The risk of familial Mediterranean fever in MEFV heterozygotes: a statistical approach

PLoS One. 2013 Jul 3;8(7):e68431. doi: 10.1371/journal.pone.0068431. Print 2013.


Background: Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disorder due to MEFV mutations and one of the most frequent Mediterranean genetic diseases. The observation of many heterozygous patients in whom a second mutated allele was excluded led to the proposal that heterozygosity could be causal. However, heterozygosity might be coincidental in many patients due to the very high rate of mutations in Mediterranean populations.

Objective: To better delineate the pathogenicity of heterozygosity in order to improve genetic counselling and disease management.

Methods: Complementary statistical approaches were used: estimation of FMF prevalence at population levels, genotype comparison in siblings from 63 familial forms, and genotype study in 557 patients from four Mediterranean populations.

Results: At the population level, we did not observe any contribution of heterozygosity to disease prevalence. In affected siblings of patients carrying two MEFV mutations, 92% carry two mutated alleles, whereas 4% are heterozygous with typical FMF diagnosis. We demonstrated statistically that patients are more likely to be heterozygous than healthy individuals, as shown by the higher ratio heterozygous carriers/non carriers in patients (p<10(-7)-p<0.003). The risk for heterozygotes to develop FMF was estimated between 2.1 × 10(-3) and 5.8 × 10(-3) and the relative risk, as compared to non carriers, between 6.3 and 8.1.

Conclusions: This is the first statistical demonstration that heterozygosity is not responsible for classical Mendelian FMF per se, but constitutes a susceptibility factor for clinically-similar multifactorial forms of the disease. We also provide a first estimate of the risk for heterozygotes to develop FMF.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Cytoskeletal Proteins / genetics*
  • Ethnicity / genetics
  • Familial Mediterranean Fever / epidemiology
  • Familial Mediterranean Fever / genetics*
  • Gene Frequency
  • Genetic Predisposition to Disease*
  • Heterozygote*
  • Humans
  • Mutation*
  • Pedigree
  • Prevalence
  • Pyrin
  • Retrospective Studies
  • Risk
  • Siblings


  • Cytoskeletal Proteins
  • MEFV protein, human
  • Pyrin

Grant support

This work was supported by grants from the Institut national de la santé et de la recherche médicale (INSERM); the Université Pierre et Marie Curie - Paris 6; and the Agence Nationale pour la Recherche (ANR) [06-MRAR-010-02]. The funders had no rule in study design, data collection and analysis, decision to publish, or preparation of the manuscript.