NLRP3 gene variants and serum NLRP3 levels in periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome.
NLRP3 gene variants
NLRP3 serum levels
PFAPA syndrome
Journal
Clinical rheumatology
ISSN: 1434-9949
Titre abrégé: Clin Rheumatol
Pays: Germany
ID NLM: 8211469
Informations de publication
Date de publication:
Jan 2023
Jan 2023
Historique:
received:
08
07
2022
accepted:
05
09
2022
revised:
25
08
2022
pubmed:
11
9
2022
medline:
11
1
2023
entrez:
10
9
2022
Statut:
ppublish
Résumé
Although most of the autoinfammatory disorders have a confirmed genetic cause, periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome still has an unknown genetic background. However, familial cases of PFAPA syndrome have been reported suggesting a genetic its basis. PFAPA syndrome may also be considered an infammasome disorder as variants in infammasome-associated genes such as CARD8, NLRP3, and MEFV have been reported to contribute to the disease. Polymerase chain reaction (PCR)/Sanger sequencing analysis was performed for the detection of the variations in 71 PFAPA patients and 71 healthy controls. NLRP3 concentrations in serum were measured in 71 PFAPA patients and 71 healthy controls. No statistically significant differences were observed in the allele or genotype frequencies of the NLRP3 polymorphisms between the controls and patients (P > 0.05). We found no significant differences for NLRP3 serum levels between PFAPA patients and controls (p > 0.05). Mutations in the MEFV gene were detected in 32.5% of our patients (13/40). It seems that the synergistic effect of different genes plays a role in the formation of PFAPA syndrome. For this reason, it may be useful to examine the presence of mutations in genes such as NLRP3, MEFV, and CARD8 together while investigating the genetics of PFAPA syndrome. Key points • Familial cases of PFAPA syndrome have been reported suggesting a genetic basis for this syndrome. • Elevated serum or plasma levels of IL-1β, IL-6, and IL-18 have been demonstrated during PFAPA flares in several studies. • It seems that the synergistic effect of different genes plays a role in the formation of PFAPA syndrome.
Identifiants
pubmed: 36087224
doi: 10.1007/s10067-022-06370-1
pii: 10.1007/s10067-022-06370-1
doi:
Substances chimiques
NLR Family, Pyrin Domain-Containing 3 Protein
0
CARD8 protein, human
0
Neoplasm Proteins
0
CARD Signaling Adaptor Proteins
0
MEFV protein, human
0
Pyrin
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
245-251Subventions
Organisme : Bilimsel Araştirma Projeleri Birimi, Istanbul Üniversitesi
ID : TYL-2020-36900
Informations de copyright
© 2022. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).
Références
Yıldız M, Haşlak F, Adrovic A, Barut K, Kasapçopur Ö (2020) Autoinflammatory diseases in childhood. Balkan Med J 37(5):236–246. https://doi.org/10.4274/balkanmedj.galenos.2020.2020.4.82
doi: 10.4274/balkanmedj.galenos.2020.2020.4.82
Yıldız M, Haslak F, Adrovic A, Ülkersoy İ, Gücüyener N, Şahin S, Barut K, Kasapçopur Ö (2022) Periodic Fever, aphthous stomatitis, pharyngitis, and adenitis syndrome: a single-center experience. Turk Arch Pediatr 57(1):46–52. https://doi.org/10.5152/TurkArchPediatr.2021.21229
doi: 10.5152/TurkArchPediatr.2021.21229
Pehlivan E, Adrovic A, Sahin S, Barut K, Kul Cınar O, Kasapcopur O (2018) PFAPA syndrome in a population with endemic familial mediterranean fever. J Pediatr 192:253–255. https://doi.org/10.1016/j.jpeds.2017.08.078
doi: 10.1016/j.jpeds.2017.08.078
