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

Camila Lopes Veronez,Renan Paulo Martin,Eli Mansour,Mar Guilarte,Anette Bygum,Agatha Ribeiro Mendes,Rozana Fátima Gonçalves,João Bosco Pesquero,Jane Da Silva,Anete Sevciovic Grumach,Rafael Filippelli-Silva,Priscila Nicolicht,Anne Aabom

doi:10.3389/fmed.2019.00028

Abstract

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.

Highlights

Hereditary angioedema (HAE) is a rare autosomal dominant disease caused by deleterious mutations in SERPING1, leading to quantitative or functional C1-inhibitor deficiency (C1-INH-HAE) [1]
Since only a few possible genetic variants have been suggested to be associated to the HAE phenotype [9,10,11,12,13], we explored 15 genes related to Kallikrein-Kinin System (KKS) in individuals from Brazil, Denmark, and Spain, by next-generation sequencing (NGS) as previously described [14]
In 26 C1-INH-HAE families, 23 mutations were considered responsible for HAE, and all hereditary angioedema with mutation in F12 gene (F12-HAE) patients carried p.Thr328Lys (Table 1)

Summary

Introduction

Hereditary angioedema (HAE) is a rare autosomal dominant disease caused by deleterious mutations in SERPING1, leading to quantitative or functional C1-inhibitor deficiency (C1-INH-HAE) [1]. Specific mutations in F12 gene (F12-HAE) can be detected in patients with HAE with normal C1-inhibitor [2, 3]. C1-INH-HAE and F12-HAE are related to the Kallikrein-Kinin System (KKS) activation and augmented production of bradykinin (BK), leading to vasodilation and angioedema episodes [1]. Carboxypeptidases N and M (genes CPN and CPM) metabolize BK into des-Arg9-BK, which preferentially activates B1-receptor (BDKRB1). Deleterious variations in genes responsible for the control of BK release, as SERPING1, or its metabolization, as CPN, CPM, angiotensin-converting enzyme (ACE), and neprilysin (MME), are able to increase the amount of BK released or its half-life, leading to or intensifying angioedema episodes. A small phenotype distinction can be noticed in HAE subtypes [2], there is a huge variation in clinical characteristics even among carriers of the same disease-causing mutation [1, 6]

Methods

Results

Conclusion