Polymorphism in cytolytic pathway genes in patients with pediatric inflammatory multisystemic syndrome temporally associated with SARS-CoV-2
Polimorfismos em genes da via citolítica em pacientes com síndrome inflamatória multissistêmica pediátrica temporariamente associada ao SARS-CoV-2
Aline Cristina Zanchettin; Laire Schidlowski; Anderson Azevedo Dutra; Vanessa Liberalesso; Ana Paula de Oliveira Pacheco; Heloisa Ilhe Garcia Giamberardino; Victor Horácio de Souza Costa-Junior; Aline Simoneti Fonseca; Luciane Regina Cavalli; Lúcia Noronha; Carolina Cardoso Mello Prando; Cleber Machado Souza
Abstract
Introduction: Pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) is a systemic hyperinflammatory disease that occurs in a small number of children after being infected with SARS-CoV-2. Macrophage activation syndrome, an aggressive condition characterized by the excessive inflammation and activation of well-differentiated macrophages, has been shown to occur in patients infected by SARS-CoV-2. Considering the clinical and pathophysiological similarities between these diseases, our main objective was to determine whether gene polymorphisms associated with macrophage activation syndrome were also present in patients with PIMS-TS. Methods: DNA from 10 pediatric patients with PIMS-TS (case group) and ten COVID-19 patients without PIMS-TS (control group) were genotyped by Real-time PCR analysis (TaqMan®) for single nucleotide polymorphisms (SNP) in four genes associated with macrophage activation syndrome: perforin 1 (PRF1), granzyme B (GZMB), syntaxin 11 (STX11), and syntaxin binding protein 2 (STXBP2). The SNP analysis was performed using the additive, dominant, and recessive models. Results: A significantly higher frequency of an SNP (C wild allele in rs6573910) in the GZMB gene was observed in both the additive and dominant models in the PIMS-TS group than controls. A borderline significant difference was also observed for the G allele in rs7764017 of the STX11 gene in the PIMS-TS group in the additive model. Conclusions: This study indicated the presence of two polymorphisms in genes associated with macrophage activation syndrome (GZMB and STX11) in patients who developed PIMS-TS. If the presence of these SNPs is validated in a larger number of PIMS-TS cases, they can be used as potential biomarkers for early identification of pediatric patients with a higher probability of developing PIMS-TS associated with SARS-CoV-2 infection.
Keywords
Resumo
Introdução: A síndrome multissistêmica inflamatória pediátrica temporariamente associada ao SARS-CoV-2 (SIMP-TS) é uma doença hiperinflamatória sistêmica que ocorre em um pequeno número de crianças após serem infectadas pelo SARS-CoV-2. A síndrome de ativação de macrófagos (SAM), uma condição agressiva caracterizada pela inflamação excessiva e ativação de macrófagos bem diferenciados, demonstrou ocorrer em pacientes infectados por SARS-CoV-2. Considerando as semelhanças clínicas e fisiopatológicas entre essas doenças, neste estudo o nosso principal objetivo foi determinar se polimorfismos gênicos associados à SAM também estavam presentes em pacientes com SIMP-TS. Métodos: DNA de dez pacientes pediátricos com SIMP (grupo caso) e dez pacientes COVID-19 sem SIMP (grupo controle) foram genotipados por análise de PCR em tempo real (tecnologia TaqMan®) para polimorfismos de nucleotídeo único (SNPs) em quatro genes selecionados associados com SAM: perforina 1 (PRF1), granzima B (GZMB), sintaxina 11 (STX11) e proteína de ligação de sintaxina 2 (STXBP2). A análise dos SNPs foi realizada utilizando o modelo aditivo, dominante e recessivo. Resultados: Uma frequência significativamente maior de um SNP (alelo selvagem C em rs6573910) no gene GZMB foi observada pelos modelos aditivo e dominante no grupo SIMP quando comparado aos controles. Além disso, uma significância limítrofe foi observada para o alelo G em rs7764017 do gene STX11 no grupo SIMP pelo modelo aditivo. Conclusões: Nosso estudo indicou a presença de dois polimorfismos em genes associados à SAM (GZMB e STX11) em pacientes que desenvolveram SIMP-TS. Uma vez validada a presença desses SNPs em um número maior de casos de SIMP-TS, eles podem ser usados como potenciais biomarcadores para a identificação precoce de pacientes pediátricos com maior probabilidade de desenvolver SIMP-TS associado à infecção por SARS-CoV-2.
Palavras-chave
Referências
1. Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet. 2020;395(10237):1607-8. doi: 10.1016/S0140- 6736(20)31094-1.
2. Verdoni L, Mazza A, Gervasoni A, Martelli L, Ruggeri M, Ciureda M, et al. An outbreak of severe Kawasaki-like disease at the Italian epicenter of the SARS-CoV-2 epidemic: An observational cohort study. Lancet. 2020;395(10239):1771-78. doi: http://doi.org/10.1016/ S0140-6736(20)31103-X.
3. Health Advisory. Pediatric Multi-System Inflammatory Syndrome Temporally Associated with COVID-19 Interim Case Definition in New York State [Internet]. Available at: https://health.ny.gov/press/ releases/2020/docs/2020-05-13_health_advisory.pdf. Acessed on: January/2022.
4. Otsuka R, Seino KI. Macrophage activation syndrome and COVID-19. Inflamm Regen. 2020;40:19. doi: https://doi.org/10.1186/s41232- 020-00131-w.
5. Brodin P. Why is COVID-19 so mild in children? Acta Paediatr. 2020;109(6):1082-83. doi: https://doi.org/10.1111/apa.15271.
