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

Kallikrein-Kinin System; Genetic variation; Hereditary angioedemaSistema calicreina-cinina; Variació genètica; Angioedema hereditariSistema calicreina-cinina; Variación genética; Angioedema hereditarioHereditary 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), SERPING1 (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

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

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), SERPING1 (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

Psychometric Field Study of Hereditary Angioedema Quality of Life Questionnaire for Adults : hAE-QoL

Background: Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) may affect health-related quality of life (HRQoL). A specific HRQoL questionnaire for adult patients with C1-INH-HAE, the HAE-QoL, has recently been developed in Spain. Objective: The objective of this study was to perform a cross-cultural validation and psychometric study of the HAE-QoL in an international setting. Methods: Cross-cultural adaptation of the Spanish HAE-QoL draft version and an international rating phase with experts were performed. The resultant version of the HAE-QoL, a clinical questionnaire, and Short Form 36-item Health Survey Version 2.0 (SF-36v2) were pilot tested internationally. Item reduction was based on both descriptive and exploratory factor analysis. Psychometric properties were assessed. Results: Cross-cultural adaptation of the HAE-QoL was performed in 18 countries. The draft version of the HAE-QoL was pilot tested in 332 patients, and accurate data were obtained from 290 patients from 11 countries. The reduction process resulted in a new version with 25 items and 7 dimensions (treatment difficulties, physical functioning and health, disease-related stigma, emotional role and social functioning, concern about offspring, perceived control over illness, and mental health). Strong psychometric properties were observed (Cronbach´s α 0.92; test-retest reliability 0.87). Convergent validity showed mild to moderate correlations with SF-36v2 physical and mental component summaries (0.45 and 0.64, respectively) and with SF-36v2 dimensions (P < .004). HAE-QoL scores discriminated significantly among severity groups (median: asymptomatic 133.5 vs severe 84.0; P < .001); between patients with and without long-term prophylaxis (median: 101 vs 90; P = .001); and between patients with and without psychiatric and/or psychological care (median: 74 vs 103; P ≤ .001). Conclusions: The HAE-QoL, currently available in 18 languages, showed good reliability and validity evidence.Fil: Prior, Nieves. Hospital Universitario Severo Ochoa; EspañaFil: Remor, Eduardo. Universidad Autónoma de Madrid; EspañaFil: Pérez Fernández, Elia. Fundacion Hospital Alcorcon; EspañaFil: Caminoa, Magdalena. Instituto de Investigacion Hospital Universitario la Paz ; EspañaFil: Gómez-Traseira, Carmen. Instituto de Investigacion Hospital Universitario la Paz ; EspañaFil: Gayá, Francisco. Instituto de Investigacion Hospital Universitario la Paz ; EspañaFil: Aabom, Anne. Odense University Hospital; DinamarcaFil: Aberer, Werner. Medical University; AustriaFil: Betschel, Stephen. Saint Michael's Hospital; CanadáFil: Boccon Gibod, Isabelle. Joseph Fourier University; Francia. Grenoble University Hospital; FranciaFil: Bouillet, Laurence. Joseph Fourier University; Francia. Grenoble University Hospital; FranciaFil: Bygum, Anette. Odense University Hospital; DinamarcaFil: Csuka, Dorottya. Semmelweis University; HungríaFil: Farkas, Henriette. Semmelweis University; HungríaFil: Gomide, Maria. Universidade de Sao Paulo; BrasilFil: Grumach, Anete. Universidade de Sao Paulo; BrasilFil: Leibovich, Iris. Chaim Sheba Medical Center; IsraelFil: Malbrán, Alejandro. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud "Dr. C. G. Malbrán"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Moldovan, Dumitru. Mures County Hospital; RumaniaFil: Mihaly, Eniko. Mures County Hospital; RumaniaFil: Obtulowicz, Krystyna. Jagiellonian University; PoloniaFil: Perpén, Cecilia. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud "Dr. C. G. Malbrán"; ArgentinaFil: Peveling Oberhag, Adriane. University Medical Center Mainz; AlemaniaFil: Porebski, Grzegorz. Jagiellonian University; PoloniaFil: Chavannes, Celine Rayonne. Saint Michael's Hospital; CanadáFil: Reshef, Avner. Chaim Sheba Medical Center; IsraelFil: Staubach, Petra. University Medical Center Mainz; AlemaniaFil: Wiednig, Michaela. Medizinische University; AustriaFil: Caballero, Teresa. Instituto de Investigacion Hospital Universitario la Paz ; Españ