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The Risk of Familial Mediterranean Fever in MEFV Heterozygotes: A Statistical Approach
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 he...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3700951/ https://www.ncbi.nlm.nih.gov/pubmed/23844200 http://dx.doi.org/10.1371/journal.pone.0068431 |
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author | Jéru, Isabelle Hentgen, Véronique Cochet, Emmanuelle Duquesnoy, Philippe Le Borgne, Gaëlle Grimprel, Emmanuel Stojanovic, Katia Stankovic Karabina, Sonia Grateau, Gilles Amselem, Serge |
author_facet | Jéru, Isabelle Hentgen, Véronique Cochet, Emmanuelle Duquesnoy, Philippe Le Borgne, Gaëlle Grimprel, Emmanuel Stojanovic, Katia Stankovic Karabina, Sonia Grateau, Gilles Amselem, Serge |
author_sort | Jéru, Isabelle |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3700951 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-37009512013-07-10 The Risk of Familial Mediterranean Fever in MEFV Heterozygotes: A Statistical Approach Jéru, Isabelle Hentgen, Véronique Cochet, Emmanuelle Duquesnoy, Philippe Le Borgne, Gaëlle Grimprel, Emmanuel Stojanovic, Katia Stankovic Karabina, Sonia Grateau, Gilles Amselem, Serge PLoS One Research Article 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. Public Library of Science 2013-07-03 /pmc/articles/PMC3700951/ /pubmed/23844200 http://dx.doi.org/10.1371/journal.pone.0068431 Text en © 2013 Jéru et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Jéru, Isabelle Hentgen, Véronique Cochet, Emmanuelle Duquesnoy, Philippe Le Borgne, Gaëlle Grimprel, Emmanuel Stojanovic, Katia Stankovic Karabina, Sonia Grateau, Gilles Amselem, Serge The Risk of Familial Mediterranean Fever in MEFV Heterozygotes: A Statistical Approach |
title | The Risk of Familial Mediterranean Fever in MEFV Heterozygotes: A Statistical Approach |
title_full | The Risk of Familial Mediterranean Fever in MEFV Heterozygotes: A Statistical Approach |
title_fullStr | The Risk of Familial Mediterranean Fever in MEFV Heterozygotes: A Statistical Approach |
title_full_unstemmed | The Risk of Familial Mediterranean Fever in MEFV Heterozygotes: A Statistical Approach |
title_short | The Risk of Familial Mediterranean Fever in MEFV Heterozygotes: A Statistical Approach |
title_sort | risk of familial mediterranean fever in mefv heterozygotes: a statistical approach |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3700951/ https://www.ncbi.nlm.nih.gov/pubmed/23844200 http://dx.doi.org/10.1371/journal.pone.0068431 |
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