Involvement of the modifier gene of a human Mendelian disorder in a negative selection process

• Published in: PloS one Vol. 4; no. 10; p. e7676
• Main Authors: Jéru, Isabelle, Hayrapetyan, Hasmik, Duquesnoy, Philippe, Cochet, Emmanuelle, Serre, Jean-Louis, Feingold, Josué, Grateau, Gilles, Sarkisian, Tamara, Jeanpierre, Marc, Amselem, Serge
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 30.10.2009; Public Library of Science (PLoS)
• Subjects: Algorithms; Amyloidosis; Amyloidosis - genetics; Armenia; Arthritis; Chi-square test; Congenital diseases; DNA Mutational Analysis; Equilibrium; Familial Mediterranean fever; Familial Mediterranean Fever - genetics; Fever; Genes; Genetic aspects; Genetics; Genetics and Genomics/Genetics of Disease; Genetics and Genomics/Medical Genetics; Genetics and Genomics/Population Genetics; Genotype; Homozygote; Homozygotes; Humans; Immunology; Inflammation; Kidneys; Life Sciences; Loci; Medical research; Models, Biological; Models, Genetic; Models, Statistical; Mutation; Negative selection; Pathology/Molecular Pathology; Patients; Population genetics; Population studies; Primary care; Proteins; Pyrin protein; Risk analysis; Risk Factors; Selection, Genetic; Serum Amyloid A Protein - genetics; Studies; Armenia; France; Armenia; Armenian people; Variant genotypes; Monte Carlo method; Chi square tests; Homozygosity
• DOI: 10.1371/journal.pone.0007676
• ISSN: 1932-6203

Identification of modifier genes and characterization of their effects represent major challenges in human genetics. SAA1 is one of the few modifiers identified in humans: this gene influences the risk of renal amyloidosis (RA) in patients with familial Mediterranean fever (FMF), a Mendelian autoinflammatory disorder associated with mutations in MEFV. Indeed, the SAA1 alpha homozygous genotype and the p.Met694Val homozygous genotype at the MEFV locus are two main risk factors for RA. HERE, WE INVESTIGATED ARMENIAN FMF PATIENTS AND CONTROLS FROM TWO NEIGHBORING COUNTRIES: Armenia, where RA is frequent (24%), and Karabakh, where RA is rare (2.5%). Sequencing of MEFV revealed similar frequencies of p.Met694Val homozygotes in the two groups of patients. However, a major deficit of SAA1 alpha homozygotes was found among Karabakhian patients (4%) as compared to Armenian patients (24%) (p = 5.10(-5)). Most importantly, we observed deviations from Hardy-Weinberg equilibrium (HWE) in the two groups of patients, and unexpectedly, in opposite directions, whereas, in the two control populations, genotype distributions at this locus were similar and complied with (HWE). The excess of SAA1alpha homozygotes among Armenian patients could be explained by the recruitment of patients with severe phenotypes. In contrast, a population-based study revealed that the deficit of alpha/alpha among Karabakhian patients would result from a negative selection against carriers of this genotype. This study, which provides new insights into the role of SAA1 in the pathophysiology of FMF, represents the first example of deviations from HWE and selection involving the modifier gene of a Mendelian disorder.