J Allergy Clin Immunol. 2015 Feb;135(2):570-3.
Hereditary angioedema: molecular and clinical differences among European populations.
Speletas M1, Szilagyi A2, Psarros F3, Moldovan D4, Magerl M5, Kompoti M1, Gramoustianou E1, Bors A6, Mihaly E4, Tordai A6, Avramouli A1, Varga L2, Maurer M5, Farkas H2, Germenis AE1.
1Department of Immunology and Histocompatibility, University of Thessaly, School of Health Sciences, Faculty of Medicine, Larissa, Greece.
2Hungarian Angioedema Center, 3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary.
3Department of Allergology, Navy Hospital, Athens, Greece.
4Allergy and Lung Function Office, University of Medicine and Pharmacy, Tirgu-Mures, Romania.
5Department of Dermatology and Allergy, Charité-Universitätsmedizin Berlin, Germany.
6Laboratory of Molecular Diagnostics, Hungarian National Blood Transfusion Service, Budapest, Hungary.
No abstract available.
Abstract supplied by the authors
Objective: To detect possible associations between the clinical phenotype and SERPING1 defects and to explore possible variations among different populations.
Methods: A large cohort of patients (149 from 79 unrelated families) from 4 European countries (Greece, Hungary, Germany, Romania) was enrolled. Medical records were reviewed and data regarding the disease onset, treatment modalities and the major clinical manifestations were recorded. A comprehensive analysis of SERPING1 was performed. The results of this cohort were pooled with those of 118 HAE patients previously genotyped by our groups.
Results: Missense mutations were the most common SERPING1 defect detected with different frequencies among the various ethnic groups. Novel mutations were observed in 38 families (48.1%), whereas no SERPING1 defect was identified in 3 families (3.8%). Patients with missense mutations displayed a significantly lower probability of manifesting HAE attacks before the 10th year-of-age. Romanian patients displayed a significantly later disease onset and the highest frequency of missense mutations. Frameshift defects were more prevalent in German patients, whereas Hungarians displayed abdominal attacks less frequently than other geographical groups.
Conclusion: The tremendous heterogeneity of SERPING1 alterations associated with HAE was confirmed. Missense mutations were identified as an index of a less severe clinical course of HAE. Variations observed among populations in both the clinical phenotype of the disease and SERPING1 defects indicate that other genetic and/or environmental factors may modulate the expression of the disease.
Allergy. 2015 Aug 6. doi: 10.1111/all.12714.
F12-46C/T polymorphism as modifier of the clinical phenotype of hereditary angioedema.
Speletas M1, Szilágyi Á2, Csuka D2, Koutsostathis N1, Psarros F3, Moldovan D4, Magerl M5, Kompoti M1, Varga L2, Maurer M5, Farkas H2, Germenis AE1.
1Department of Immunology & Histocompatibility, School of Health Sciences, Faculty of Medicine, University of Thessaly, Larissa, Greece.
23rd Department of Internal Medicine, Hungarian Angioedema Center, Semmelweis University, Budapest, Hungary.
3Department of Allergology, Navy Hospital, Athens, Greece.
4Department of Allergy-Immunology, University of Medicine and Pharmacy, Mures County Hospital, Tîrgu Mureș, Romania.
5Department of Dermatology and Allergy, Charité – Universitätsmedizin Berlin, Berlin, Germany.
The factors influencing the heterogeneous clinical manifestation of hereditary angioedema due to C1-INH deficiency (C1-INH-HAE) represent one of the oldest unsolved problems of the disease. Considering that factor XII (FXII) levels may affect bradykinin production, we investigated the contribution of the functional promoter polymorphism F12-46C/T in disease phenotype. We studied 258 C1-INH-HAE patients from 113 European families, and we explored possible associations of F12-46C/T with clinical features and the SERPING1 mutational status. Given that our cohort consisted of related subjects, we implemented generalized estimating equations (GEEs), an extension of the generalized linear model accounting for the within-subject correlation. F12-46C/T carriers exhibited a significantly delayed disease onset (P<0.001) and did not need long-term treatment (P=0.02). In a GEE linear regression model, the presence of F12-46C/T was significantly associated with a 7-year delay in disease onset (P<0.0001) regardless of SERPING1 mutational status. It is concluded that F12-46C/T carriage acts as an independent modifier of C1-INH-HAE severity.
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Prof. Anastasios E. Germenis, M.D. Ph.D.