Ter Haar N, Lachmann H, Özen S, Woo P, Uziel Y, Modesto C, Koné-Paut I, Cantarini L, Insalaco A, Neven B, Hofer M, Rigante D, Al-Mayouf S, Touitou I, Gallizzi R, Papadopoulou-Alataki E, Martino S, Kuemmerle-Deschner J, Obici L, Iagaru N, Simon A, Nielsen S, Martini A, Ruperto N, Gattorno M, Frenkel J, Paediatric Rheumatology International Trials Organisation (PRINTO) and the Eurofever/Eurotraps Projects (2013) Treatment of autoinflammatory diseases: results from the Eurofever Registry and a literature review. Ann Rheum Dis 72:678–85. https://doi.org/10.1136/annrheumdis-2011-201268
doi: 10.1136/annrheumdis-2011-201268
Stojanov S, Lapidus S, Chitkara P, Feder H, Salazar JC, Fleisher TA, Brown MR, Edwards KM, Ward MM, Colbert RA, Sun HW, Wood GM, Barham BK, Jones A, Aksentijevich I, Goldbach-Mansky R, Athreya B, Barron KS, Kastner DL (2011) Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is a disorder of innate immunity and Th1 activation responsive to IL-1 blockade. Proc Natl Acad Sci USA 108:7148–7153. https://doi.org/10.1073/pnas.1103681108
doi: 10.1073/pnas.1103681108
Kolly L, Busso N, von Scheven-Gete A, Bagnoud N, Moix I, Holzinger D, Simon G, Ives A, Guarda G, So A, Morris MA, Hofer M (2013) Periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome is linked to dysregulated monocyte IL-1 β production. J Allergy Clin Immunol 131:1635–1643. https://doi.org/10.1016/j.jaci.2012.07.043
doi: 10.1016/j.jaci.2012.07.043
Rigante D, Gentileschi S, Vitale A, Tarantino G, Cantarini L (2017) Evolving frontiers in the treatment of periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome. Isr Med Ass J 19:444–447
Wekell P, Karlsson A, Berg S, Fasth A (2016) Review of autoinflammatory diseases, with a special focus on periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome. Acta Paediatr 105(10):1140–1151. https://doi.org/10.1111/apa.13531
doi: 10.1111/apa.13531
Hashkes PJ, Toker O (2012) Autoinflammatory syndromes. Pediatr Clin North Am 59(2):447–470. https://doi.org/10.1016/j.pcl.2012.03.005
doi: 10.1016/j.pcl.2012.03.005
Sampaio IC, Rodrigo MJ, Monteiro Marques JG (2009) Two siblings with periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome. Pediatr Infect Dis J 28(3):254–255. https://doi.org/10.1097/INF.0b013e31818c8ea5
doi: 10.1097/INF.0b013e31818c8ea5
Valenzuela PM, Majerson D, Tapia JL, Talesnik E (2009) Syndrome of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) in siblings. Clin Rheumatol 28(10):1235–1237. https://doi.org/10.1007/s10067-009-1222-z
doi: 10.1007/s10067-009-1222-z
Antón-Martín P, Ortiz Movilla R, Guillén Martín S, Allende LM, Cuesta Rubio MT, López González MF, Ramos Amador JT (2011) PFAPA syndrome in siblings. Is there a genetic background? Eur J Pediatr 170(12):1563–8. https://doi.org/10.1007/s00431-011-1479-5
doi: 10.1007/s00431-011-1479-5
Manthiram K, Nesbitt E, Morgan T, Edwards KM (2016) Family history in periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome. Pediatrics 138(3):e20154572. https://doi.org/10.1542/peds.2015-4572
doi: 10.1542/peds.2015-4572
Perko D, Debeljak M, Toplak N, Avcin T, Avčin T (2015) Clinical features and genetic background of the periodic fever syndrome with aphthous stomatitis, pharyngitis, and adenitis: a single center longitudinal study of 81 patients. Mediators Infamm 293417. https://doi.org/10.1155/2015/293417
Yildiz M, Adrovic A, Ulkersoy I, Gucuyener N, Koker O, Sahin S, Haslak F, Barut K, Kasapcopur O (2021) The role of Mediterranean fever gene variants in patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome. Eur J Pediatr 180(4):1051–1058. https://doi.org/10.1007/s00431-020-03840-z
doi: 10.1007/s00431-020-03840-z
Berkun Y, Levy R, Hurwitz A, Meir-Harel M, Lidar M, Livneh A, Padeh S (2011) The familial Mediterranean fever gene as a modifier of periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome. Semin Arthritis Rheum 40(5):467–472. https://doi.org/10.1016/j.semarthrit.2010.06.009
