysis, M694V, M694I, M680I, V726A, R761H, A744S, F479L, P369S, R202Q and
E148Q variants are evaluated.

 

Results: A total of 605 patients were included in
the study. In patients who had M694V mutation, arthritis and erysipelas were
observed more frequently (p=0.04, p=0.008). Increased family history of FMF was
identified in patients with M694V mutation (p<0.001).  In patients with M694V mutation, it was found
that age of onset of FMF symptoms, age of diagnosis, and age of treatment
initiation 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 developing
amyloidosis was higher in M694V homozygous (Odds ratio 7.46, 95% confidence
interval: 2.92-19.05).

Conclusions: In conclusion, homozygous M694V mutation
leads to severe disease. There was no clinical variability in other MEFV gene
variants.

Keywords

Familial Mediterranean Fever, MEFV gene

References

• 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&lt;1879::AID-ART23&gt;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