Journal Mobile Options
Table of Contents
Vol. 25, No. 5, 2005
Issue release date: September–October 2005
Am J Nephrol 2005;25:434–440

Genetic Risk Factors of Amyloidogenesis in Familial Mediterranean Fever

Delibaş A. · Öner A. · Balcı B. · Demircin G. · Bülbül M. · Bek K. · Erdoğan Ö. · Baysun Ş. · Yilmaz E.
To view the fulltext, log in and/or choose pay-per-view option

Individual Users: Register with Karger Login Information

Please create your User ID & Password

Contact Information

I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in


Background/Aims: Evaluation of the risk factors, and phenotype-genotype correlation of familial Mediterranean fever (FMF) gene (MEFV) and serum amyloid A1 (SAA1) gene polymorphisms in renal amyloidosis. Methods: We investigated MEFV and SAA1 genotypes (α, β, and γ isoforms) in 50 FMF patients and 50 healthy children. Tel-Hashomer criteria were used for the diagnosis and severity scoring of FMF. Results: The most common MEFV mutation and SAA1 genotype were M694V/M694V (n = 26/50) and SAA1 α/α (n = 26/50), respectively. Positive family history for amyloidosis was significantly higher (p < 0.001) with more severe clinical course (p = 0.006) in the amyloidosis group than the non-amyloid group. In M694V/M694V mutation, erysipelas-like skin erythema (p = 0.029), arthritis (p = 0.004), arthralgia (p < 0.001) were significantly more frequent with higher severity scores (p = 0.008) than the patients with other mutations. Comparison of the SAA1 α/α genotype with other genotypes revealed more frequent arthritis (p = 0.003) in the SAA1 α/α genotype. In amyloidosis group patients having both M694V/M694V and SAA1 α/α genotypes were the largest subgroup (n = 14, p < 0.001). Logistic regression analysis for amyloidosis corrected risk revealed a 1.2 times increase in M694V/M694V, a 2.4 times increase in SAA1 α/α genotypes and a 2.5 times increase when both are together. Conclusion: Positive family history for amyloidosis and presence of SAA1 α/α genotype in M694V/M694V mutation may predispose to amyloidosis by increasing the clinical severity. Therefore, in such children early colchicine treatment might be recommended even if they are asymptomatic.

Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.