doi: 10.1016/j.semarthrit.2010.06.009
Kolly L, Busso N, von Scheven-Gete A, Bagnoud N, Moix I, Holzinger D, Simon G, Ives A, Guarda G, So A, Morris MA, Hofer M (2013) Periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome is linked to dysregulated monocyte IL-1β production. J Allergy Clin Immunol 131(6):1635–1643. https://doi.org/10.1016/j.jaci.2012.07.043
doi: 10.1016/j.jaci.2012.07.043
Cheung MS, Theodoropoulou K, Lugrin J, Martinon F, Busso N, Hofer M (2017) Periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis syndrome is associated with a CARD8 variant unable to bind the NLRP3 inflammasome. J Immunol 198(5):2063–2069. https://doi.org/10.4049/jimmunol.1600760
doi: 10.4049/jimmunol.1600760
Forsvoll J, Kristoffersen EK, Oymar K (2013) Elevated levels of CXCL10 in the periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA) during and between febrile episodes; an indication of a persistent activation of the innate immune system. Pediatr Rheumatol Online J 11(1):38. https://doi.org/10.1186/1546-0096-11-38
doi: 10.1186/1546-0096-11-38
Yamazaki T, Hokibara S, Shigemura T, Kobayashi N, Honda K, Umeda Y, Agematsu K (2014) Markedly elevated CD64 expressions on neutrophils and monocytes are useful for diagnosis of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome during flares. Clin Rheumatol 33(5):677–683. https://doi.org/10.1007/s10067-014-2542-1
doi: 10.1007/s10067-014-2542-1
Kubota K, Ohnishi H, Teramoto T, Kawamoto N, Kasahara K, Ohara O, Kondo N (2014) Clinical and genetic characterization of Japanese sporadic cases of periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome from a single medical center in Japan. J Clin Immunol 34(5):584–593. https://doi.org/10.1007/s10875-014-0043-2
doi: 10.1007/s10875-014-0043-2
Adrovic A, Sahin S, Barut K, Kasapcopur O (2019) Familial Mediterranean fever and periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome: shared features and main differences. Rheumatol Int 39(1):29–36. https://doi.org/10.1007/s00296-018-4105-2
doi: 10.1007/s00296-018-4105-2
Yalçinkaya F, Ozen S, Ozçakar ZB, Aktay N, Cakar N, Düzova A, Kasapçopur O, Elhan AH, Doganay B, Ekim M, Kara N, Uncu N, Bakkaloglu A (2009) A new set of criteria for the diagnosis of familial Mediterranean fever in childhood. Rheumatology (Oxford) 48(4):395–398. https://doi.org/10.1093/rheumatology/ken509
doi: 10.1093/rheumatology/ken509
Asna Ashari K, Rezaei N (2021) PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and adenitis) syndrome: an overview of genetic background. Clin Rheumatol 40(11):4437–4444. https://doi.org/10.1007/s10067-021-05770-z
doi: 10.1007/s10067-021-05770-z
Akelma AZ, Cizmeci MN, Kanburoglu MK, Mete E, Bozkaya D, Tufan N, Catal F (2013) Is PFAPA syndrome really a sporadic disorder or is it genetic? Med Hypotheses 81(2):279–281. https://doi.org/10.1016/j.mehy.2013.04.030
doi: 10.1016/j.mehy.2013.04.030
Menu P, Vince JE (2011) The NLRP3 inflammasome in health and disease: the good, the bad and the ugly. Clin Exp Immunol 166:1–15. https://doi.org/10.1111/j.1365-2249.2011.04440.x
doi: 10.1111/j.1365-2249.2011.04440.x
Mathews RJ, Robinson JI, Battellino M, Wong C, Taylor JC (2014) Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS), Eyre S, Churchman SM, Wilson AG, Isaacs JD, Hyrich K, Barton A, Plant D, Savic S, Cook GP, Sarzi-Puttini P, Emery P, Barrett JH, Morgan AW, McDermott MF (2013) Evidence of NLRP3-inflammasome activation in rheumatoid arthritis (RA); genetic variants within the NLRP3-inflammasome complex in relation to susceptibility to RA and response to anti-TNF treatment. Ann Rheum Dis 73(6):1202-10. https://doi.org/10.1136/annrheumdis-2013-203276
