title: 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=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.
authors.affiliation: Department of Diabetes and Metabolic Medicine, Barts and London, Queen Mary's School of Medicine and Dentistry, Whitechapel, London, UK.
authors.forename: E
authors.initials: E
authors.lastname: Aganna
authors.forename: P N
authors.initials: PN
authors.lastname: Hawkins
authors.forename: S
authors.initials: S
authors.lastname: Ozen
authors.forename: T
authors.initials: T
authors.lastname: Pettersson
authors.forename: A
authors.initials: A
authors.lastname: Bybee
authors.forename: S A
authors.initials: SA
authors.lastname: McKee
authors.forename: H J
authors.initials: HJ
authors.lastname: Lachmann
authors.forename: L
authors.initials: L
authors.lastname: Karenko
authors.forename: A
authors.initials: A
authors.lastname: Ranki
authors.forename: A
authors.initials: A
authors.lastname: Bakkaloglu
authors.forename: N
authors.initials: N
authors.lastname: Besbas
authors.forename: R
authors.initials: R
authors.lastname: Topaloglu
authors.forename: H M
authors.initials: HM
authors.lastname: Hoffman
authors.forename: G A
authors.initials: GA
authors.lastname: Hitman
authors.forename: P
authors.initials: P
authors.lastname: Woo
authors.forename: M F
authors.initials: MF
authors.lastname: McDermott
mesh_terms: D019943:Amino Acid Substitution; D000686:Amyloidosis / Q000235:genetics* / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins; D010505:Familial Mediterranean Fever / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D009154:Mutation; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010375:Pedigree; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D000071198:Pyrin
chemical_list: D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C000604192:MEFV protein, human; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D011506:Proteins; D000071198:Pyrin