Abstract
Objective
To evaluate the effects of MEFV genotypes and the major histocompatibility complex class I chain-related gene A (MICA) triplet repeat polymorphism on the severity and clinical features of familial Mediterranean fever (FMF) and amyloidosis in a group of Turkish FMF patients.
Methods
We evaluated 105 adult FMF patients (with or without amyloidosis, 33 and 72, respectively) along with 107 healthy controls who were neither related to the patients nor had a family history of FMF or Behcet’s disease. After recording the demographic and clinical data, the predominant mutations in the MEFV gene locus (M694V, M680I, V726A, M694I, and E148Q) were investigated by direct sequencing. MICA transmembrane polymorphisms in exon 5 were studied by vertical gel electrophoresis and fragment analysis of the amplicons obtained from MICA locus with appropriate primers.
Results
Earlier age at onset, increased frequency of attacks, arthritis attacks, erysipelas-like erythema, increased severity scores and amyloidosis were significantly more common in M694V homozygous patients compared to the patients not M694V homozygous (P = 0.005, OR 4.55; P = 0.001, OR 7.60; P = 0.003, OR 4.57; P = 0.002, OR 7.58; P = 0.004, OR 5.15 and P = 0.018, OR 3.33, respectively). We did not detect any modifying effects of MICA alleles as an independently risk factor on the amyloidosis development. However, when we examined the effects of MICA alleles on the course of the disease and development of amyloidosis in the M694V homozygous patients, A5 allele had a protective effect against the development of amyloidosis (P = 0.038, ORadj 0.26 with A5 and P = 0.009, ORadj 4.42 without A5).
Conclusion
Though the effects of the MEFV genotypes seem clear, there are definitely other modifying factors or genes on the development of amyloidosis and on the course of the disease. For example, some MICA alleles have a protective effect on the prognostic factors in FMF.
Similar content being viewed by others
References
Anon (1997) Ancient misses mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. The International FMF Consortium. Cell 90:797–807
Centola M, Wood G, Frucht DM, Galon J, Aringer M, Farrel C et al (2000) The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators. Blood 95:3223–3231
Mansfield E, Chae JJ, Komarrow HD, Brotz TM, Frucht DM, Aksentijevich I et al (2001) The familial Mediterranean fever protein, pyrin, associates with microtubules and co-localizes with actin filaments. Blood 98:851–859
Touitou I, Lesage S, McDermott M, Cuısset L, Hoffman H, Dode C, Shoham N, Aganna E, Hugot JP, Wise C, Waterham H, Pugnere D, Demaille J, Sarrauste de Menthhiere C (2004) Infevers: an evolving mutation database for auto-inflammatory syndromes. Hum Mutat 24:194–198
Dewalle M, Domingo C, Rozenbaum M, Ben-Cherit E, Cattan D, Bernot A et al (1998) Phenotype-genotype correlation in Jewish patients suffering from familial Mediterranean fever (FMF). Eur J Hum Genet 6:95–97
Cazeneuve C, Sarkisian T, Pecheux C, Dervichian M, Nedelec B, Reinert P 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 65:88–97
Tekin M, Yalcinkaya Y, Cakar N, Akar N, Misirlioglu M, Tastan H et al (2000) MEFV mutations in multiplex familial with familial Mediterranean fever: is a particular genotype necessary for amyloidosis? Clin Genet 57:430–434
Yalcınkaya F, Cakar N, Misirlioglu M, Tumer N, Akar N, Tekin M et al (2000) Genotype-phenotype correlation in a large group of Turkish patients with familial Mediterranean fever: evidence for mutation independent amyloidosis. Rheumatology 39:67–72
Booth DR, Gillmore JD, Booth SE, Pepys MB, Hawkins PN (1998) Pyrin/marenostrin mutations in familial Mediterranean fever. Q J Med 91:603–606
Yalcınkaya F, Akar N, Misirlioglu M (1998) Familial Mediterranean fever-amyloidosis and the Val726Ala mutation. N Engl J Med 338:993–994
Yalcınkaya F, Topaloglu R, Yilmaz E, Emre S, Erken E, On behalf of the Turkish FMF Study Group (2002) Distribution of MEFV mutations and phenotype analysis in Turkish patients with FMF: a nation wide study (abstract). Clin Exp Rheumatol 20(Suppl 26):S90
Saatci U, Yalcınkaya F, Oner A, Besbas N, Baskin E (2002) On behalf of the Turkish FMF Study Group. Renal involvement in Turkish patients with FMF (abstract). Clin Exp Rheumatol 20(Suppl 26):S89
Tunca M, Akar S, Onen F, Ozdogan H, Kasapcopur O, Yalcinkaya F. On behalf of the Turkish FMF Study Group (2005) Familial Mediterranean Fever (FMF) in Turkey: results of a Nationwide Multicenter Study. Medicine 84:1–11
Gershoni-Baruch R, Brik R, Zacks N, Shinawi M, Lidar M, Livneh A (2003) The contribution of genotypes at the MEFV and SAA1 loci to amyloidosis and the severity in patients with familial Mediterranean fever. Arthritis Rheum 48:1149–1155
Zwirner NW, Fernandez-Vina MA, Stastny P (1998) MICA, a new polymorphic HLA-related antigen, is expressed mainly by keratinocytes, endothelial cells, and monocytes. Immunogenetic 47:139–148
Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL et al (1999) Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 285:727–729
Wu J, Song Y, Bakker ABH, Bauer S, Spies T, Lanier LL et al (1999) An activating immunoreceptor complex formed by NKG2D and DAP10. Science 285:730–732
Goto K, Ota M, Ando H, Muziki N, Nakamura S, Inoue K et al (1998) MICA gene polymorphisms and HLA-B27 subtypes in Japanese patients with HLA-B27 associated acute anterior uveitis. Invest Ophtalmol Vis Sci 39:634–637
Gonzalez S, Martinez-Borra J, Torre-Alonso JC, Gonzalez-Roces S, Sanchez del Rio J, Rodriguez Perez A et al (1999) The MICA-A9 triplet repeat polymorphism in the transmembrane region confers additional susceptibility to the development of psoriatic arthritis and is independent of the association of Cw*0602 in psoriasis. Arthritis Rheum 42:110–116
Rueda B, Pascual M, Lopez-Nevot MA, Koeleman BPC, Ortega E, Maldonado J et al (2003) Association of MICA-A5.1 allele with susceptibility to celiac disease in a family study. Am J Gastroenterol 98:359–362
Gambelunghe G, Falorni A, Ghaderi M, Laureti S, Tortoioli C, Santeusanio F et al (1999) Microsatellite polymorphism of the MHC class I chain-related gene (MICA-A and MICA-B) genes marks the risk for autoimmune Addison’s disease. J Clin Endocrinol Metab 84:3701–3707
Lee YJ, Huang FY, Wang CH, Lo FS, Tsan KW, Hsu CH et al (2000) Polymorphism in the transmembrane region of the MICA gene and type 1 diabetes. J Pediatr Endocrinol Metab 13:489–496
Hassan AB, Nikitina-Zake L, Padyukov L, Karlsson G, Gupta M, Lundberg IE et al (2003) MICA4/HLA-DRB1*04/TNF1 haplotype is associated with mixed connective tissue disease in Swedish Patients. Hum Immunol 64:290–296
Kawabata Y, Ikegami H, Kawaguchi Y, Fujisawa T, Hotto M, Ueda H et al (2000) Age-related association of MHC class I chain-related gene A (MICA) with type 1 (insuline-dependent) diabetes mellitus. Hum Immunol 61:624–629
Huang F, Lee Y, Chen M, Hsu C, Lin S, Sung T et al (2000) Polymorphisms of transmembrane region of MICA gene and Kawasaki disease. Exp Clin Immunogenet 17:130–137
Mizuki N, Ota M, Kimura M, Ohno S, Ando H, Katsuyama Y et al (1997) Triplet repeat polymorphism in the transmembrane region of the MICA gene: a strong association of six GCT repetitions with Behcet’s disease. Proc Natl Acad Sci USA 94:1298–1303
Salvarani C, Boiardi L, Mantovani V, Olivieri I, Ciancio G, Cantini F et al (2001) Association of MICA alleles and HLA-B51 in Italian patients with Behçet’s disease. J Rheumatol 28:1867–1870
Cohen R, Metzger S, Nahir M, Chajek-Shaul T (2002) Association of the MIC-A gene and HLA-B51 with Behçet’s disease in Arabs and non-Ashkenazi Jews in Israel. Ann Rheum Dis 61:157–160
Touitou I, Picot MC, Domingo C, Notarnicola C, Cattan D, Demaille J et al (2001) The MICA region determines the first modifier locus in familial Mediterranean fever. Arthritis Rheum 44:163–169
Medlej-Hashim M, Delague V, Chouery E, Salem N, Rawashdeh M, Lefranc G et al (2004) Amyloidosis in familial Mediterranean fever patients: correlation with MEFV genotype and SAA1 and MICA polymorphisms effects. BMC Medical Genetics 5:4 (http://www.biomedcentral.com/1471–2350/5/4)
Livneh A, Langevitz P, Zemer D, Zaks N, Kees S, Lidar T, et al (1997) Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum 40:1879–1885
Pras E, Livneh A, Balow JE Jr, Pras E, Kastner DL, Pras M, et al (1998) Clinical differences between North African and Iraqi Jews with familial Mediterranean fever. Am J Med Genet 75:216–219
Gershoni-Baruch R, Kepten I, Shinawi M, Brik R (1999) Direct detection of common mutations in familial Mediterranean fever gene (MEFV) using naturally occurring and primer mediated restriction fragment analysis. Mutation in brief no. 257. Hum Mutat (Online)
Sayhan N, Ozdoğan H, Kasapcopur O, Melikoglu M, Altıparmak MR, Tunc R, Yazici H, Sonmez M, Tuzuner N, erek E, Arisoy N (2000) MEFV gene analysis in familial Mediterranean fever patients from Turkey: prognostic value of M694V homozygous phenotype [absract]. Clin Exp Rheumatol 18:286
Yilmaz E, Balci B, Kutlay S, Ozen S, Erturk S, Oner A, Besbas N, Bakkaloglu A (2003) Analysis of the modifying effects of SAA1, SAA2 and TNF-alpha gene polymorphisms on development of amyloidosis in FMF patients. Turk J Pediatr 45:198–202
Acknowledgment
This study is supported by the Foundation of Academic Research Projects of Ankara University (No: 2003-0809093).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Turkcapar, N., Tuncalı, T., Kutlay, S. et al. The contribution of genotypes at the MICA gene triplet repeat polymorphisms and MEFV mutations to amyloidosis and course of the disease in the patients with familial Mediterranean fever. Rheumatol Int 27, 545–551 (2007). https://doi.org/10.1007/s00296-006-0255-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00296-006-0255-8