title: F12-46C/T polymorphism as modifier of the clinical phenotype of hereditary angioedema.
abstract: 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.
authors.affiliation: Department of Immunology & Histocompatibility, School of Health Sciences, Faculty of Medicine, University of Thessaly, Larissa, Greece.
authors.forename: M
authors.initials: M
authors.lastname: Speletas
authors.affiliation: 3rd Department of Internal Medicine, Hungarian Angioedema Center, Semmelweis University, Budapest, Hungary.
authors.forename: Á
authors.initials: Á
authors.lastname: Szilágyi
authors.affiliation: 3rd Department of Internal Medicine, Hungarian Angioedema Center, Semmelweis University, Budapest, Hungary.
authors.forename: D
authors.initials: D
authors.lastname: Csuka
authors.affiliation: Department of Immunology & Histocompatibility, School of Health Sciences, Faculty of Medicine, University of Thessaly, Larissa, Greece.
authors.forename: N
authors.initials: N
authors.lastname: Koutsostathis
authors.affiliation: Department of Allergology, Navy Hospital, Athens, Greece.
authors.forename: F
authors.initials: F
authors.lastname: Psarros
authors.affiliation: Department of Allergy-Immunology, University of Medicine and Pharmacy, Mures County Hospital, Tîrgu Mureș, Romania.
authors.forename: D
authors.initials: D
authors.lastname: Moldovan
authors.affiliation: Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Magerl
authors.affiliation: Department of Immunology & Histocompatibility, School of Health Sciences, Faculty of Medicine, University of Thessaly, Larissa, Greece.
authors.forename: M
authors.initials: M
authors.lastname: Kompoti
authors.affiliation: 3rd Department of Internal Medicine, Hungarian Angioedema Center, Semmelweis University, Budapest, Hungary.
authors.forename: L
authors.initials: L
authors.lastname: Varga
authors.affiliation: Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Maurer
authors.affiliation: 3rd Department of Internal Medicine, Hungarian Angioedema Center, Semmelweis University, Budapest, Hungary.
authors.forename: H
authors.initials: H
authors.lastname: Farkas
authors.affiliation: Department of Immunology & Histocompatibility, School of Health Sciences, Faculty of Medicine, University of Thessaly, Larissa, Greece.
authors.forename: A E
authors.initials: AE
authors.lastname: Germenis
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D003174:Complement C1 Inactivator Proteins / Q000235:genetics; D050718:Complement C1 Inhibitor Protein; D004252:DNA Mutational Analysis; D005174:Factor XII / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D056829:Hereditary Angioedema Types I and II / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D003174:Complement C1 Inactivator Proteins; D050718:Complement C1 Inhibitor Protein; C469952:SERPING1 protein, human; D005174:Factor XII
keywords: C1-inhibitor deficiency; F12-46C/T polymorphism; hereditary angioedema