title: The risk of familial Mediterranean fever in MEFV heterozygotes: a statistical approach.
abstract: 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.
authors.affiliation: UMR_S933, Institut National de la Santé et de la Recherche Médicale, Paris, France. isabelle.jeru@trs.aphp.fr
authors.forename: Isabelle
authors.initials: I
authors.lastname: Jéru
authors.forename: Véronique
authors.initials: V
authors.lastname: Hentgen
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Cochet
authors.forename: Philippe
authors.initials: P
authors.lastname: Duquesnoy
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Le Borgne
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Grimprel
authors.forename: Katia Stankovic
authors.initials: KS
authors.lastname: Stojanovic
authors.forename: Sonia
authors.initials: S
authors.lastname: Karabina
authors.forename: Gilles
authors.initials: G
authors.lastname: Grateau
authors.forename: Serge
authors.initials: S
authors.lastname: Amselem
mesh_terms: D000483:Alleles; D003598:Cytoskeletal Proteins / Q000235:genetics*; D005006:Ethnicity / Q000235:genetics; D010505:Familial Mediterranean Fever / Q000453:epidemiology / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D009154:Mutation; D010375:Pedigree; D015995:Prevalence; D000071198:Pyrin; D012189:Retrospective Studies; D012306:Risk; D035781:Siblings
chemical_list: D003598:Cytoskeletal Proteins; C000604192:MEFV protein, human; D000071198:Pyrin