The relative contribution of environmental and genetic factors to phenotypic variation in familial Mediterranean fever (FMF)

Abstract

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 < 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.

Introduction

Familial Mediterranean fever (FMF) is a genetic disease, with an autosomal recessive trait, caused by mutations in the MEFV (MEditerranean FeVer) gene (Fig. 1) and characterized by bouts of febrile serositis, including 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 exists 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 addition 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, Akar et al., 2006b, Gershoni-Baruch et al., 2003, Medlej-Hashim et al., 2004, Ozen et al., 2006, Ozen et al., 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 disconcordance in non-identical twins provides a mean to assess the effect of MGs (MacGregor et al., 2000). To date, twin studies in FMF are scarce. Only one study was published, showing that phenotype concordance was higher in monozygotic (MZ) than in dizygotic (DZ) twins, thereby providing an evidence, missing at that time, for the genetic origin of FMF (Shohat et al., 1992). An analysis attempting to estimate the relative role of MEFV mutation, MGs and EFs in FMF phenotype has never been reported, and it is the subject of the present study.