  1. Sohar E, Gafni J, Pras M, Heller H: Familial Mediterranean fever: A survey of 470 cases and rewieved of the literature. Am J Med 1967;43:227–253.
  2. Ben-Chetrit E, Levy M: Familial Mediterranean fever. Lancet 1998;351:659–664.
  3. Pras M, Bronshpigel N, Zemer D, Gafni J: Variable incidence of amyloidosis in familial Mediterranean fever among different ethnic groups. Johns Hopkins Med J 1982;150:22–26.
  4. Öner A, Erdoğan Ö, Demircin G, Bülbül M, Memiş L: Efficacy of colchicine therapy in amyloid nephropathy of familial Mediterranean fever. Pediatr Nephrol 2003;18:521–526.
  5. Tuğlular S, Yalçınkaya F, Paydaş S, Öner A, Utaş C, Bozfakioğlu S, Ataman R, Akpolat T, Ok E, Şen S, Düsünsel R, Evrenkaya R, Akoğlu E: A retrospective analysis for aetiology and clinical findings of 287 secondary amyloidosis cases in Turkey. Nephrol Dial Transplant 2002;17:2003–2005.
  6. The International FMF Consortium: Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 1997;90:797–807.
  7. French FMF Consortium: A candidate gene for familial Mediterranean fever. Nature Genet 1997;17:25–31.
  8. Touitou I, Lesage S, McDermott M, Cuisset L, Hoffman H, Dode C, Shoham N, Aganna E, Hugot JP, Wise C, Waterham H, Pugnere D, Demaille J, Sarrauste de Menthiere C: Infevers: An evolving mutation database for auto-inflammatory syndromes. Hum Mutat 2004;24:194–198.
  9. Samuels J, Aksentijevich I, Torosyan Y, Centola M, Deng Z, Sood R, Kastner DL: 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) 1998;77:268–297.
  10. Cazeneuve C, Sarkisian T, Pecheux C, Dervichian M, Nedelec B, Reinert P, Ayvazyan A, Kouyoumdijan JC, Ajrapetyan H, Delpech M, Goossens M, Dode C, Grateau G, Amselem S: 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 1999;65:88–97.
  11. Gilmore JD, Lovat LB, Persey MR, Pepys MB, Hawkins PN: Amyloid load and clinical outcome in AA amyloidosis in relation to circulating concentration of serum amyloid A protein. Lancet 2001;358:24–29.
  12. Kluve-Beckerman B, Naylor SL, Marshall A, Gardner JC, Shows TB, Benson MD: Localization of human SAA gene(s) to chromosome 11 and detection of DNA polymorphisms. Biochem Biophys Res Commun 1986;137:1196–1204.
  13. Baba S, Masago SA, Tahahashi T, Kasama T, Sugimura H, Tsugane S, Tsutsui Y, Shirasawa H: A novel allelic variant of serum amyloid A, SAA1-gamma: Genomic evidence, evolution, frequency, and implication as a risk factor for reactive systemic AA-amyloidosis. Hum Molec Genet 1995;4:1083–1087.
  14. De Beer FC, Mallya RK, Fagan EA, Lanham JG, Hughes GR, Pepys MB: Serum amyloid-A protein concentration in inflammatory disease and its relationship to the incidence of reactive systemic amyloidosis. Lancet 1982;2:231–234.
  15. Booth DR, Booth SE, Gillmore JD, Hawkins PN, Pepys MB: SAA1 alleles as risk factors in reactive systemic amyloidosis. Amyloid 1998;5:262–265.
  16. Cazeneuve C, Ajrapetyan H, Papin S, Roudot-Thoraval F, Genevieve D, Mndjoyan E, Papazian M, Sarkisian A, Babloyan A, Boissier B, Duquesnoy P, Kouyoumdjian JC, Girodon-Boulandet E, Grateau G, Sarkisian T, Amselem S: Identification of MEFV-independent modifying genetic factors for familial Mediterranean fever. Am J Hum Genet 2000;67:1136–1143.
  17. Gershoni-Baruch R, Brik R, Zacks N, Shinawi M, Lidar M, Livneh A: The contribution of genotype at MEFV and SAA1 loci to amyloidosis and disease severity in patients with familial Mediterranean fever. Arthritis Rheum 2003;48:1149–1155.
  18. Yılmaz E, Balcı B, Kutlay S, Özen S, Ertürk Ş, Öner A, Beşbaş N, Bakkaloğlu A: Analysis of the modifying effects of SAA1, SAA2 and TNF alpha polymorphisms on developing of amyloidosis in FMF patients. Turk J Pediatr 2003;45:198–202.

