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Genetic Variation of Kallikrein-Kinin System and Related Genes in Patients With Hereditary Angioedema

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Veronez, Camila Lopes [1] ; Aabom, Anne [2, 3] ; Martin, Renan Paulo [1, 4] ; Filippelli-Silva, Rafael [1] ; Goncalves, Rozana Fatima [5] ; Nicolicht, Priscila [1] ; Mendes, Agatha Ribeiro [1] ; Da Silva, Jane [6] ; Guilarte, Mar [7] ; Grumach, Anete Sevciovic [8] ; Mansour, Eli [9] ; Bygum, Anette [2, 3] ; Pesquero, Joao Bosco [1]
Número total de Autores: 13
Afiliação do(s) autor(es):
[1] Univ Fed Sao Paulo, Dept Biophys, Sao Paulo - Brazil
[2] Odense Univ Hosp, Dept Dermatol, Odense - Denmark
[3] Odense Univ Hosp, Allergy Ctr, Odense - Denmark
[4] Johns Hopkins Univ, Inst Med Genet, Baltimore, MD - USA
[5] Private Allergy & Immunol Clin, Belo Horizonte, MG - Brazil
[6] Univ Fed Santa Catarina, Prof Polydoro Ernani Sao Thiago Univ Hosp, Allergy Clin, Dept Med, Florianopolis, SC - Brazil
[7] Hosp Univ Vall dHebron, Internal Med Dept, Allergy Sect, Barcelona - Spain
[8] Fac Med ABC, Div Clin Immunol, Santo Andre - Brazil
[9] Univ Estadual Campinas, Dept Internal Med, Campinas, SP - Brazil
Número total de Afiliações: 9
Tipo de documento: Artigo Científico
Fonte: FRONTIERS IN MEDICINE; v. 6, FEB 21 2019.
Citações Web of Science: 0

Hereditary angioedema (HAE) is an autosomal dominant disease caused by C1-INH deficiency due to mutations in SERPING1 (C1-INH-HAE) in most of the cases, or by specific mutations in factor XII gene, F12 (F12-HAE). Identification of polymorphisms in the genes encoding proteins from key pathways driving HAE can help to understand how genetic diversity contributes to its phenotypic variability. Here, 15 genes related to the Kallikrein-Kinin System (KKS) were analyzed by next generation sequencing in 59 patients with C1-INH-HAE or F12-HAE from Brazil, Denmark and Spain, and 19 healthy relatives in a total of 31 families. We identified 211 variants, from which 23 occurred only in Danish subjects and 79 were found only in Brazilian individuals, resulting in 109/211 variations in common between European and Brazilian population in the HAE families analyzed. BDKRB2 and CPM presented a large number of variants in untranslated regions, 46/49 and 19/24, respectively: whereas ACE (n = 26), SERP1NG1 (n = 26), CPM (n = 24), and NOS3 (n = 16) genes presented the higher number of variants directly affecting amino acid sequence. Despite the large amount of variants identified, the lack of association between genotype and phenotype indicates that the modulation of HAE symptom requires a more complex regulation, probably involving pathways beyond the KKS, epigenetics and environmental factors. Considering the new HAE types recently described, molecules involved in the regulation of vasculature and in plasminogen activation become promising targets for future genetic studies. (AU)

Processo FAPESP: 15/25494-1 - Desenvolvimento de um modelo de terapia gênica para angioedema hereditário baseado na edição do gene SERPING1 pelo sistema CRISPR-Cas9
Beneficiário:Camila Lopes Veronez
Linha de fomento: Bolsas no Brasil - Pós-Doutorado
Processo FAPESP: 13/02661-4 - Genética do angioedema hereditário
Beneficiário:João Bosco Pesquero
Linha de fomento: Auxílio à Pesquisa - Regular
Processo FAPESP: 14/27198-8 - Estabelecimento de um centro de pesquisa genética e molecular para desafios clínicos
Beneficiário:João Bosco Pesquero
Linha de fomento: Auxílio à Pesquisa - Temático