6. Soy M, Atagündüz P, Atagündüz I, Sucak GT. Hemophagocytic lymphohistiocytosis: a review inspired by the COVID-19 pandemic. Rheumatol Int. 2021;41(1):7-18. doi: 10.1007/s00296-020- 04636-y
7. WHO/2019-nCOV/MIS_Children_CRF/2020.2 [Internet]. Available at: https://www.who.int/publications/i/item/WHO-2019-nCoVMIS_Children_CRF-2020.2. Acessed in January 2022.
8. Azevedo MLV, Zanchettin AC, Vaz de Paula CB, Motta Júnior JDS, Malaquias MAS, Raboni SM, et al. Lung Neutrophilic Recruitment and IL-8/IL-17A Tissue Expression in COVID-19. Front Immunol. 2021;12:656350. doi: 10.3389/fimmu.2021.656350.
9. Zhang M, Behrens EM, Atkinson TP, Shakoory B, Grom AA, Cron RQ. Genetic defects in cytolysis in macrophage activation syndrome. Curr Rheumatol Rep. 2014;16(9):439. doi: 10.1007/s11926-014- 0439-2.
10. Garzón-Tituaña M, Arias MA, Sierra-Monzón JL, Morte-Romea E, Santiago L, Ramirez-Labrada A, et al. The Multifaceted Function of Granzymes in Sepsis: Some Facts and a Lot to Discover. Front Immunol. 2020;11:1054. doi: 10.3389/fimmu.2020.01054.
11. SNPinfo [Internet]. Available at: https://snpinfo.niehs.nih.gov/cgi-bin/ snpinfo/snptag.cgi.
12. Caso F, Costa L, Ruscitti P, Navarini L, Del Puente A, Giacomelli R, et al. Could Sars-coronavirus-2 trigger autoimmune and/ or autoinflammatory mechanisms in genetically predisposed subjects? Autoimmun Rev. 2020;19(5):102524. doi: 10.1016/j. autrev.2020.102524.
13. Ministério da Saúde – Brazil [Internet]. Available at: https://www. gov.br/saude/ptbr/assuntos/media/pdf/2020/outubro/23/boletim_ epidemiologico_svs_40.pdf. Acessed on: January/2022.
14. Minoia F, Davi S, Horne A, Demirkaya E, Bovis F, Li C, et al. Clinical features, treatment, and outcome of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a multinational, multicenter study of 362 patients. Arthritis Rheumatol. 2014;66(11):3160-9. doi: 10.1002/art.38802.
15. Ravelli A, Grom A, Behrens E, Cron RQ. Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment. Genes Immun. 2012;13:289-98. doi: 10.1038/gene.2012.3.
16. Ramanan AV, Grom AA. Does systemic-onset juvenile idiopathic arthritis belong under juvenile idiopathic arthritis? Rheumatology (Oxford). 2005;44:1350-53. doi: 10.1093/rheumatology/keh710.
17. Hadchouel M, Prieur AM, Griscelli C. Acute hemorrhagic, hepatic, and neurologic manifestations in juvenile rheumatoid arthritis: possible relationship to drugs or infection. J Pediatr. 1985;106:561-6. doi: 10.1016/s0022-3476(85)80072-x.
18. Ramos-Casals M, Brito-Zerón P, López-Guillermo A, Khamashta MA, Bosch X. Adult haemophagocytic syndrome. Lancet. 2014;383(9927):1503-16. doi: https://doi.org/10.1016/S0140- 67336(13)6148-X.
19. National Center for Biotechnology Information (NCBI) [Internet]. GZMB granzyme B [ Homo sapiens (human) ]. Available at: https:// www.ncbi.nlm.nih.gov/gene/3002. Acessed on: January/2022.
20. Zeglinski MR, Granville DJ. Granzymes in cardiovascular injury and disease. Cell Signal. 2020;76:109804. doi: https://doi.org/10.1016/j. cellsig.2020.109804.
21. Ngan DA, Wilcox PG, Aldaabil M, Li Y, Leipsic JA, Sin DD, et al. The relationship of systemic inflammation to prior hospitalization in adult patients with cystic fibrosis. BMC Pulm Med. 2021;(14)12:3. doi: 10.1186/1471-2466-12-3.
22. Ramcharan T, Nolan O, Lai CY, Prabhu N, Krishnamurthy R, Richter AG, et al. Paediatric Inflammatory Multisystem Syndrome: Temporally Associated with SARS-CoV-2 (PIMS-TS): Cardiac Features, Management and Short-Term Outcomes at a UK Tertiary Paediatric Hospital. Pediatr Cardiol. 2020;41(7):1391-401. doi: 10.1007/s00246-020-02391-2.
23. Vaz de Paula CB, de Azevedo MLV, Nagashima S, Martins APC, Malaquias MAS, Miggiolaro AFRDS, et al. IL-4/IL-13 remodeling pathway of COVID-19 lung injury. Sci Rep. 2020;10(1):18689. doi: 10.1038/s41598-020-75659-5.
24. Ojo AS, Balogun SA, Williams OT, Ojo OS. Pulmonary Fibrosis in COVID-19 Survivors: Predictive Factors and Risk Reduction Strategies. Pulm Med. 2020;2020:6175964. doi: 10.1155/2020/6175964.
25. National Center for Biotechnology Information (NCBI) [Internet]. STX11 syntaxin 11 [ Homo sapiens (human) ]. Available at: https:// www.ncbi.nlm.nih.gov/gene/8676. Acessed on: January/2022.
26. National Center for Biotechnology Information (NCBI) [Internet]. Available at: https://www.ncbi.nlm.nih.gov/snp/?term=rs7764017. Acessed on: January/2022.
Submetido em:
10/06/2022
Aceito em:
10/12/2022
Facebook
Google+
Twitter
LinkedIn
Mendeley
StumbleUpon
CiteULike
Reddit
Email