Predicting genetic risk factors for AA amyloidosis in Algerian patients with familial Mediterranean fever

Premier auteur : Djouher Ait-Idir

Revue :  Molecular Genetics and Genomics

Reference :   https://doi.org/10.1007/s00438-024-02133-6

Lien vers l’article : https://pubmed.ncbi.nlm.nih.gov/38451362/

Introduction:

Amyloid-associated renal amyloidosis (AA) is a severe complication of familial Mediterranean fever (FMF). Its occurrence has been reported to be associated with polymorphisms in the serum amyloid A1 (SAA1) gene and variants in the MEFV gene, associated with FMF respectively.

In Algeria, the association between SAA1 variants and FMF-related amyloidosis had not been studied, hence the aim of this case-control study.

Methods:

120 subjects were included including 60 healthy controls and 60 unrelated FMF patients (39 with amyloidosis and 21 without). All were genotyped for SAA1 alleles (SAA1.1, SAA1.5 and SAA1.3), and a subset for the 13 C/T polymorphism using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Comparisons between genotype and allele frequencies were made using the chi-square and Fisher tests.

Results:

Among the 39 FMF patients with AA amyloidosis, there were 18 males for 21 females; mean age was 39.5 years with a mean age at onset of FMF of 11.5 years and a mean number of FMF progression years of 24.5 years; In 36% of cases there was consanguinity and a family history. 77% were treated with colchicine. There was no significant difference for these elements compared with FMF patients without amyloidosis.

The SAA1.1/1.1 genotype was predominant in patients with FMF complicated with AA amyloidosis compared with patients with FMF without amyloidosis (p = 0.001) and controls (p < 0.0001).

The SAA1.1/1.5 genotype was higher in patients without amyloidosis (p = 0.0069) and controls (p = 0.0082) than in patients with amyloidosis.

Bivariate logistic regression revealed an increased risk of AA amyloidosis with three genotypes, SAA1.1/1.1 [odds ratio 7.589 (OR); 95% confidence interval (CI): 2.130-27.041] (p = 0.0018), SAA1. 1/1.3 [OR 5.700; 95% CI: 1.435-22.644] (p = 0.0134), and M694I/M694I [OR 4.6; 95% CI: 1.400-15.117] (p = 0.0119).

The SAA1.1/1.5 - 13 C/C genotype group [OR 0.152; 95% CI: 0.040-0.587] (p = 0.0062) was protective against amyloidosis.

In all groups, the -13 C/C genotype predominated and was not associated with renal complications [OR 0.88; 95% CI: 0.07-10.43] (p = 0.915).

Discussion and conclusion:

In conclusion, unlike the -13 C/T polymorphism, the SAA1.1/1.1, SAA1.1/1.3 and M694I/M694I genotypes may increase the risk of developing renal AA amyloidosis in the Algerian population with familial Mediterranean fever.

Functional diversity of NLRP3 gain-of-function mutants associated with CAPS autoinflammation

First author: Camille Cosson and al.

Link to article: DOI: 10.1084/jem.20231200

Abstract

NLRP3-associated autoinflammatory disease is a heterogenous group of monogenic conditions caused by NLRP3 gain-of-function mutations associated with CAPS autoinflammation. The poor functional characterization of most NLRP3 variants hinders diagnosis despite efficient anti-IL-1 treatments.

Additionally, while NLRP3 is controlled by priming and activation signals, gain-of-functions have only been investigated in response to priming. Here, we characterize 34 NLRP3 variants in vitro, evaluating their activity upon induction, priming, and/or activation signals, and their sensitivity to four inhibitors.

We highlight the functional diversity of the gain-of-function mutants and describe four groups based on the signals governing their activation, correlating partly with the symptom severity. We identify a new group of NLRP3 mutants responding to the activation signal without priming, associated with frequent misdiagnoses.

Our results identify key NLRP3 residues controlling inflammasome activity and sensitivity to inhibitors, and antagonistic mechanisms with broader efficacy for therapeutic strategies. They provide new insights into NLRP3 activation, an explanatory mechanism for NLRP3-AID heterogeneity, and original tools for NLRP3-AID diagnosis and drug development.

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Monogenic auto-inflammatory diseases associated with actinopathies: A review ofthe literature

P. Mertz a, V. Hentgenb, G. Boursier c, J. Delond, S. Georgin-Laviallee,∗,f

Link to article: https://doi.org/10.1016/j.revmed.2023.06.005

Abstract:

Auto-inflammatory diseases (AIDs) are diseases resulting from an inappropriate activation of innate immunity in the absence of any infection. The field of monogenic AIDs is constantly expanding, with the discovery of new pathologies and pathophysiological mechanisms thanks to pangenomic sequencing. Actinopathies withauto-inflammatorymanifestations are anew emerging group of AIDs, linked to defects in the regulation of the actin cytoskeleton dynamics. These diseases most often begin in the neonatal period and combine to varying degrees a more or less severe primary immune deficiency, cytopenias (especially thrombocytopenia), auto-inflammatory manifestations (especially cutaneous and digestive), atopic and auto-immune manifestations. The diagnosis is to be evoked essentially in front of a cutaneousdigestive auto-inflammation picture of early onset, associated with a primary immune deficiency and thrombocytopenia or a tendency to bleed. Some of these diseases have specificities, including a risk of macrophagic activation syndrome or a tendency to atopy or lymphoproliferation. We propose here a review of the literature on these new diseases, with a proposal for a practical approach according to the main associated biological abnormalities and some clinical particularities. However, the diagnosis remains genetic, and several differential diagnoses must be considered. The pathophysiology of these diseases is not yet fully elucidated, and studies are needed to better clarify the inherent mechanisms that can guide the choice of therapies. In most cases, the severity of the picture indicates allogeneic marrow transplantation.

© 2023 Publié par Elsevier Masson SAS au nom de Société Nationale Française de Médecine Interne (SNFMI).