Allelic variants in genes associated with hereditary periodic fever syndromes as susceptibility factors for reactive systemic AA amyloidosis

Abstract

We investigated the hypothesis that low-penetrance mutations in genes (TNFRSF1A, MEFV and NALP3/CIAS1) associated with hereditary periodic fever syndromes (HPFs) might be risk factors for AA amyloidosis among patients with chronic inflammatory disorders, including rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), Crohn's disease, undiagnosed recurrent fevers and HPFs themselves. Four of 67 patients with RA plus amyloidosis had MEFV variants compared with none of 34 RA patients without amyloid (P value ¼ 0.03). The E148Q variant of MEFV was present in two of the three patients with TNF receptor-associated periodic syndrome (TRAPS) complicated by amyloid in two separate multiplex TRAPS families containing 5 and 16 affected members respectively, and the single patient with Muckle-Wells syndrome who had amyloidosis was homozygous for this variant. The R92Q variant of TNFRSF1A was present in two of 61 JIA patients with amyloidosis, and none of 31 nonamyloidotic JIA patients. No HPF gene mutations were found in 130 healthy control subjects. Although allelic variants in HPFs genes are not major susceptibility factors for AA amyloidosis in chronic inflammatory disease, low-penetrance variants of MEFV and TNFRSF1A may have clinically significant proinflammatory effects.

TNFRSF1A Gene Causing Tumor Necrosis Factor Receptor-associated Periodic Syndrome in 2 Siblings Displaying Variable Disease Severity and Discordant Heterozygosity for an MEFV E148Q Variant

“…The E148Q found in this family has been shown to display features to suggest that it is likely a susceptibility variant for autoinflammation rather than an FMF-causing mutation 4,5,6,7 . It is unlikely that this variant has contributed to the periodic fever syndrome seen in this family.…”

Inflammasome is a central player in the induction of obesity and insulin resistance

“…However, NLRs also contribute to inflammation by sensing "danger signals" (i.e., endogenous molecules that are produced during tissue damage or inflammation) (3)(4)(5). A prominent example of an NLR protein implicated in autoinflammatory disease is Nlrp3 (also called Cryopyrin) (6). Nlrp3 activation induces the recruitment and autocatalytic activation of the cystein protease caspase-1 in a large cytosolic protein complex named the "inflammasome" (2-7).…”

Systemic AA amyloidosis as a unique manifestation of a combined mutation of TNFRSF1A and MEFV genes

“…Finally, the underlying autoinflammatory syndrome was diagnosed by means of extensive genetic testing. Although allelic variants in TRAPS and FMF genes are not major susceptibility factors for AA amyloidosis in chronic inflammatory disease, low-penetrance variants of MEFV and TNFRSF1A may have clinically significant proinflammatory effects [7]. The genotypes including two mutations located within mutational ''hot-spots'' (codons 680 or 694) of the MEFV gene are associated with severe phenotypes, high penetrance and risk of amyloidosis, whereas mild phenotypes are associated with some other mutations [8].…”