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

The Risk of Familial Mediterranean Fever in MEFV Heterozygotes: A Statistical Approach

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Free PMC article

The Risk of Familial Mediterranean Fever in MEFV Heterozygotes: A Statistical Approach

Isabelle Jéru et al. PLoS One. .
Free PMC article

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.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. MEFV genotype distribution in affected siblings of FMF probands.
The upper part of the figure gives a schematic representation of the FMF familial forms included in this analysis: each proband presented a clinical diagnosis of FMF, carried two MEFV mutations and had at least one affected sibling. The lower part of the figure displays the MEFV genotype distribution in affected siblings. Numbers in each genotype class are indicated by labels next to each sector; numbers in brackets correspond to percentages. m: mutated MEFV allele; N: normal MEFV allele.
Figure 2
Figure 2. MEFV genotype distributions in FMF patients from at-risk origin and meeting established clinical criteria.
All included patients (n = 557) were unrelated, had a clinical diagnosis of FMF, met Tel Hashomer's criteria and had parents originating from one of the most at-risk populations. The genotype distribution in all patients fulfilling these inclusion criteria is presented at the top. Detailed genotype distributions according to the origin of patients are displayed below. n indicates the number of patients in each group. Numbers in brackets correspond to percentages. The total number of patients is higher than the sum in each at-risk population, since a few patients had parents from two different at-risk origins. m: mutated MEFV allele; N: normal MEFV allele.
Figure 3
Figure 3. Risk and relative risk for heterozygotes to develop FMF.
Considering the prevalence of FMF reported in Turks and Sephardic Jews –, as well as the distribution of MEFV genotypes in affected and healthy individuals, we could make a rough estimate of the risk and relative risk for heterozygotes to develop FMF, as compared to healthy individuals. Risks are indicated by labels next to each sector, relative risks are displayed below each genotype distribution. m: mutated MEFV allele; N: normal MEFV allele.

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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.
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