Over 450 genetic alterations of SERPING1 gene encoding for C1-esterase inhibitor (C1-INH) have been recognized after systematic mutation analysis performed in several cohorts of patients with hereditary angioedema due to C1-INH deficiency (C1-INH-HAE). However, strong evidence for a linkage between all of these mutations and the disease is missing since this linkage has been deduced from their consequences on the structure/function properties of C1-INH. Thus, it remains elusive whether the presence of all SERPING1 alterations considered so far responsible for C1-INH-HAE, are isolated or are expressed in tandem with either functional alterations on the genes involved in the function or degradation of bradykinin, or display SERPING1 polymorphisms and mutations with as yet unknown functionality. Two recently identified forms of hereditary angioedema with normal C1-INH levels, i.e. a form linked to specific mutations in the coagulation Factor XII (HAE-FXII) and another one without genetic alterations neither in the SERPING1 nor in the FXII gene (HAE-unknown), challenge the hypothesis of other pathogenic gene damages. This hypothesis is also favored by the fact that in about 5% of C1-INH-HAE cases, no SERPING1 alterations can be detected even after meticulous analysis of the coding region of the gene.
On the other hand, the clinical expression of C1-INH-HAE is characterized by a substantial variability between patients, even if they were members of the same family, with regards to severity, provoking factors, impact of co-morbid conditions, and response to treatment. This clinical heterogeneity is rather unpredictable and efforts made up to now have not concluded in uncovering genotype-phenotype correlations. Unavoidably, this feature of the disease is interrelated to the increasing complexity of the available treatment options appeared within the last few years. Newer treatment options for acute attacks and prophylaxis of hereditary angioedema currently authorized and available in the market include plasma-derived and recombinant C1-INH (pdC1-INH and rC1-INH), a kallikrein inhibitor, ecallantide, and a bradykinin B2 receptor antagonist, icatibant. These medications, however, have very different modes of action and unpredictable risk-to-benefit profiles. As a result, the determination of optimal therapy is based on individualization of patient history and preferences. Therefore, uncovering biological parameters affecting the severity of the disease and/or the effectiveness of the various treatment modalities might result in the optimization of HAE management and provide a reasonable return on investment.
In effort to detect genetic markers linked to the clinical phenotype of C1-INH-HAE, we investigated, in a large cohort of patients derived from 4 European countries, the existence of correlations between clinical parameters of the disease and the type of SERPING1 genetic alterations, on the one hand, and defects in other genes involved in the metabolism and function of bradykinin, on the other. For a first time in the literature, we uncovered that carriage of SERPING1 missense mutations and of the functional promoter polymorphism F12-46C/T are independently correlated with parameters related to the clinical severity of C1-INH-HAE. Such correlations of the clinical phenotype of the disease did not detected neither with the I/D polymorphism of the ACE gene encoding for angiotensin-converting enzyme nor with functional polymorphisms in the gene of bradykinin B2 receptor (BDKR1 gene). Furthermore, we found that the proportion of the various types of disease-related SERPING1 alterations is different between different geographical regions. This finding indicates the possible implication of environmental factors either in the mutagenesis or in the epigenetic regulation of the SERPING1 gene.
These results provide strong evidence in favor of our initial hypothesis that C1-INH-HAE clinical phenotype is modified by genetic alterations in genes involved in kinin (mainly bradykinin) metabolism. To further investigate our hypothesis, we have developed a next generation sequencing (NGS) platform to study a panel of about 60 genes (genes that encode serine proteases, serine protease inhibitors, endothelial cell receptors, enzymes involved in bradykinin breakdown, etc.) possibly involved in C1-INH-HAE pathogenesis. This panel has been compiled from literature data on C1-INH-HAE and genetic predisposition, protein-protein interaction networks, and pathway analysis. Obviously, the standardization of the method used for the evaluation of the disease severity attempted by other investigators is expected to invigorate the validity of our future findings.
The expected detection of genetic markers linked with C1-INH-HAE clinical phenotype will allow the recognition of patients at specific risks and will result in appropriate modifications of the current prognostic and therapeutic approach, in the prevention and/or timely management of symptoms threatening the patients’ life and its quality, and finally in the minimization of the financial burden of the disease.
Anastasios E. Germenis, M.D., Ph.D.
Professor and Chair
Department of Immunology & Histocompatibility
School of Medicine
University of Thessaly
Larissa – Greece