Short Communication The relative contribution of environmental and genetic factors to phenotypic variation in familial Mediterranean fever (FMF) ☆ Ilan Ben-Zvi a, ⁎ , 1 , Benny Brandt a, 1 , Yackov Berkun b , Merav Lidar a , Avi Livneh a a Department of Internal Medicine F and the national FMF center, Sheba Medical Center, Ramat-Gan, 52621 Israel b Department of Pediatrics A, Sackler School of Medicine, Tel Aviv University, Israel abstract article info Article history: Accepted 1 October 2011 Available online 13 October 2011 Received by A.J. van Wijnen Keywords: Familial Mediterranean fever Twins Phenotype Environment Genetics Introduction: Familial Mediterranean fever (FMF) is an autosomal recessive disease, caused by mutations in the FMF gene MEFV (MEditerranean FeVer). It has a large phenotypic diversity even in patients with similar genotypes. Despite evidence that environmental factors (EFs) and genetic factors, including MEFV mutations (such as M694V, E148Q) and background modifier genes (MGs), affect the clinical manifestations of FMF, the relative contribution of each remains unknown. Methods: To investigate the relative contribution of environmental and genetic factors to the phenotype of FMF, we compared the intra-pair clinical concordance of 10 mono and 7 dizygotic twins with FMF. The part played by EFs was determined by the phenotypic discordance of the monozygous twins, and the MGs effect was determined by deducing the environmental effect, computed for MZ twins, from the phenotypic discordance of the dizygous twins. Results: The mean ± SD of intra-pair concordance was higher in the MZ than in DZ twin group (88.1 ± 13.2 vs. 70.7 ± 14.1 respectively, P value b 0.05). Based on the concordance in clinical manifestations in MZ and DZ twins, the environmental effect on the phenotype of FMF is estimated as 11.9% ± 6.6% and the MGs effect as 17.4% ± 15.5% in average. Conclusions: In FMF the phenotype is affected by MEFV mutations, MGs and EFs in an estimated ratio of about 6:1.5:1 respectively. © 2011 Elsevier B.V. All rights reserved. 1. Introduction Familial Mediterranean fever (FMF) is a genetic disease, with an auto- somal recessive trait, caused by mutations in the MEFV (MEditerranean FeVer) gene (Fig. 1) and characterized by bouts of febrile serositis, in- cluding peritonitis, pleuritis and synovitis (Lidar and Livneh, 2007). Some patients have a subclinical chronic inflammatory state, resulting in chronic manifestations (e.g. anemia, splenomegaly) (Ben-Zvi and Livneh, 2010), which might lead to the development of AA amyloidosis, the most severe manifestation of FMF. There is an association between FMF and other diseases, especially vasculitides such as Henoch–Schonlein purpura (HSP), polyarteritis nodosa (PAN) and Bechet's disease (BD) (Balbir-Gurman et al., 2007; Ozdogan et al., 1997). Some of the MEFV mutations, mainly the p.Met694Val mutation, were found to correlate with a more severe form of FMF and confer a higher risk for the development of amyloidosis (Kone Paut et al., 2000; Shinar et al., 2000). However, there is no linearity in genotype- phenotype correlation, and great diversity of clinical characteristics ex- ists among patients carrying the same MEFV mutations, even in the same family (Kutlay et al., 2006). This phenotype-heterogeneity points out to the influence of other factors on disease manifestations, in addi- tion to the MEFV mutations, including modifier genes (MGs), outside the MEFV locus, and environmental factors (EFs). The impact of EFs on FMF severity was illustrated by the finding that country of residence, rather than MEFV mutation, affects the severity of the disease (Ozen et al., 2009; Schwabe and Peters, 1974; Touitou et al., 2007). Other EFs, and a series of modifier genes, were also found to have an effect on disease phenotype and on the risk of amyloidosis (Akar et al., 2006a, 2006b; Gershoni-Baruch et al., 2003; Medlej-Hashim et al., 2004; Ozen et al., 2006, 2009; Touitou et al., 2001; Turkcapar et al., 2007; Yilmaz et al., 2003). Twin studies may serve as an important tool in genetic diseases, for the assessment of the relative role of genetic factors and EFs in disease phenotype. A variability in the clinical course of a disease in identical twins, with identical genetic background, provides a way to estimate the effect of EFs on disease phenotype, while studying phenotype Gene 491 (2012) 260–263 Abbreviations: FMF, familial Mediterranean fever; MGs, modifier genes; EFs, environmental factors; MZ, monozygotic; DZ, dizygotic. ☆ All authors declare no conflict of interest related to this work. ⁎ Corresponding author at: Department of Medicine F and the Rheumatology Unit, Sheba Medical Center, Tel-Hashomer, affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel, 52621 Israel. Tel.: + 972 35302156; fax: + 972 35308044. E-mail address: Ilan.Benzvi@sheba.health.gov.il (I. Ben-Zvi). 1 These authors contributed equally. 0378-1119/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.gene.2011.10.005 Contents lists available at SciVerse ScienceDirect Gene journal homepage: www.elsevier.com/locate/gene