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

Updated: Dec 11, 2024

Premier auteur : Djouher Ait-Idir

 

Revue :  Molecular Genetics and Genomics


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.


 
 
 

Waldenstrom macroglobulinaemia with AA amyloidosis reveals a B-cell-restricted NLRP2 variant

First author: Terré et al.

Link to article: DOI: 10.1111/bjh.19383


Waldenstrom macroglobulinaemia with AA amyloidosis

Summary

Waldenström macroglobulinemia (WM) is a rare malignant hematopathy characterized by lymphoplasmacytic lymphoma (LPL) secreting IgM. Some patients with WM exhibit chronic inflammation, sometimes complicated by AA amyloidosis, which involves the deposition of insoluble fibrils derived from serum amyloid A (SAA) protein. However, the underlying mechanism of this inflammation remains poorly understood.


We report the case of an 86-year-old female patient with WM complicated by AA amyloidosis. Whole-exome sequencing (WES) revealed a somatic mutation in NLRP2 restricted to B cells. We investigated the functional consequences of this mutation.


The analyses showed that the NLRP2 p.Asp121Gly mutation leads to a reduction in ASC aggregation, a marker of inflammasome activation. In a WM model, the loss of NLRP2 resulted in an increased secretion of CCL-5, a cytokine promoting IL-6 production by stromal cells. IL-6 is a key factor in the induction of SAA, and our results suggest that the NLRP2 mutation may have contributed to the development of AA amyloidosis in this patient.


These findings highlight the importance of somatic mutations in inflammatory regulation and the need for further studies to clarify the role of NLRP2 in the pathophysiology of inflammatory WM (IWM).





 
 
 

Anakinra-Associated Systemic Amyloidosis

Updated: Dec 10, 2024

First author: S Alehashemi

Journal : Arthritis and Rheumatology

Reference : DOI : 10.1002/art.42664



This article reports the first case of iatrogenic systemic amyloidosis due to prolonged use of anakinra, an interleukin-1 receptor antagonist (IL-1Ra), in a patient suffering from multisystem inflammatory disease of neonatal onset (NOMID).


After several years of treatment with daily injections, the patient developed nodules at the injection site, a nephrotic syndrome and amyloid deposits in various organs (skin, kidney, stomach). Mass spectrometry analysis identified these deposits as being due to recombinant anakinra protein, distinct from the endogenous version.


This case highlights a rare complication of injectable biologic treatments, exacerbated by high and prolonged doses. It highlights the importance of monitoring serum protein levels, varying injection sites, and considering a change of therapy if anakinra-related amyloidosis is diagnosed.



 
 
 
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