Yüksel Ş, Eren E, Hatemi G, Sahillioğlu AC, Gültekin Y, Demiröz D, Akdiş C, Fresko İ, Özören N (2014) Novel NLRP3/cryopyrin mutations and pro-inflammatory cytokine profiles in Behçet’s syndrome patients. Int Immunol 26(2):71–81. https://doi.org/10.1093/intimm/dxt046
doi: 10.1093/intimm/dxt046
Verma D, Särndahl E, Andersson H, Eriksson P, Fredrikson M, Jönsson JI, Lerm M, Söderkvist P (2012) The Q705K polymorphism in NLRP3 is a gain-of-function alteration leading to excessive interleukin-1β and IL-18 production. PLoS ONE 7(4):e34977. https://doi.org/10.1371/journal.pone.0034977
doi: 10.1371/journal.pone.0034977
Hitomi Y, Ebisawa M, Tomikawa M, Imai T, Komata T, Hirota T, Harada M, Sakashita M, Suzuki Y, Shimojo N, Kohno Y, Fujita K, Miyatake A, Doi S, Enomoto T, Taniguchi M, Higashi N, Nakamura Y, Tamari M (2009) Associations of functional NLRP3 polymorphisms with susceptibility to food-induced anaphylaxis and aspirin-induced asthma. J Allergy Clin Immunol 124(4):779–85.e6. https://doi.org/10.1016/j.jaci.2009.07.044
doi: 10.1016/j.jaci.2009.07.044
Imani D, Azimi A, Salehi Z, Rezaei N, Emamnejad R, Sadr M, Izad M (2018) Association of nod-like receptor protein-3 single nucleotide gene polymorphisms and expression with the susceptibility to relapsing-remitting multiple sclerosis. Int J Immunogenet 45(6):329–336. https://doi.org/10.1111/iji.12401
doi: 10.1111/iji.12401
Addobbati C, da Cruz HLA, Adelino JE, Melo Tavares Ramos AL, Fragoso TS, Domingues A, Branco Pinto Duarte ÂL, Oliveira RDR, Louzada-Júnior P, Donadi EA, Pontillo A, de Azevêdo SJ, Crovella S, Sandrin-Garcia P (2018) Polymorphisms and expression of inflammasome genes are associated with the development and severity of rheumatoid arthritis in Brazilian patients. Inflamm Res 67(3):255–264. https://doi.org/10.1007/s00011-017-1119-2
doi: 10.1007/s00011-017-1119-2
Ben Hamad M, Cornelis F, Marzouk S, Chabchoub G, Bahloul Z, Rebai A, Fakhfakh F, Ayadi H, Petit-Teixeira E, Maalej A (2012) Association study of CARD8 (p.C10X) and NLRP3 (p.Q705K) variants with rheumatoid arthritis in French and Tunisian populations. Int J Immunogenet 39(2):131–6. https://doi.org/10.1111/j.1744-313X.2011.01070.x
doi: 10.1111/j.1744-313X.2011.01070.x
Su Z, Niu Q, Huang Z, Yang B, Zhang J (2020) Association of nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 polymorphisms with systemic lupus erythematosus disease activity and biomarker levels: a case-control study in Chinese population. Medicine (Baltimore) 99(35):e21888. https://doi.org/10.1097/MD.0000000000021888
doi: 10.1097/MD.0000000000021888
Pontillo A, Girardelli M, Kamada AJ, Pancotto JA, Donadi EA, Crovella S, Sandrin-Garcia P (2012) Polimorphisms in inflammasome genes are involved in the predisposition to systemic lupus erythematosus. Autoimmunity 45(4):271–278. https://doi.org/10.3109/08916934.2011.637532
doi: 10.3109/08916934.2011.637532
Theodoropoulou K, Wittkowski H, Busso N, Von Scheven-Gête A, Moix I, Vanoni F, Hengten V, Horneff G, Haas JP, Fischer N, Palm-Beden K, Berendes R, Heubner G, Jansson A, Lainka E, Leimgruber A, Morris M, Foell D, Hofer M (2020) Increased prevalence of NLRP3 Q703K variant among patients with autoinflammatory diseases: an international multicentric studY. Front Immunol 14(11):877. https://doi.org/10.3389/fimmu.2020.00877
doi: 10.3389/fimmu.2020.00877
Di Gioia SA, Bedoni N, von Scheven-Gête A, Vanoni F, SupertiFurga A, Hofer M et al (2015) Analysis of the genetic basis of periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. Sci Rep 5:10200. https://doi.org/10.1038/srep10200
doi: 10.1038/srep10200