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.

The functional promoter F12‐46C/T variant predicts the asymptomatic phenotype of C1‐INH‐HAE

“…Therefore, research on genetic predisposition influencing the clinical expression of the disease and identifying patients who are more likely to develop severe and frequent attacks in comparison to individuals who are more likely to be asymptomatic despite carrying the same disease‐causing SERPING1 gene mutation has been focused on other genes mainly involved in bradykinin metabolism. The most promising functional variant in the F12 gene ( F12 ‐46C/T, rs1801020) was found (also by our group) to be strongly associated with disease onset . Since the association of this F12 variant with disease onset was clearly demonstrated, we speculated that it might also predict the asymptomatic phenotype of C1‐INH‐HAE.…”

“…The most promising functional variant in the F12 gene (F12-46C/T, rs1801020) was found (also by our group) to be strongly associated with disease onset. 6,7,9 Since the association of this F12 variant with disease onset was clearly demonstrated, we speculated that it might also predict the asymptomatic phenotype of C1-INH-HAE.…”

Genetic Determinants of C1 Inhibitor Deficiency Angioedema Age of Onset

“…Beyond SERPING1 alterations leading to C1-INH deficiency, alterations associated with normal C1-INH angioedema have been detected in the F12 gene [15,16] and, recently, in the ANGPT1 gene encoding for angiopoietin-1 that targets key mechanisms contributing to maintenance of the endothelial barrier function [17] as well as in the plasminogen gene [18,19] . On the other hand, with regard to the clinical expression of C1-INH-HAE, we have shown that carriage of missense SERPING1 mutations [13,14] or the functional promoter polymorphism F12 -46C/T (rs1801020) is associated with a less severe clinical course [12] .…”

“…All patients were previously genotyped for SERPING1 mutations and the F12 -46C/T polymorphism [12][13][14] . Patients' medical records were reviewed and data regarding disease onset, treatment modalities, and the major clinical manifestations were recorded.…”

“…The combined effect of the concomitant carriage of this polymorphism and another functional polymorphism that we had previously shown to be associated with age at disease onset, i.e., the F12 -46C/T polymorphism (rs1801020) [12] , was also examined.…”