    External Resources

  19. Akar N, Hasipek M, Akar E, Ekim M, Yalcinkaya F, Cakar N: Serum amyloid A1 and tumor necrosis factor-alpha alleles in Turkish familial Mediterranean fever patients with and without amyloidosis. Amyloid 2003;10:12–16.
  20. Medlej-Hashim M, Delague V, Chouery E, Salem N, Rawashdeh M, Lefranc G, Loiset J, Mégarbané A: Amyloidosis in familial Mediterranean fever: Correlation with MEFV genotype and SAA1 and MICA polymorphism effects. BMC Med Genet 2004;5:4–10.
  21. Livneh A, Langevitz P, Zemer D: Criteria for the diagnosis of familial Mediterranean fever. Semin Arthritis Rheum 1996;26:612–627.
  22. Langevitz P, Livneh A, Padeh S, Zaks N, Zemer D, Pras E, Pras M: Familial Mediterranean fever: New aspects and prospects at the end of Millennium. Isr Med Assoc J 1999;1:31–36.
  23. Touitou I: The spectrum of familial Mediterranean fever (FMF) mutations. Eur J Hum Genet 2001;9:473–483.
  24. Masato M, Chihino T, Yumi K, et al: Influence of genotypes at SAA1 and SAA2 loci on the development and the length of latent period of secondary AA amyloidosis in patients with rheumatoid arthritis. Hum Genet 1999;105:360–366.
  25. Zhang J, Yu KF: What’s the relative risk? JAMA 1998;280:1690–1691.
  26. Schwabe AD, Peters RS: Familial Mediterranean fever in Armenians: Analysis of 100 cases. Medicine 1974;53:453–462.
  27. Dewalle HJ, Domingo C, Rosenbaum M, Ben-Chetrit E, Cattan D, Bernot A: Phenotye-genotype correlation in Jewish patients suffering from familial Mediterranean fever. Eur J Hum Genet 1998;6:95–97.
  28. Shohat M, Magal N, Shohat T, Chen X, Dagan T, Miomouni A, Danon Y, Lotan R, Ogur G, Şirin A, Schlenzinger M, Halpern GJ, Schwabe A, Kastner D, Rotter JI, Fischel-Ghodsian N: Phenotype-genotype correlation in familial Mediterranean fever: Evidence for an association between Met694Val and amyloidosis. Eur J Hum Genet 1999;7:287–292.
  29. Ben-Chetrit E, Backenroth R: Amyloidosis induced, end stage renal disease in patients with renal disease in patients with familial Mediterranean fever is highly associated with point mutations in the MEFV gene. Ann Rheum Dis 2001;60:146–149.
  30. Shinar Y, Livneh A, Langevitz P, Zaks N, Aksentiewich I, Koziol DE: Genotype-phenotype assessment of common genotypes among patients with familial Mediterranean fever. J Rheumatol 2000;27:1703–1707.
  31. Gershoni-Baruch R, Brik R, Shinawi M, Lidar M, Livneh A: Male sex coupled with articular manifestations cause a 4-fold increase in susceptibility to amyloidosis in familial Mediterranean fever patients homozygous for the M694V-MEFV mutation. J Rheumatol 2003;30:308–312.
  32. Yalçınkaya F, Tekin M, Çakar N, Akar E, Akar N, Tümer N: Familial Mediterranean fever and systemic amyloidosis in untreated Turkish patients. Q J Med 2000;93:681–684.
  33. Yalçınkaya F, Çakar N, Mısırlıoğlu M, Tümer N, Akar N, Tekin M, Taştan H, Koçak H, Özkaya N, Elhan A: Genotype-phenotype correlation in a large group of Turkish patients with familial Mediterranean fever: Evidence for mutation-independent amyloidosis. Rheumatology 2000;39:67–72.
  34. Akar E, Yalçınkaya F, Akar N: Is the Ala138Gly alteration of MEFV gene important for amyloidosis? Hum Mutat 2001;17:71.
  35. Balcı B, Tınaztepe K, Yılmaz E, Güçer Ş, Özen S, Topaloğlu R, Beşbaş N, Özgüç M, Bakkaloğlu A: MEFV gene mutations in familial Mediterranean fever phenotype II patients with renal amyloidosis in childhood: A retrospective clinicopathological and molecular study. Nephrol Dial Transplant 2002;17:1921–1923.
  36. Yalçınkaya F, Topaloğlu R, Yılmaz E, Emre S, Erken E, on behalf of The Turkish FMF Study Group (FMF-TR): Distribution of MEFV mutations and phenotype and genotype correlation in Turkish patients with familial Mediterranean fever: A nationwide data (abstract). Clin Exp Rheum 2002;20(suppl 26):S22.
  37. Touitou I, Picot MC, Domingo C, Notarnicola C, Cattan D, Demaille J, Kone-Paut I: The MICA region determines the first modifier locus in familial Mediterranean fever. Arthritis Rheum 2001;44:163–169.
  38. Ben-Chetrit, Levy M: Colchicine: 1998 update. Semin Arthritis Rheum 1998;28:972–973.

Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50